Bordia A, Verma SK, Srivastava KC
Department of Medicine, R.N.T. Medical College, Udaipur, India.
Prostaglandins Leukot Essent Fatty Acids 1997 May;56(5):379-84

In a placebo-controlled study the effect of ginger and fenugreek was examined on blood lipids, blood sugar, platelet aggregation, fibrinogen and fibrinolytic activity. The subjects included in this study were healthy individuals, patients with coronary artery disease (CAD), and patients with non-insulin-dependent diabetes mellitus (NIDDM) who either had CAD or were without CAD. In patients with CAD powdered ginger administered in a dose of 4 g daily for 3 months did not affect ADP- and epinephrine-induced platelet aggregation. Also, no change in the fibrinolytic activity and fibrinogen level was observed. However, a single dose of 10 g powdered ginger administered to CAD patients produced a significant reduction in platelet aggregation induced by the two agonists. Ginger did not affect the blood lipids and blood sugar. Fenugreek given in a dose of 2.5 g twice daily for 3 months to healthy individuals did not affect the blood lipids and blood sugar (fasting and post prandial). However, administered in the same daily dose for the same duration to CAD patients also with NIDDM, fenugreek decreased significantly the blood lipids (total cholesterol and triglycerides) without affecting the HDL-c. When administered in the same daily dose to NIDDM (non-CAD) patients (mild cases), fenugreek reduced significantly the blood sugar (fasting and post prandial). In severe NIDDM cases, blood sugar (both fasting and post prandial) was only slightly reduced. The changes were not significant. Fenugreek administration did not affect platelet aggregation, fibrinolytic activity and fibrinogen.

Drvota V, Vesterqvist O, Green K
Department of Clinical Chemistry and Blood Coagulation, Karolinska Hospital, Stockholm, Sweden.
Adv Prostaglandin Thromboxane Leukot Res 1991;21A:153-6

Most NSAIDs seem to have inhibitory effects on the in vivo synthesis of both TxA2 and PGI2. However there are large differences in the duration of the inhibitory effects as shown in the table below. Aspirin, indomethacin, naproxen and piroxicam inhibit the second wave of platelet aggregation. This effect on platelet aggregation persists as long as each drug causes inhibition of TxA2 synthesis. Thus, inhibition of TxA2 synthesis is likely to be the reason for the effect of NSAIDs on platelet function. The lack of effect of paracetamol on TxA2 synthesis together with the lack of effect on platelet aggregation by paracetamol are in further support of this. [table: see text]

Garrett NE, Malcangio M, Dewhurst M, Tomlinson DR
Department of Pharmacology, St. Bartholomew's, Queen Mary and Westfield College, London, UK.
Neurosci Lett 1997 Feb 7;222(3):191-4

This study compared the effects of treatment of diabetic rats with either alpha-lipoic acid (100 mg/kg/day i.p. 5 days/week) or with recombinant human nerve growth factor (rhNGF; 0.2 mg/kg s.c. 3 days/week) on NGF-like immunoreactivity (NGFLI) and neuropeptide Y-like immunoreactivity (NPYLI) levels in the sciatic nerve and on the release of substance P-like immunoreactivity (SPLI) from the spinal cord in response to electrical stimulation of the dorsal roots in vitro. Diabetic rats showed depletion of NGFLI and NPYLI, together with reduced release of SPLI. Treatment with NGF increased the sciatic nerve NGFLI (to four times that seen in untreated diabetic rats) and normalised stimulus-evoked release of SPLI, but did not affect the sciatic nerve NPYLI. Treatment with alpha-lipoic acid caused a small non-significant increase in sciatic nerve NGFLI, but normalised both NPYLI levels and stimulus-evoked release of SPLI. These findings indicate that alpha-lipoic acid can boost neurotrophic support in diabetic rats, with effects beyond those related to NGF.

Koutsikos D, Agroyannis B, Tzanatos-Exarchou H
University of Athens, Aretaieon University Hospital, Greece.
Biomed Pharmacother 1990;44(10):511-4

Biotin in high doses was given for 1-2 years to three diabetic patients suffering from severe diabetic peripheral neuropathy. Within 4-8 weeks there was a marked improvement in clinical and laboratory findings. It is suggested that in diabetes may exist a deficiency, inactivity or unavailability of Biotin, resulting in disordered activity of biotin-dependent enzyme, pyruvate carboxylase, leading to accumulation of pyruvate and/or depletion of aspartate, both of which play a significant role in nervous system metabolism. Based on our good results, regular biotin administration could be suggested for every diabetic patient for the prevention and management of peripheral neuropathy although extensive randomised clinical trials are required.

Malik NS, Meek KM
Biophysics Group, Open University, Boars Hill, Oxford, U.K.
Biochem Biophys Res Commun 1994 Mar 15;199(2):683-6

With age human collagen demonstrates, amongst other changes, reductions in solubility, elasticity and permeability. Many of these changes have been attributed to non-enzymic glycosylation (glycation)-a spontaneous addition of sugar molecules to any protein with free amino groups. The resulting formation and accumulation of Advanced Glycation End-products, some of which may be cross-links, has been shown in both long- and short-lived proteins. We have shown that glycation of human corneal and scleral collagen increases with age and that this is accompanied by increases in cross-linking and collagen intermolecular spacing. We have now investigated several compounds that have been used to inhibit glycation, including aspirin, and have shown that all the inhibitors also prevent the increase in intermolecular spacing caused by glycation.

Mogensen CE
BMJ 1998 Sep 12;317(7160):693-4

No abstract.

Pozzilli P, Browne PD, Kolb H
Cattedra di Endocrinologia (I), University of Rome La Sapienza, Italy.
Diabetes Care 1996 Dec;19(12):1357-63

OBJECTIVE: Nicotinamide, a vitamin of the B group, has in vitro actions capable of interfering with the pathogenetic process leading to IDDM. Since 1987, several studies have evaluated nicotinamide as a means of protecting beta-cells from end-stage destruction in insulin-treated patients with newly diagnosed IDDM. The aim of the study was to determine whether nicotinamide protects residual beta-cell function when given at IDDM diagnosis.

RESEARCH DESIGN AND METHODS: We performed a meta-analysis of the integrated parameters of metabolic control (C-peptide, glycosylated hemoglobin, insulin dose) in 10 randomized (5 of which were placebo) controlled trials conducted in recent-onset IDDM patients for a total of 211 nicotinamide-treated patients. Data on the adverse effects of nicotinamide were also collected from an additional four trials to yield a grand total of 291 nicotinamide-receiving patients.

RESULTS: One year after diagnosis, baseline C-peptide was significantly higher in nicotinamide-treated patients, compared with control patients (0.73 +/- 0.65 vs. 0.32 +/- 0.56 ng/ml, P < 0.005). This statistical difference remained also when the five placebo-controlled trials only were considered (P < 0.05). No differences were observed in the insulin dose required or glycosylated hemoglobin values between nicotinamide and control patients. Adverse effects were reported in few patients (transient elevation of transaminase, n = 2; skin rash, n = 2; recurrent hypoglycemia, n = 2).

CONCLUSIONS: This combined analysis demonstrates a therapeutic effect of nicotinamide in preserving residual beta-cell function when given at IDDM diagnosis in addition to insulin. Since adverse effects were negligible, we suggest that prolonged use of nicotinamide after IDDM diagnosis should be tested to see whether residual beta-cell function can be preserved for longer periods.

Quatraro A, Roca P, Donzella C, Acampora R, Marfella R, Giugliano D
Diabetologia 1995 Jan;38(1):123

No abstract.

Sagara M, Satoh J, Wada R, Yagihashi S, Takahashi K, Fukuzawa M, Muto G, Muto Y, Toyota T
Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Diabetologia 1996 Mar;39(3):263-9

N-acetylcysteine (NAC) is a precursor of glutathione (GSH) synthesis, a free radical scavenger and an inhibitor of tumour necrosis factor alpha (TNF). Because these functions might be beneficial in diabetic complications, in this study we examined whether NAC inhibits peripheral neuropathy. Motor nerve conduction velocity (MNCV) was significantly decreased in streptozotocin-induced-diabetic Wistar rats compared to control rats. Oral administration of NAC reduced the decline of MNCV in diabetic rats. Structural analysis of the sural nerve disclosed significant reduction of fibres undergoing myelin wrinkling and inhibition of myelinated fibre atrophy in NAC-treated diabetic rats. NAC treatment had no effect on blood glucose levels or on the nerve glucose, sorbitol and cAMP contents, whereas it corrected the decreased GSH levels in erythrocytes, the increased lipid peroxide levels in plasma and the increased lipopolysaccharide-induced TNF activity in sera of diabetic rats. Thus, NAC inhibited the development of functional and structural abnormalities of the peripheral nerve in streptozotocin-induced diabetic rats.

Thomas DE, Brotherhood JR, Brand JC
Department of Biochemistry, University of Sydney.
Int J Sports Med 1991 Apr;12(2):180-6

Low glycemic index (GI) foods may confer an advantage when eaten before prolonged strenuous exercise by providing a slow-release source of glucose to the blood without an accompanying insulin surge. To test this hypothesis, eight trained cyclists pedalled to exhaustion one hour after ingestion of equal carbohydrate portions of four test meals: lentils, a low GI food (LGI); potato, a high GI food (HGI), and glucose and water. Plasma glucose and insulin levels were lower after LGI than after HGI from 30 to 60 min after ingestion (p less than 0.05). Plasma free fatty acid (FFA) levels were highest after water (p less than 0.05) followed by LGI and then glucose and HGI. From 45 to 60 min after ingestion, plasma lactate was higher in the HGI trial than in the LGI trial (p less than 0.05) and remained higher throughout the period of exercise. The rank order from lowest to highest for total carbohydrate oxidation during exercise was water, lentils, glucose and potato. Endurance time was 20 min longer after LGI than after HGI (p less than 0.05). These findings suggest that a low GI pre-game meal may prolong endurance during strenuous exercise by inducing less post-prandial hyperglycemia and hyperinsulinemia, lower levels of plasma lactate before and during exercise, and by maintaining plasma glucose and FFA at higher levels during critical periods of exercise.

UK Prospective Diabetes Study (UKPDS) Group.
Lancet 1998 Sep 12;352(9131):854-65
Published erratum appears in Lancet 1998 Nov 7;352(9139):1557

BACKGROUND: In patients with type 2 diabetes, intensive blood-glucose control with insulin or sulphonylurea therapy decreases progression of microvascular disease and may also reduce the risk of heart attacks. This study investigated whether intensive glucose control with metformin has any specific advantage or disadvantage.

METHODS: Of 4075 patients recruited to UKPDS in 15 centres, 1704 overweight (>120% ideal bodyweight) patients with newly diagnosed type 2 diabetes, mean age 53 years, had raised fasting plasma glucose (FPG; 6.1-15.0 mmol/L) without hyperglycaemic symptoms after 3 months' initial diet. 753 were included in a randomised controlled trial, median duration 10.7 years, of conventional policy, primarily with diet alone (n=411) versus intensive blood-glucose control policy with metformin, aiming for FPG below 6 mmol/L (n=342). A secondary analysis compared the 342 patients allocated metformin with 951 overweight patients allocated intensive blood-glucose control with chlorpropamide (n=265), glibenclamide (n=277), or insulin (n=409). The primary outcome measures were aggregates of any diabetes-related clinical endpoint, diabetes-related death, and all-cause mortality. In a supplementary randomised controlled trial, 537 non-overweight and overweight patients, mean age 59 years, who were already on maximum sulphonylurea therapy but had raised FPG (6.1-15.0 mmol/L) were allocated continuing sulphonylurea therapy alone (n=269) or addition of metformin (n=268).

FINDINGS: Median glycated haemoglobin (HbA1c) was 7.4% in the metformin group compared with 8.0% in the conventional group. Patients allocated metformin, compared with the conventional group, had risk reductions of 32% (95% CI 13-47, p=0.002) for any diabetes-related endpoint, 42% for diabetes-related death (9-63, p=0.017), and 36% for all-cause mortality (9-55, p=0.011). Among patients allocated intensive blood-glucose control, metformin showed a greater effect than chlorpropamide, glibenclamide, or insulin for any diabetes-related endpoint (p=0.0034), all-cause mortality (p=0.021), and stroke (p=0.032). Early addition of metformin in sulphonylurea-treated patients was associated with an increased risk of diabetes-related death (96% increased risk [95% CI 2-275], p=0.039) compared with continued sulphonylurea alone. A combined analysis of the main and supplementary studies showed fewer metformin-allocated patients having diabetes-related endpoints (risk reduction 19% [2-33], p=0.033). Epidemiological assessment of the possible association of death from diabetes-related causes with the concurrent therapy of diabetes in 4416 patients did not show an increased risk in diabetes-related death in patients treated with a combination of sulphonylurea and metformin (risk reduction 5% [-33 to 32], p=0.78).

INTERPRETATION: Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight diabetic patients, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in these patients.

Vlassara H
Picower Institute for Medical Research, Manhasset, NY 11030.
J Lab Clin Med 1994 Jul;124(1):19-30

No abstract.

Lampeter EF; Klinghammer A; Scherbaum WA; Heinze E; Haastert B; Giani G; Kolb H
Diabetes Research Institute at the University of Dusseldorf, Germany.
Diabetes (United States) Jun 1998, 47 (6) p980-4

On the basis of the positive outcome of animal experiments, several large placebo-controlled trials are underway and aiming for the first time at the prevention of an immune-mediated disease, type 1 diabetes. The first of these trials, The Deutsche Nicotinamide Intervention Study (DENIS), evaluated the clinical efficacy of high doses of nicotinamide in children at high risk for IDDM. Nicotinamide has been shown to protect beta-cells from inflammatory insults and to improve residual beta-cell function in patients after onset of IDDM. Individuals at high risk for developing IDDM within 3 years were identified by screening the siblings (age 3-12 years) of patients with IDDM for the presence of high titer (> or =20 Juvenile Diabetes Foundation [JDF] U) islet cell antibodies. Probands (n = 55) were randomized into placebo and nicotinamide (slow release, 1.2 g x m(-2) x day(-1)) receiving groups and followed prospectively in a controlled clinical trial using a sequential design. Rates of diabetes onset were similar in both groups throughout the observation period (maximum 3.8 years, median 2.1 years). This sequential design provides a 10% probability of a type II error against a reduction of the cumulative diabetes incidence at 3 years from 30 to 6% by nicotinamide. The trial was terminated when the second sequential interim analysis after the eleventh case of diabetes showed that the trial had failed to detect a reduction of the cumulative diabetes incidence at 3 years from 30 to 6% (P = 0.97). The group receiving nicotinamide exhibited decreased first-phase insulin secretion in response to intravenous glucose (P = 0.03). No other side effects were observed. We conclude that in this subgroup of diabetes-prone individuals at very high risk and with an assumed rapid disease progression, nicotinamide treatment did not cause a major decrease or delay of diabetes development. However, the data do not exclude the possibility of a less strong, but potentially meaningful, risk reduction in this cohort, or a major clinical effect of nicotinamide in individuals with less risk of progression to IDDM than studied here.

Cook V.V.; Hurley J.S.
Dr. V.V. Cook, Gila River Indian Community, Department of Public Health, Sacaton, AZ 85247 United States
Clinical Pediatrics (United States), 1998, 37/2 (123-130)

The incidence of type 2 diabetes has increased dramatically in the past decade in Pima (Akimel O'odham) children, aged 5-17 years, living in the Gila River Indian Community (GRIC). As a result, a diabetes primary prevention program called Quest was implemented in 1996 at an elementary school in the GRIC for students in kindergarten and grades 1-2. The Quest program has four components: (1) biochemical and anthropometric assessments, (2) classroom instruction about diabetes, (3) increased daily physical activity at school, and (4) a structured school breakfast and lunch program. Preliminary results of the program indicate that the school provides a stable environment for behavior change and interventions that slow weight gain in early childhood.

Andreani D
Centro per gli stati disendocrini e dismetabolici, Universita degli studi di Roma La Sapienza.
Bull Mem Acad R Med Belg (Belgium) 1994, 149 (12) p435-43; discussion 443-4

A better knowledge of the pathogenesis of type 1 diabetes (IDDM) may open the road to the prevention of the diseases. Primary prevention is meant to identify susceptible subjects, either soon after birth or before the immunological aggression of beta cells. The practical approach in this respect is very difficult because multiple obstacles must be overcome. Secondary prevention involves subjects who already show immunological or metabolic alterations, as the presence of ICA, antiinsulin antibodies, GAD antibodies and a defect of the first phase of insulin secretion. Most authors attach great interest to trials with insulin and nicotinamide. Insulin seems to reduce antigen expression when beta cells are damaged. Nicotinamide exerts a protection toward diabetes in animals, and, as scavanger of free radicals, facilitates beta cell regeneration. Research is going on, all over the world, and special multicenter trials are in progress both in the USA and Europe.

Sakurai H; Tsuchiya K; Nukatsuka M; Sofue M; Kawada J
Faculty of Pharmaceutical Science, University of Tokushima, Japan.
J Endocrinol (England) Sep 1990, 126 (3) p451-9

Recent studies have indicated that the blood glucose level of rats with streptozotocin (STZ)-induced diabetes (type 1) is normalized without an increase in the plasma insulin level by administration of sodium orthovanadate in the drinking water. The mechanism of this insulin-like effect of vanadate is unknown. In this study, we investigated whether vanadyl ion, which is less toxic than vanadate to rats, also has an insulin-like effect in rats with STZ-induced diabetes. When rats with STZ-induced diabetes were given a daily i.p. injection of vanadyl sulphate (9.3 and 4.6 mg vanadium/kg body weight), their blood glucose level decreased from about 22.2 to about 7.2 mmol glucose/l within 2 days and remained low for at least 12 weeks. This treatment did not affect their low plasma insulin level. Quantitative electron spin resonance (ESR) spectrometry showed that most of the vanadium (about 90%) in their tissues was present as a vanadyl form (VO2+). ESR analysis also showed that the vanadyl ion in tissues was bound endogenously with four oxygen ligands from either water or oxyamino acid residues in proteins. Vanadyl sulphate accelerated glucose incorporation into adipocytes of rats, suggesting that the action of vanadyl ion is peripheral. Interestingly, vanadyl sulphate at a high concentration (about 10 mmol/l) was more effective than insulin in enhancing glucose uptake. This study demonstrated that: (1) vanadyl sulphate (+4 oxidation state), like vanadate ion, normalizes the blood glucose levels of rats with STZ-induced diabetes; (2) the action of vanadyl ion is peripheral; and (3) the active form of vanadium for an insulin-like effect may be a vanadyl form, not vanadate.

Tan KT; Cheah JS
Department of Medicine I, Singapore General Hospital.
Ann Acad Med Singapore (Singapore) Jul 1990, 19 (4) p506-11

The majority of patients with diabetes mellitus can be classified as suffering from either Type 1 or Type 2 diabetes. The pathogenetic pathways for these two categories of diabetes appear to be distinct and separate. Both forms of diabetes have a genetic as well as environmental component in their pathogenesis. Type 1 diabetes has a weaker genetic link; its association with HLA antigens is well established. Type 2 diabetes has a stronger genetic association but the exact gene or genes responsible is unknown. The environmental trigger in Type 1 diabetes may be a viral infection while urbanisation, obesity, physical inactivity and stress may trigger the development of Type 2 diabetes . Type 1 diabetes is a chronic autoimmune disease where beta cell destruction may occur over a number of years before clinical diabetes is diagnosed. Type 2 diabetes is the result of an interplay of relative insulin deficiency or a defect in insulin release together with insulin resistance. Hyperglycaemia perpetuates the problem of beta cell defect and insulin resistance. The understanding of pathogenesis of diabetes is the key to prevention and treatment of diabetes mellitus.

Shibata Y.; Ohta T.; Nakatsuka M.; Ishizu H.; Matsuda Y.; Shindo T.; Takeuchi F.; Yoshino M.; Hirano S.; Noguchi T.
Department of Biochemistry, Aichi Medical University,Aichi Japan
Advances in Experimental Medicine and Biology (United States) 1996, 403/- (55-58)

i. In vitamin Binf 6 deficient rats, xanthurenic acid shows a diabetogenic action. In diabetes induced by the Znsup 2sup + chelating agent, 8-hydroxyquinoline oxine, proinsulin synthesis is inhibited. The cytosolic enzyme, kynureninase is inhibited, but not the mitochondrial enzyme, kynurenine aminotransferase.

ii. Xanthurenic acid excretion increases in vitamin Binf 6 deficiency, and xanthurenic acid also inhibits kynureninase.

iii. In our experiments, taurine had a beneficial action in diabetes mellitus patients.

iv. Zinc can improve the disturbance of taste in diabetes mellitus patients. Sometimes, zinc content in such patients is decreased. Zinc, in vitro, inhibits kynureninase activity. In vitamin Binf 6 deficient rats, Znsup 2sup + content in the brain stem is increased. In vivo, administration of Znsup 2sup + inhibits DOPA decarboxylase activity in liver and brain stem.

v. Hypertension and hypercholesterolemia develops in rats given excess methionine, but not in rats given excess taurine .

vi. In STZ diabetic rats, vitamin Binf 6 deficiency was not observed, but the formation of pyridoxal from pyridoxine decreased.

Martensson J.; Hermansson G.
Department of Clinical Chemistry, University of Linkoping, S-581 85 Linkoping Sweden
Metabolism: Clinical and Experimental (United States) 1984, 33/5 (425-428)

Sulfur amino acid metabolism was studied in non-fasting nonketotic and ketotic juvenile-onset diabetic children and the results were compared to age-matched healthy children on an ordinary diet. An increased excretion of total sulfur and inorganic sulfate was found in diabetic children, probably a result of a decreased protein-serum synthesis and/or increased endogenous protein catabolism, although as a result of hyperglycemia a decreased tubular reabsorption may also have contributed. All diabetics showed a normal excretion of methionine. For cyst(e)ine and taurine an increased excretion was seen in ketotic diabetics, probably also a consequence of an increased endogenous protein degradation. As a sign of the latter, an increased output of 3-methylhistidine was also observed, a confirmation of earlier reports. The increased output of mercaptolactate and mercaptoacetate found in ketotic patients, was probably also a result of enhanced endogenous protein degradation. An increased urinary excretion of N-acetylcysteine was seen in diabetic children, which may reflect an enhanced availability to acetyl coenzyme A.

Chappell, L.T. and Stahl, J.P.
J Adv Med 1993, 6, 139.

No abstract.

Hancke, C and Flytie K
J Advancement in Medicine, 1993 Fall, 6:3.

No abstract.

Continued on the next page...

Acetyl-L-carnitine effects on nerve conduction and glycemic regulation in experimental diabetes

Soneru I.L.; Khan T.; Orfalian Z.; Abraira C.
Dr. I.L. Soneru, Hines VA Hospital, Hines, IL 60141 USA
Endocrine Research (USA), 1997, 23/1-2 (27-36)

Acetyl-L-Carnitine (ALC), an activator of carnitine, can accelerate nerve regeneration after experimental surgical injury in rats. In this study, we examined the ability of ALC to improve nerve conduction velocity and its effect on intravenous glucose tolerance test in streptozotocin-induced diabetic rats. Diabetic (blood glucose > 200 mg%) and normal animals were treated intraperitoneally for four weeks with ALC, 50 mg/Kg/d and 150 mg/Kg/d. Nerve conduction velocity was measured by direct exposure of sural nerve. Two-hour IVGTT was studied by measuring plasma glucose, insulin and free fatty acids after intravenous injection of glucose, 1.75 gm/Kg/body weight in animals treated either with ALC 150 mg/Kg/d or saline alone. Six weeks of STZ-induced diabetes resulted in impairment of nerve conduction velocity in animals injected with saline (16.05 plus or minus 1.09 m/s), as compared to saline-treated normals who did not receive streptozotocin (31.9 plus or minus 0.84 m/s, p<0.0005). Diabetic animals treated with ALC, 150 mg/Kg/d, preserved near normal nerve conduction (27.10plus or minus1.42 m/s), compared with the saline-treated diabetic animals (p<0.0005), but diabetic animals treated with ALC, 50 mg/Kg/d, had a non-significant increase in nerve conduction (23.68plus or minus1.6). ALC treatment had no effect on fasting or post-intravenous plasma glucose in normal or diabetic rats, although it moderately reduced baseline and 40 minute insulin levels (p<0.02) in normal rats as compared with their saline- treated counterparts. ALC treatment lowered baseline free fatty acids in normal (p<0.04) and diabetic (p<0.03) animals, and the 60 minute levels in the normal group only (p<0.003). Conclusion: ALC at a dose of 150 mg/Kg/d given for one month, produced near normalization of nerve conduction velocity in streptozotocin-induced diabetes with no adverse effects on glucose, insulin or free fatty acid levels.

Age-related decreases in chromium levels in 51,665 hair, sweat, and serum samples from 40,872 patients - Implications for the prevention of cardiovascular disease and type II diabetes mellitus

Davies S.; Howard J.M.; Hunnisett A.; Howard M.
United Kingdom
Metabolism: Clinical and Experimental (USA), 1997, 46/5 (469-473)

This report shows, for the first time using modern analytical techniques, highly significant age-related decreases in chromium levels in 51,665 hair, sweat, and serum samples obtained from 40,872 patients referred by their physicians to an independent medical research clinic and laboratory (r = -.598 to -.762, P < .0001 for all correlations). Males were found to have significantly lower mean chromium levels than females (P < .05 to .0001). There was good correlation between chromium levels in hair, sweat, and serum (r = 536 to .729, P < .0001 for all correlations), indicating that hair and sweat chromium levels are valid additions to the serum levels in assessing chromium status. Chromium measurements in sweat, hair, and serum were performed using graphite furnace atomic absorption spectrophotometry. The influences that age-related decreases in chromium levels might have on increasing the risk to develop age-related impaired glucose metabolism, disordered lipid metabolism, coronary heart disease, arteriosclerosis, and type II diabetes mellitus are outlined, and the role that refined carbohydrates play in the development of compromised chromium status is presented.

Lipoic acid (thioctic acid): Antioxidant properties and their clinical implications

Packer L.
Prof. L. Packer, Dept. of Molecular and Cell Biology, University of California, 251 LSA, Berkeley, CA 94720 USA
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (98-101)

The following article describes the protective effects of alpha-lipoic acid and the enantiomers of alpha-lipoic acid and dihydrolipoic acid on the in vitro cataractogenesis in rat lenses incubated with glucose (55.6 mM). Glucose also leads to a leakage of lactate dehydrogenase into the medium (32 plus or minus 3 units/g lens fresh weight/day). R-lipoic acid inhibited the leakage of LDH (4.34 plus or minus 3.23 units/g lens fresh weight/day, p < 0.001) and lens opacity. In addition, lipoic acid inhibited cataract formation in newborn rats under buthionine sulfoxide (BSO). While 100% of the rats given BSO showed cataract formation, this was observed only in 40 plus or minus 8% of the animals receiving BSO and alpha-lipoic acid (p < 0.005). Further influences of lipoic acid and dihydrolipoic acid on the cataract model are under discussion. The established interactions between dihydrolipoic acid and other antioxidants certainly have implications for both cataractogenesis and the clinical use of alpha-lipoic acid.

Effect of lipoic acid (thioctic acid) on peripheral nerve of experimental diabetic neuropathy

Low P.A.; Nagamatsu M.; Nickander K.; Schmelzer J.D.; Raya A.; Tritschler H.J.
USA Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (94-97)

Oxidative stress is present in the diabetic state. Our work in streptozotocin-diabetic rats has focussed on its presence in peripheral nerve. Antioxidant enzymes are reduced in peripheral nerve and are further reduced in diabetic nerves. That lipid peroxidation will cause neuropathy is supported by evidence of the development of neuropathy de novo when normal rat nerve is rendered alpha-tocopherol deficient and augmentation of the conduction deficit in diabetic nerves subjected to this insult. The mechanism of oxidative stress appears to be primarily due to the processes of nerve ischemia and hyperglycemia auto-oxidation. The indices of oxidative stress include an increase in nerve, dorsal root and sympathetic ganglia lipid hydroperoxides and conjugated dienes. However the most reliable and sensitive index is a reduction in reduced glutathione. Experimental diabetic neuropathy results in myelinopathy of dorsal roots and a vacuolar neuropathy of dorsal root ganglion. The vacuoles are mitochondrial; we posit that lipid peroxidation causes mitochondrial DNA mutations that increase reduced oxygen species, causing further damage to mitochondrial chain and function, resulting in a sensory neuropathy. alpha-lipoic acid is a potent antioxidant that prevents lipid peroxidation in vitro and in vivo. We evaluated the efficacy of the drug in doses of 20, 50 and 100 mg/kg, administered intraperitoneally to streptozotocin diabetic rats in preventing the biochemical, electrophysiologic and nerve blood flow deficits in peripheral nerve of experimental diabetic neuropathy. alpha-lipoic acid dose- and time-dependently prevented the deficits in nerve conduction, nerve blood flow and biochemical abnormalities of a reduction in reduced glutathione and lipid peroxidation. The nerve blood flow deficit was 50% (p < 0.001). Supplementation dose-dependently prevented the deficit; at the highest concentration, nerve blood flow was not different to control nerves. Digital nerve conduction underwent a dose-dependent improvement at 1 month (p < 0.05). By 3 months, all treated groups had lost their deficit. The antioxidant drug is potentially efficacious for human diabetic sensory neuropathy.

Lipoic acid alpha-potential modulator of insulin sensitivity in patients with non-insulin-dependent diabetes mellitus

Jacob S.; Clancy D.E.; Schiemann A.-L.; Simon I.; Jung W.-I.; Henriksen E.J.; Tritschler H.J.; Augustin H.J.; Dietze G.J.
Germany
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (64-70)

Thioctic acid, also known as alpha lipoic acid (ALA), a naturally occuring compound, is frequently used for the treatment of diabetic polyneuropathy and was shown to be a safe and reliable drug. Experimental studies revealed enhanced glucose transport and utilization in different animal models. Therefore, it was of interest to investigate whether ALA is also capable to stimulate glucose disposal in clinical conditions of reduced insulin sensitivity, such as NIDDM. A case report supported the hypothesis, and pilot studies were initiated, in which well controlled Type 2 diabetics received ALA (1.000 mg/500 ml NaCl; or vehicle only) during a hyperinsulinemic glucose-clamp (placebo controlled study) or 500 ml ALA/d over 10 d in an open uncontrolled study. While the acute administration of vehicle had no significant effect on insulin sensitivity (MCR1 3,6 plus or minus 0,21 vs. MCR2 4,01 plus or minus 0,19 ml/kg/min), the infusion of ALA resulted in a marked increase of glucose disposal by about 50% (MCR1 3,91 plus or minus 0,6 vs. MCR2 5,89 plus or minus 0,8 ml/kg/min, p less than or equal to 0,05, Wilcoxon-Rank-Sumtest). The ten day treatment of type II diabetics with ALA enhanced insulin-stimulated whole body glucose disposal by about 30% (MCR1 2,47 plus or minus 0,28 vs. MCR2 3,15 plus or minus 0,35 ml/kg/min, p less than or equal to 0,05, Wilcoxon-Rank-Sumtest). Meanwhile other groups have confirmed these observations. In conclusion, the present data indicate that parenteral administration of thioctic acid enhances insulin-stimulated glucose disposal in NIDDM. Animal studies suggest that the compound increases insulin-stimulated glucose transport activity, non-oxidative glucose disposal and glucose oxidation in peripheral tissues, such as skeletal muscle.

Lipoic acid acutely ameliorates insulin sensitivity in obese subjects with type 2 diabetes

Rett K.; Wicklmayr M.; Ruus P.; Nehrdich D.; Hermann R.; Standl E.
Germany
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (59-63)

Background: Alpha-lipoic acid, a natural cofactor of pyruvate-dehydrogenase, has long been suggested to improve glucose oxidation. Recent data from insulin resistant muscle models demonstrate, that glucose transport and hence non-oxidative glucose metabolism are ameliorated with this substance. Corresponding data in man are lacking.

Methods: The effect of an acute infusion of 600 mg alpha-lipoic acid on insulin sensitivity was investigated in a double blind randomised placebo controlled cross-over study using the isoglycemic glucose clamp technique in 12 obese, insulin resistant subjects (4 postmenopausal women, 8 men) aged between 48 and 69 years with poorly controlled type 2 diabetes.

Results: The infusion was well tolerated, only one subject complained of headache. Of the 12 multimorbid subjects, Z (58,3%) responded to the acute infusion of 600 mg alpha-lipoic acid with a clinically relevant increase (> 20%) in insulin sensitivity (metabolic clearance rate >MCR<). The mean relative increase of MCR of all participants (including nonresponders) was 27% (p = 0.002).

Conclusion: For the first time, a single infusion of 600 mg alpha-lipoic acid is shown to improve attenuated insulin sensitivity in a controlled study in a defined insulin resistant group of subjects with type 2 diabetes. The high number of nonresponders gives rise to further studies.

Treatment of symptomatic diabetic peripheral neuropathy with alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study)

Ziegler D.; Hanefeld M.; Ruhnau K.J.; Meissner H.P.; Lobisch M.; Schutte K.; Gries F.A.; Ticinelli E.-C.; Hahnzog B.; Nehrdich D.; Netten C.; Dannehl K.; Peukert M.; Wessel K.; Anders M.; Brauning H.; Brun M.; Brunner E.; V. Bultzingslowen S.; Donaubauer B.; Forchheim W.; Funke K.; Gerlach-Eniyew S.; Hampel T.; Hoche I.; Hunecke I.; Klinkenstein C.; v. Klitzing K.L.; Kluttig G.; Konig I.; Krause I.; Kruger R.; Kunz U.; Mantz S.; Marquardt C.; Meissner H.P.; Mende M.; Myrach-Rahn A.; Richter E.; Ruhnau K.J.; Ruthe W.D.; Sand K.; Schubert R.; Schultz U.; Seebacher M.L.; Simonsohn M.; Stoll M.; Stundel M.; Szilleweit G.; Walch O.; Walz E.; Wittmann N.
Germany
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (102-110)

Treatment with anti-oxidants reduces oxidative stress and prevents neuropathy in experimental diabetes. Such a therapeutic approach based on pathogenetic mechanisms may have potential in diabetic patients with neuropathy. The efficacy and safety of the anti-oxidant alpha-lipoic acid (thioctic acid) were studied in a 3-week multicentre, randomized, double-blind placebo-controlled trial (Alpha-Lipoic Acid in Diabetic Neuropathy: ALADIN) in 328 Type 2 diabetic patients with symptomatic peripheral neuropathy who were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (ALA 1200 mg/600 mg/100 mg) or placebo (PLAC). Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) were scored at baseline and each visit (days 2-5, 8-12, and 15-19) prior to infusion. In addition, the Hamburg Pain Adjective List (HPAL), a multidimensional specific pain questionnaire, as well as the Neuropathy Symptom Score (NSS) and Neuropathy Disability Score (NDS) were assessed at baseline and day 19. According to the protocol 260 (65/63/66/66) patients completed the study. The total symptom score (TSS) in the feet decreased from baseline to day 19 (mean plus or minus SD;%) by -4.5 plus or minus 3.7 (-58.6%) points in ALA 1200, -5.0 plus or minus 4.1 (-63.5%) points in ALA 600, -3.3 plus or minus 2.8 (-43.2%) points in ALA 100, and -2.6 plus or minus 3.2 (-38.4%) points in PLAC (ALA 1200 vs PLAC: p = 0.003; ALA 600 vs PLAC: p < 0.001). The response rates, defined as an improvement in the TSS of at least 30% after 19 days, were 70.8% in ALA 1200, 82.5% in ALA 600, 65.2% in ALA 100, and 57.6% in PLAC (ALA 600 vs PLAC: p = 0.002). The total scale of the HPAL was significantly reduced in ALA 1200 and ALA 600 as compared with PLAC after 19 days (both p < 0.01). The rates of adverse events were 32.6% in ALA 1200, 18.2% in ALA 600, 13.6% in ALA 100, and 20.7% in PLAC. These findings substantiate the efficacy of intravenous treatment with alpha-lipoic acid using a dose of 600 mg/day over 3 weeks that is superior to placebo in reducing symptoms of diabetic peripheral neuropathy, without causing significant adverse reactions.

Effect of lipoic acid (thioctic acid) on glucose homeostasis and muscle glucose transporters in diabetic rats

Khamaisi M.; Potashnik R.; Tritschler H.; Wessel K.; Bashan N.
Prof. N. Bashan, Clinical Biochemistry Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva Israel
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (50-54)

Background: alpha-Lipoic acid (LA), a cofactor of alpha-ketodehydrogenase, is a natural antioxidant. Though clinically used in treating peripheral diabetic polyneuropathy, its mode of action is not clear. In this study we tested whether LA affects glucose homeostasis and muscle glucose transporters.

Methods: LA was administrated to fasting control and streptozotocin diabetic rats either acutely (100 mg/kg, i.v.) or chronically (30 mg/kg, i.p. for 10 days).

Results: Acute administration reduced blood glucose, 76 plus or minus 16 vs. 38 plus or minus 9 mg% (p < 0.01) by 1 hour in control, and 255 plus or minus 22 vs. 185 plus or minus 41 mg% (p < 0.05) by 2 hours in diabetic rats. Chronic treatment reduced blood glucose concentration in diabetic, 341 plus or minus 36 vs. 189 plus or minus 48 mg% (p = 0.001), but not in control rats. Gastrocnemius GLUT4-protein content was increased by LA approximately 2-fold in both control and diabetic rats, resulting in normalization ot muscle GLUT4 content in diabetic rats. Muscle lactate was increased in diabetic rats (19.9 plus or minus 5.5 vs. 10.4 plus or minus 2.8 in control p < 0.05, respectively), and normalized by chronic LA treatment.

Conclusions: Chronic LA treatment improves glycemia of streptozotocin diabetic rats by increasing muscle GLUT4-protein content. This may improve diabetes related muscle glucose metabolism abnormalities.

Altered 14C-deoxyglucose incorporation in rat brain following treatment with alpha-lipoic acid (thioctic acid). Clinical implications for diabetic neuropathy and neurodegenerative disorders

Jenner P.; Seaton T.A.; Marsden C.D.
Prof. Dr. P. Jenner, King's College, University of London, Biomedical Science Division, Manresa Road, London SW3 GLX United Kingdom
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (31-35)

The incorporation of 14C-2-deoxyglucose (2DG) into areas of basal ganglia was investigated in rats treated acutely or for 5 days with R- or S-thioctic acid (alpha-lipoic acid). In addition, the effect of animal source and age (up to 30 months) on the ability of R- and S-thioctic acid to alter 14C-2DG incorporation was studied. Following acute administration, R-thioctic acid was more effective than S-thioctic acid in altering 14C-2DG incorporation. For example, in substantia nigra of acute administration R-thioctic acid caused an approximately 40% increase in 14C-2DG incorporation while S-thioctic acid was without effect. However, the effects observed were dependent on basal 14C-DG incorporation in different rat strains. Following subacute administration, the pattern of change in 14C-2DG incorporation was altered and now both isomers were equally effective. The effects of R-thioctic acid were largely maintained with increasing animal age but the ability of the S-isomer to alter 14C-2DG incorporation was lost by 30 months. The data indicate an ability of thioctic acid to alter glucose utilisation in vivo which may be relevant to the treatment of diabetic neuropathy and neurodegenerative disorders, such as Parkinson's disease.

Studies on the bioavailability of alpha lipoic acid in type I and type II diabetics with diabetic neuropathy

Rosak C, Hoffken P, Baltes W, Drinda H, Ulrich H, Tritschler HJ, Elze M, Blume H
Germany
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (23-26)

In a controlled randomized cross-over study with two parallel groups 24 type I and type II diabetics with diabetes-induced polyneuropathy were given alpha lipoic acid in two different dosages and methods of administration. Group A (12 patients) was given 600 mg of alpha lipoic acid administered intravenously as a defined short infusion and orally in tablet form. Group B (12 patients) was given 200 mg of alpha lipoic acid administered intravenously as a defined short infusion and orally in tablet form. The extent of the bioavailability (AUC) of free alpha lipoic acid in plasma after intravenously administering 600 mg of alpha lipoic acid was 13.1 microg/ml.h and after 200 mg was 2.2 microg/ml.h. After 600 mg of orally administered alpha lipoic acid the AUC was 2.1 microg/ml.h and after 200 mg it was 0.4 microg/ml.h. The AUC of the single dose of 600 mg administered intravenously and orally was thus about twice as high as the adjusted dosage AUC of 200 mg. This difference was statistically significant. These results support the recommended therapy plan of 600 mg intravenously followed by an oral maintenance therapy of 1 x 600 mg daily.

On the pharmacokinetics of alpha-lipoic acid in patients with diabetic polyneuropathy

Preiss R.; Teichert J.; Preiss C.; Kern J.; Tritschler H.J.; Ulrich H.
Germany
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (17-22)

After the administration von 600 mg alpha lipoic acid (alpha-L) per oral (Thioctacid(R) 200 film tablets) or as an intravenous infusion over 20 minutes (Thioctacid(R) T ampules) the kinetics of alpha-L in plasma were investigated in 12 diabetes type II-patients with normal liver and renal function and symptoms of diabetic neuropathy. alpha-L was electrochemically detected as a total fraction of lipoic and dihydrolipoic acid. alpha-L is quickly absorbed. Maximum plasma concentrations were found after 42.9 plus or minus 45.6 minutes. In seven of the 12 patients alpha-L showed alpha second peak behaviour with a mean difference of 89,1 minutes between the first and the second plasma peak. a-L was quickly eliminated from plasma with a mean terminal hallife time of 32.8 plus or minus 9.4 minutes. 7-10 hours after the start of the application of alpha-L its endogenous basic levels in plasma are reached, which are measured in a magnitude of 10 ng/ml. With respect to Thioctacid(R) 200 film tablets a mean absolute oral bioavailability of 20.2% (13.1-26.8%) for alpha-L was estimated. After a dose of 200 mg alpha-L healthy volunteers showed with 29.1% a 44% significantly higher bioavailability of a-L. The reduced bioavailability of alpha-L in patients with diabetic neuropathy is caused by a dose-inadequate, stronger elevation of the plasma levels of alpha-L after its intravenous administration. In patients with diabetic neuropathy the oral absorption behaviour of alpha-L is not different from that of normal persons.

Chromium oligopeptide activates insulin receptor tyrosine kinase activity

Davis C.M.; Vincent J.B.
USA
Biochemistry (USA), 1997, 36/15 (4382-4385)

A possible new mechanism for the amplification of insulin receptor tyrosine kinase activity in response to insulin has been identified. The chromium-containing oligopeptide low molecular weight chromium-binding substance (LMWCr) does not effect the tyrosine protein kinase activity of rat adipocytic membrane fragments in the absence of insulin; however, insulin- stimulated kinase activity in the membrane fragments is increased up to 8- fold by the oligopeptide. Using isolated rat insulin receptor, LMWCr has been shown to bind to insulin-activated insulin receptor with a dissociation constant of circa 250 pM, resulting in the increase of its tyrosine protein kinase activity. The ability of LMWCr to stimulate insulin receptor tyrosine kinase activity is dependent on its chromium content. The results appear to explain the previously poorly understood relationship between chromium and adult-onset diabetes and cardiovascular disease.

Effect of chromium nicotinic acid supplementation on selected cardiovascular disease risk factors

Thomas V.L.K.; Gropper S.S.
S.S. Gropper, Department of Nutrition/Food Science, 328 Spidle Hall, Auburn University, Auburn, AL 36849 USA
Biological Trace Element Research (USA), 1996, 55/3 (297-305)

The effects of daily supplemental chromium (200 microg) complexed with 1.8 mg nicotinic acid on plasma glucose and lipids, including total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides, were assessed in 14 healthy adults and 5 adults with noninsulin-dependent diabetes mellitus (NIDDM) using a double-blind crossover study with 8-wk experimental periods. Eight of the 14 healthy subjects and all 5 subjects with NIDDM also underwent an oral glucose tolerance test with assessment of 90 min postprandial plasma glucose and insulin concentrations. No statistically significant effects of chromium nicotinic acid supplementation were found on plasma insulin, glucose, or lipid concentrations, although chromium nicotinic acid supplementation slightly lowered fasting plasma total and LDL cholesterol, triglycerides, and glucose concentrations, and 90-min postprandial glucose concentrations in individuals with NIDDM.

Modulation of cellular reducing equivalent homeostasis by alpha-lipoic acid. Mechanisms and implications for diabetes and ischemic injury

Roy S.; Sen C.K.; Tritschler H.J.; Packer L.
Dr. S. Roy, 251 Life Sciences Addition, Dept. of Molecular/Cell Biology, University of California, Berkeley, CA 94720-3200 USA
Biochemical Pharmacology (USA), 1997, 53/3 (393-399)

The therapeutic potential of alpha-lipoic acid (thioctic acid) was evaluated with respect to its influence on cellular reducing equivalent homeostasis. The requirement of NADH and NADPH as cofactors in the cellular reduction of alpha-lipoic acid to dihydrolipoate has been reported in various cells and tissues. However, there is no direct evidence describing the influence of such reduction of alpha-lipoate on the levels of cellular reducing equivalents and homeostasis of the NAD(P)H/NAD(P) ratio. Treatment of the human Wurzburg T-cell line with 0.5 mM alpha-lipoate for 24 hr resulted in a 30% decrease in cellular NADH levels. alpha-Lipoate treatment also decreased cellular NADPH, but this effect was relatively less and slower compared with that of NADH. A concentration-dependent increase in glucose uptake was observed in Wurzburg cells treated with alpha-lipoate. Parallel decreases (30%) in cellular NADH/NAD+ and in lactate/pyruvate -*--ratios were observed in alpha-lipoate-treated cells. Such a decrease in the NADH/NAD+ ratio following treatment with alpha-lipoate may have direct implications in diabetes, ischemia-reperfusion injury, and other pathologies where reductive (high NADH/NAD+ ratio) and oxidant (excess reactive oxygen species) imbalances are considered as major factors contributing to metabolic disorders. Under conditions of reductive stress, alpha-lipoate decreases high NADH levels in the cell by utilizing it as a co-factor for its own reduction process, whereas in oxidative stress both alpha-lipoate and its reduced form, dihydrolipoate, may protect by direct scavenging of free radicals and recycling other antioxidants from their oxidized forms.

Endothelial dysfunction: Clinical implications

Drexler H.
Germany
Progress in Cardiovascular Diseases (USA), 1997, 39/4 (287-324)

The endothelium is involved in the control of vascular tone and homeostasis. Risk factors for arteriosclerosis, as well as other conditions have been shown to be associated with a dysfunctional endothelium. Clinically, endothelial function and dysfunction have been mostly evaluated by the assessment of endothelial dependent relaxation, for example in response to acetylcholine or increase inflow. The functional implications of endothelial dysfunction in cardiovascular disease are not well defined, but recent clinical trials have suggested that endothelial dysfunction may affect vascular tone and organ perfusion particularly during stress situations such as exercise. Moreover, endothelial dysfunction may represent an early event in the development of arteriosclerosis. Therefore, recent clinical studies have been performed to restore normal endothelial function in patients, using interventions such as L-arginine, lipid lowering drugs, vitamin C, other antioxidants, or exercise.

Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients: A 4-month randomized controlled multicenter trial (DEKAN study)

Ziegler D.; Schatz H.; Conrad F.; Gries F.A.; Ulrich H.; Reichel G.; Schifferdecker E.; Heieck F.; Koeppen S.; Diener H.C.; Richter W.O.; Rolfs H.C.; Scharafinski H.-W.; Schulze-Schleppinghoff B.; Schultz-Venrath U.; Winkelmann W.
Germany
Diabetes Care (USA), 1997, 20/3 (369-373)

OBJECTIVE - To evaluate the efficacy and safety of oral treatment with the antioxidant alpha-lipoic acid (ALA) in NIDDM patients with cardiac autonomic neuropathy (CAN), assessed by heart rate variability (HRV).

RESEARCH DESIGN AND METHODS - In a randomized, double-blind placebo-controlled multicenter trial (Deutsche Kardiale Autonome Neurophatic (DEKAN) Study), NIDDM patients with reduced HRV were randomly assigned to treatment with a daily oral dose of 800 mg ALA (n = 39) or placebo (n = 34) for 4 months. Parameters of HRV at rest included the coeficient of variation (CV), root mean square successive difference (RMSSD), and spectral power in the low-frequency (LF; 0.5-0.15 Hz) and high-frequency (HF; 0.15-0.5 Hz) bands. In addition, cardiovascular autonomic symptoms were assessed.

RESULTS - Seventeen patients dropped out of the study (ALA n= 10; placebo n = 7). Mean blood pressure and HbA1 levels did not differ between the groups at baseline and during the study, but heart rate at baseline was higher in the group treated with ALA (P < 0.05). RMSSD increased from baseline to 4 months by 1.5 ms (-37.6 to 77.1) (median (minimum-maximum)) in the group given ALA and decreased by -0.1 ms (-19.2 to 32.8) in the placebo group (P < 0.05 for ALA vs. placebo). Power spectrum in the LF band incresed by 0.06 bpm2 (-0.09 to 0.62) in ALA, whereas it declined by -0.01 bpm2 (-0.48 to 1.86) in placebo (P < 0.05 for ALA vs. placebo). Furthermore, there was a trend toward a favorable effect of ALA versus placebo for the CV and HF band power spectrum (P = 0.097 and P = 0.094 for ALA vs. placebo. The charges in cardiovascular autonomic symptoms did not differ significantly between the groups during the period studied. No differences between the groups were noted regarding the rates of adverse events.

CONCLUSIONS - These findings suggest that treatment with AlA using a well-tolerated oral dose of 800 mg/day for months may slightly improve CAN in NIDDM patients.

alpha-Lipoic acid corrects neuropeptide deficits in diabetic rats via induction of trophic support

Garrett N.E.; Malcangio M.; Dewhurst M.; Tomlinson D.R.
D.R. Tomlinson, Department of Pharmacology, St.Bartholomew's/Royal Sch. Medicine, Queen Mary/Westfield College, Mile End Road, London E1 4NS United Kingdom
Neuroscience Letters (Ireland), 1997, 222/3 (191-194)

This study compared the effects of treatment of diabetic rats with either alpha-lipoic acid (100 mg/kg/day i.p. 5 days/week) or with recombinant human nerve growth factor (rhNGF; 0.2 mg/kg s.c. 3 days/week) on NGF-like immunoreactivity (NGFLI) and neuropeptide Y-like immunoreactivity (NPYLI) levels in the sciatic nerve and on the release of substance P-like immunoreactivity (SPLI) from the spinal cord in response to electrical stimulation of the dorsal roots In vitro. Diabetic rats showed depletion of NGFLI and NPYLI, together with reduced release of SPLI. Treatment with NGF increased the sciatic nerve NGFLI (to four times that seen in untreated diabetic rats) and normalised stimulus-evoked release of SPLI, but did not affect the sciatic nerve NPYLI. Treatment with alpha-lipoic acid caused a small non-significant increase in sciatic nerve NGFLI, but normalised both NPYLI levels and stimulus;evoked release of SPLI. These findings indicate that alpha-lipoic acid can boost neurotrophic support in diabetic rats, with effects beyond those related to NGF.

Chromium picolinate supplementation improves cardiac metabolism, but not myosin isoenzyme distribution in the diabetic heart

Morris G.S.; Hasten D.L.; Hegsted M.; Guidry K.L.
USA
Journal of Nutritional Biochemistry (USA), 1996, 7/11 (617-622)

Because chromium (Cr) containing compounds are thought to improve glucose homeostasis, we hypothesized that chromium picolinate (CrP) could partially reverse diabetes-induced damage to cardiac tissue. Young, adult female rats were fed either a basal diet (CONT), a basal diet containing no CrP and made diabetic (DIAB-CONT), or a basal diet containing 600 ng/g of CrP (3 times the suggested daily chromium intake) and made diabetic (DIAB-CrP). Diabetes was induced by a single streptozotocin injection, 55 mg/kg i.p. After 8 weeks animals were sacrificed, hearts removed, and spectrophotometrically analyzed for citrate synthase (CS), hexokinase (HK), and beta hydroxyacyl CoA dehydrogenase activity (HOAD). Cardiac myosin isoenzymes were separated from crude myofibril extracts by PAGE electrophoresis. Diabetes did not alter CS activity relative to the CONT group, but did significantly (P < 0.05) reduce HK and HOAD activity and expression of the high ATPase myosin isoenzyme VI. In contrast, DIAB-CrP animals displayed normal HK activity and greater HOAD activity relative to CONT animals. Surprisingly, the addition of CrP to the diet further reduced expression of the VI myosin isoenzyme. These results demonstrate thet dietary CrP supplementation has diverse effects on the subcellular properties of the diabetic heart. The functional impact of these CrP-induced changes remains to be defined.

Dehydroepiandrosterone and diseases of aging

Watson R.R.; Huls A.; Araghinikuam M.; Chung S.
Arizona Prevention Center, University of Arizona, School of Medicine, Tucson, AZ 85724 USA
Drugs and Aging (New Zealand), 1996, 9/4 (274-291)

Dehydroepiandrosterone (DHEA; prasterone) is a major adrenal hormone with no well accepted function. In both animals and humans, low DHEB levels occur with the development of a number of the problems of aging: immunosenesence, increased mortality, increased incidence of several cancers, loss of sleep, decreased feelings of well-being, osteoporosis and atherosclerosis. DHEA replacement in aged mice significantly normalised immunosenescence, suggesting that this hormone plays a key role in aging and immune regulation in mice. Similarly, osteoclasts and lymphoid cells were stimulated by DHEA replacement, an effect that may delay osteoporosis, Recent studies do not support the original suggestion that low serum DHEA levels are associated with Alzheimer's disease and other forms of cognitive dysfunction in the elderly. As DHEA modulates energy metabolism, low levels should affect lipogenesis and gluconeogenesis, increasing the risk of diabetes mellitus and heart disease. Most of the effects of DHEA replacement have been extrapolated from epidemiological or animal model studies, and need to be tested in human trials, Studies that have been conducted in humans show essentially no toxicity of DHEA treatment at dosages that restore serum levels, with evidence of normalisation in some aging physiological systems. Thus, DHEA deficiency may expedite the development of some diseases that are common in the elderly.

Sex hormones and DHEA-SO4 in relation to ischemic heart disease mortality in diabetic subjects: The Wisconsin Epidemiologic Study of Diabetic Retinopathy

Haffner S.M.; Moss S.E.; Klein B.E.K.; Klein R.
Univ. of Texas Hlth. Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78284-7873 USA
Diabetes Care (USA), 1996, 19/10 (1045-1050)

OBJECTIVE - Sex hormones are associated with atherogenic changes in lipoproteins and changes in glucose and insulin metabolism, yet few data are available on the relationship of sex hormones and dehydroepiandrosterone sulfate (DHEA-SO4) to ischemic heart disease (IHD) in diabetic subjects, a group with very high levels of IHD.

RESEARCH DESIGN AND METHODS - We examined the relation of total and free testosterone, sex hormone binding globulin, estrone, estradiol, and DHEA-SO4 to the 5-year IHD mortality in the older- onset diabetic subjects in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) in a matched diabetic subject-control design (two control subjects for every diabetic subject).

RESULTS - In men (n = 123), none of the sex hormones or DHEA-SO4 significantly predicted IHD mortality. In women (n = 120), lower levels of DHEA-SO4 (P < 0.01) and total testosterone (P = 0.07) predicted IHD mortality. These results were essentially unchanged after adjustment for duration of diabetes, GHb, diuretic use, and serum creatinine, which are major predictors of IHD mortality in the WESDR. Finding lower testosterone levels in diabetic subjects of IHD in women is contrary to data on risk factors, which suggests that increased androgen activity may he associated with worse IHD risk factors.

CONCLUSIONS - This study suggests that alterations in sex hormones and DHEA-SO4 are unlikely to explain a major proportion of the variation in IHD mortality in diabetic subjects.

The effects of acetyl-L-carnitine and sorbinil on peripheral nerve structure, chemistry, and function in experimental diabetes

Malone J.I.; Lowitt S.; Salem A.F.; Miranda C.; Korthals J.K.; Carver J.
USF College of Medicine, MDC Box 45, 12901 Bruce B. Downs Blvd, Tampa, FL 33612-4799 USA
Metabolism: Clinical and Experimental (USA), 1996, 45/7 (902-907)

Nerve conduction velocity (NCV) increased with age in nondiabetic male Wistar rats for the first 26 weeks of life. The NCV of animals made hyperglycemic at age 6 weeks by administration of streptozotocin (STZ) also increases, but at a slower rate. Animals with 4 weeks of hyperglycemia and reduced NCV treated with an aldose reductase inhibitor (sorbinil) or a short- chain acyl-carnitine (acetyl-L-carnitine (ALC)) daily for 16 weeks showed an improvement in NCV. Morphometric studies of tibial nerves collected from animals after 20 weeks of hyperglycemia (age 26 weeks) showed a consistent reduction in the width of the myelin sheath and little change in axon area. The number of large myelinated fibers (>6.5 microm) found in nerves collected from hyperglycemic animals was less than the number found in nondiabetic animals. Treatment of hyperglycemic rats with either sorbinil or ALC was associated with increased NCV, myelin width, and large myelinated fibers. The apparent metabolic effect of these agents was similar for fatty acid metabolism, but different for polyol pathway activity. We conclude that in animals hyperglycemic long enough to slow NCV, sorbinil and/or ALC treatment reduces the functional, structural, and biochemical changes associated with hyperglycemia that occur in the myelin sheath.

Acetyl-L-carnitine deficiency as a cause of altered nerve myo-inositol content, Na,K-ATPase activity, and motor conduction velocity in the streptozotocin-diabetic rat

Stevens M.J.; Lattimer S.A.; Feldman E.L.; Helton E.D.; Millington D.S.; Sima A.A.F.; Greene D.A.
5570 MSRB II, Box 0678, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0678 USA
Metabolism: Clinical and Experimental (USA), 1996, 45/7 (865-872)

Defective metabolism of long-chain fatty acids and/or their accumulation in nerve may impair nerve function in diabetes by altering plasma or mitochondrial membrane integrity and perturbing intracellular metabolism and energy production. Carnitine and its acetylated derivatives such as acetyl- L-carnitine (ALC) promote fatty acid beta-oxidation in liver and prevent motor nerve conduction velocity (MNCV) slowing in diabetic rats. Neither the presence nor the possible implications of putative ALC deficiency have been definitively established in diabetic nerve. This study explored sciatic nerve ALC levels and the dose-dependent effects of ALC replacement on sciatic nerve metabolites, Na,K-ATPase, and MNCV after 2 and 4 weeks of streptozotocin- induced diabetes (STZ-D) in the rat. ALC treatment that increased nerve ALC levels delayed (to 4 weeks) but did not prevent nerve myo-inositol (Mf) depletion, but prevented MNCV slowing and decreased ouabain-sensitive (but not-insensitive) ATPase activity in a dose-dependent fashion. However, ouabain-sensitive ATPase activity was also corrected by subtherapeutic doses of ALC that did not increase nerve ALC affect MNCV. These data implicate nerve ALC depletion in diabetes as a factor contributing to alterations in nerve intermediary and energy metabolism and impulse conduction in diabetes, but suggest that these alterations may be differentially affected by various degrees of ALC depletion.

Unrecognized pandemic subclinical diabetes of the affluent nations: Causes, cost and prevention

Ely J.T.A.
Radiation Studies, University of Washington, Box 351560, Seattle, WA 98195 USA
Journal of Orthomolecular Medicine (Canada), 1996, 11/2 (95-99)

Regarding populations on the industrialized 'western affluent diet', arguments are made that:

(1) plasma glucose values commonly seen and accepted as normal are abnormal;
(2) their glucose tolerance is innately unstable;
(3) most of their morbidity and mortality is produced by hyperglycemia far below glycosuria and/or arteriosclerosis which can occur independently or together;
(4) simple low cost methods for preventing and treating both have been in the literature for decades (correction of the sugar, fat and protein excesses; and controlled supplementation of pyridoxine (vitamin B6). Mg, Cr and coenzyme Q10); and
(5) these lessons were missed by main stream medicine because of the vast size of the literature, enforcement of 'treatment of choice', and lack of computer aided diagnosis. Cited as striking evidence of this tragic situation is the failure of mainstream clinical medicine to understand the cause of the remarkable decline in CVD in the 1960s and 1970s that followed U.S. enrichment of cereals with pyridoxine (vitamin B6). Recommendations are made for correction of unnecessary costly delays between publication and implementation of such research findings.

Evidence of a relationship between childhood-onset type I diabetes and low groundwater concentration of zinc

Haglund B.; Ryckenberg K.; Selinus O.; Dahlquist G.
Dept. of Epidemiology/Public Health, Umea University, S-901 85 Umea Sweden
Diabetes Care (USA), 1996, 19/8 (873-875)

OBJECTIVE - Zinc deficiency ha shown to increase the risk for diabetes in diabetes-prone experimental animals. Low concentrations of zinc have also been shown in serum of recent onset cases with IDDM. The present study examines the hypothesis that exposure to a low concentration of zinc in drinking water could increase the risk for future onset of IDDM.

RESEARCH DESIGN AND METHODS - Using the Swedish childhood diabetes registry and data on residence 3 years before the onset of disease, a case-control study was designed comparing cases and control subjects with estimates of groundwater contents of zinc obtained in biogeochemical samples from areas of residence.

RESULTS - A high groundwater concentration of zinc was associated with a significant decrease in risk (odds ration (OR) = 0.8; 95% CI = 0.7-0.9). The same OR was obtained when the model included information of other metals that might act as possible confounders (chromium, vanadium, cobalt selenium, cadmium, lead, and mercury). In small rural areas, in which drinking water is taken from local wells and thus is closely associated with the groundwater content within the area, an even stronger association between zinc and diabetes (OR = 0.6; 95% CI = 0.4-0.9) was found.

CONCLUSIONS - It is concluded that this study for the first time provides evidence that a low groundwater content of zinc, which may reflect long-term exposure through drinking water, is associated with later development of childhood onset diabetes.

Improved pallesthetic sensitivity of pudendal nerve in impotent diabetic patients treated with acetyl-L-carnitine

Giammusso B.; Morgia G.; Spampinato A.; Motta M.
Catania University, Catania Italy
Acta Urologica Italica (Italy), 1996, 10/3 (185-187)

Neurogenic impotence in diabetic patients seems to be largely associated with abnormal sensory nerve conduction of pudendal nerve afferent pathways. This condition accounts for a hypoactivity in the mechanisms of erection reflex and has been described as sensory-deficit impotence. Our study investigates the pharmacological action of acetyl-L-carnitine (ALC) in the treatment of this neurological disorder. Penile biothesiometry was applied to two groups of diabetic patients, whose impotence was principally neurogenic, in order to assess their vibration perception threshold variables. The groups were treated with ALC (1,500 mg/day) and placebo, respectively. The results obtained show a significant improvement in dorsal nerve somatosensory conduction in patients treated with ALC.

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Sima A.A.F.; Ristic H.; Merry A.; Kamijo M.; Lattimer S.A.; Stevens M.J.; Greene D.A.
Wayne State University, 540 East Canfield Avenue, Detroit, MI 48201 USA
Journal of Clinical Investigation (USA), 1996, 97/8 (1900-1907)

The abnormalities underlying diabetic neuropathy appear to be multiple and involve metabolic neuronal and vasomediated defects. The accumulation of long-chain fatty acids and impaired beta-oxidation due to deficiencies in carnitine and/or its esterified derivatives, such as acetyl-L-carnitine, may have deleterious effects. In the present study, we examined, in the diabetic bio-breeding Worcester rat, the short- and long-term effects of acetyl-L- carnitine administration on peripheral nerve polyols, myoinositol, Na+/K+- ATPase, vasoactive prostaglandins, nerve conduction velocity, and pathologic changes. Short-term prevention (4 mo) with acetyl-L-carnitine had no effects on nerve polyols, but corrected the Na+/K+-ATPase defect and was associated with 63% prevention of the nerve conduction defect and complete prevention of structural changes. Long-term prevention (8 mo) and intervention (from 4 to 8 mo) with acetyl-L-carnitine treatment normalized nerve PGE1 whereas 6-keto PGF(1alpha) and PGE2 were unaffected. In the prevention study, the conduction defect was 73% prevented and structural abnormalities attenuated. Intervention with acetyl-L-carnitine resulted in 76% recovery of the conduction defect and corrected neuropathologic changes characteristic of 4- mo diabetic rats. Acetyl-L-carnitine treatment promoted nerve fiber regeneration, which was increased two-fold compared to nontreated diabetic rats. These results demonstrate that acetyl-L-carnitine has a preventive effect on the acute Na+/K+-ATPase defect and a preventive and corrective effect on PGE1 in chronically diabetic nerve associated with improvements of nerve conduction velocity and pathologic changes.

Vitamin and mineral deficiencies which may predispose to glucose intolerance of pregnancy

Jovanovic-Peterson L.; Peterson C.M.
Sansum Medical Research Foundation, 2219 Bath Street, Santa Barbara, CA 93105 USA
Journal of the American College of Nutrition (USA), 1996, 15/1 (14-20)

There is an increased requirement for nutrients in normal pregnancy, not only due to increased demand, but also increased loss. There is also an increased insulin resistant state during pregnancy mediated by the placental anti-insulin hormones estrogen, progesterone, human somatomammotropin; the pituitary hormone prolactin; and the adrenal hormone, cortisol. If the maternal pancreas cannot increase production of insulin to sustain normoglycemia despite these anti-insulin hormones, gestational diabetes occurs. Gestational diabetes is associated with excessive nutrient losses due to glycosuria. Specific nutrient deficiencies of chromium, magnesium, potassium and pyridoxine may potentiate the tendency towards hyperglycemia in gestational diabetic women because each of these four deficiencies causes impairment of pancreatic insulin production. This review describes the pathophysiology of the hyperglycemia and the nutrient loss in gestational diabetes and further postulates the mechanism whereby vitamin/mineral supplementation may be useful to prevent or ameliorate pregnancy-related glucose intolerance.

Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus

Maxwell S.R.J.; Thomason H.; Sandler D.; Leguen C.; Baxter M.A.; Thorpe G.H.G.; Jones A.F.; Barnett A.H.
Dr. S.R.J. Maxwell, Division of Clinical Pharmacology, Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX United Kingdom
European Journal of Clinical Investigation (United Kingdom), 1997, 27/6 (484-490)

Oxidative damage by free radicals has been implicated in the pathogenesis of vascular disease in diabetes. We compared the radical- scavenging antioxidant activity of serum from 28 patients with insulin- dependent diabetes mellitus and 24 patients with non-insulin-dependent diabetes mellitus uncomplicated by vascular disease with age-matched non- diabetic control subjects. Patients with insulin-dependent diabetes had significantly reduced total antioxidant activity (320.2plus or minus11.3 vs. 427.5plus or minus19.2similarmolL 1 P<0.001). This was attributable to lower urate (209.4plus or minus 10.4 vs. 297.1 plus or minus 16.7similarmolL 1; P<0.001) and vitamin C levels (63.6 plus or minus 6.0 vs. 87.5 plus or minus 4.9 micromol L ; P < 0.0 1). Patients with non-insulin-dependent diabetes had lower total antioxidant activity than age-matched control subjects (433.8 plus or minus 25.4 vs. 473.9 plus or minus 30.2micromol L 1 NS), reflecting lower urate (299.5 plus or minus 19.4 vs. 324.8 plus or minus21.4/micromolL -P; NS) and vitamin C levels (38.6plus or minus5.7 vs. 58.5 plus or minus 5.3micromol L -1; P<0.05). Multiple regression analysis showed that urate, vitamin C and vitamin E were the major contributors to serum total antioxidant activity. These results show that diabetic patients have significant defects of antioxidant protection, which may increase vulnerability to oxidative damage and the development of diabetic complications.

Nutrient intake and food use in an Ojibwa-Cree community in Northern Ontario assessed by 24h dietary recall

Wolever T.M.S.; Hamad S.; Gittelsohn J.; Hanley A.J.G.; Logan A.; Harris S.B.; Zinman B.
Canada
Nutrition Research (USA), 1997, 17/4 (603-618)

As part of a diabetes prevention program in a remote Ojibwa-Cree community in Northern Ontario, 72% of residents >9y of age (729/1019) underwent an oral glucose tolerance test; >98% (718/729) of participants provided a complete 24h dietary recall. Their diet was typical of that for aboriginal North American populations undergoing rapid cultural change, being high in saturated fat (similar13% energy), cholesterol and simple sugars (similar22% energy), low in dietary fibre (11g/d) and nigh in glycaemic index (similar90). There were high prevalences of inadequate intakes of vitamin A (77%), calcium (58%), vitamin C (40%) and folate (37%). Adolescents aged 10-19y consumed more simple sugars and less protein than adults aged >49y and ate more potato chips, flied potatoes, hamburger, pizza, soft drinks and table sugar. Adults >49y retained more traditional eating habits, using more bannock (fried bread) and wild meats than younger individuals. Interventions to prevent diabetes in the community should include culturally appropriate and effective ways to improve the nutritional adequacy of the diet, reduce fat intake and increase the use of less refined carbohydrate foods.

Effect of vitamin C supplementation on hepatic cytochrome P450 mixed-function oxidase activity in streptozotocin-diabetic rats

Clarke J.; Snelling J.; Ioannides C.; Flatt P.R.; Barnett C.R.
United Kingdom
Toxicology Letters (Ireland), 1996, 89/3 (249-256)

The effect of vitamin C supplementation on hepatic cytochrome P450 expression was investigated in streptozotocin (STZ) diabetic male Wistar Albino rats. STZ-treated rats displayed the usual characteristics of diabetes including; hyperphagia, polydipsia, decreased body weight gain and also the increased expression and activity of hepatic CYP1A, 2B, 2E and 4A proteins. Vitamin C administration in drinking water (2% w/v) was associated with significant decreases in the levels of hyperglycaemia (P < 0.05), glycosylated haemoglobin (P < 0.05), hyperlipidaemia (P < 0.001), and hyperketonaemia (P < 0.001) associated with STZ-diabetes. Vitamin C-treatment selectively reduced the activity and expression of CYP2E proteins (P < 0.001). These effects on CYP2E expression may be mediated by the reduced levels of circulating ketone bodies, however, a direct effect on CYP2E expression in diabetes cannot be discounted.

The effect of dietary treatment on lipid peroxidation and antioxidant status in newly diagnosed noninsulin dependent diabetes

Armstrong A.M.; Chestnutt J.E.; Gormley M.J.; Young I.S.
Department of Clinical Biochemistry, Institute of Clinical Science, Royal Victoria Hospital, Belfast BT12 6BJ Ireland
Free Radical Biology and Medicine (USA), 1996, 21/5 (719-726)

Increased lipid peroxidation and reduced antioxidant status may contribute to the development of complications in diabetes. The aim of this study was to assess the effects of dietary treatment of noninsulin-dependent diabetes on these parameters. Twenty patients with newly diagnosed noninsulin-dependent diabetes were recruited along with 20 age, sex, and smoking-status-matched control subjects. Dietary intake was assessed by food frequency questionnaire and 24-h dietary recall and blood collected for biochemical analyses before and 2 months after dietary treatment was initiated. Carbohydrate, fat, and protein intake fell in patients following dietary advice. Among micronutrients, intakes of vitamins C, E, and A, carotene, selenium, copper, zinc, and iron were similar in patients and controls. Vitamin C intake in patients rose following dietary advice (44.6 plus or minus 11.7 vs. 49.5 plus or minus 5.5 mg/d, p < .05), while there was no change in intake of other micronutrients. Fasting plasma glucose in diabetic subjects fell from 13.6 plus or minus 1.1 mmol/l at recruitment to 9.7 plus or minus 1.1 mmol/l after diet (p < .01), and this was accompanied by a fall in hemoglobin Alc from 7.44 plus or minus 0.67% to 5.91 plus or minus 0.57% (p < .01). Serum malondialdehyde was higher in patients than controls at T0 (2.39 plus or minus 0.55 micromol/l vs. 1.48 plus or minus 0.33; p < .01), and fell following diet to 1.42 micromol/l (p < 0.01). Ascorbate was lower in patients than controls (12.7 plus or minus 2.9 micromol/l vs. 41.4 plus or minus 9.3; p < .01) at baseline and rose after diet to 27.8 plus or minus 6.4 (p < .01). beta-Carotene also rose after diet in patients (0.13 plus or minus 0.04 micromol/l vs. 0.17 plus or minus 0.04; p < 0.05), as did lipid corrected alpha-tocopherol (4.39 plus or minus 1.09 micromol/mmol cholesterol vs. 5.16 plus or minus 1.18; p < .05). Reduced lipid peroxidation and improved antioxidant status may be one mechanism by which dietary treatment contributes to the prevention of diabetic complications.

Vitamin B6 alleviates the vascular complications of insulin-treated STZ-induced diabetic rats

Chang S.-J.; Chiang C.-L.
Graduate Institute of Biology, National Cheng Kung University, Tainan Taiwan
Nutritional Sciences Journal (Taiwan), 1996, 21/3 (235-248)

The purpose of this study is to investigate whether vitamin B6 alleviates the vascular complications of insulin-treated streptozotocin (STZ)-induced diabetes in rats. Diabetic animals were treated with or without vitamin B6 and/or insulin. Platelet aggregation induced by ADP (10 microM) or thrombin (0.05 D/mL) was measured in platelet rich plasma of normal and diabetic animals. 14C-Thromboxane B2 (14C-TxB2) production of platelets, using 14C-Arachidonic Acid (14C-AA) as a precursor, was assayed by means of scanning radiochromatography and autoradiography. 14C-TxB2 was quantitied by scintillation counter. The results showed that vitamin B6 in conjuction with insulin treatment resulted in lower blood glucose than either vitamin B6 or insulin treatment alone. Similarly, platelet aggregation and TxB2 production in diabetics with vitamin B6 and insulin treatment were significantly decreased. These data indicated that vitamin B6 in conjunction with insulin treatment seemed to be better than vitamin B6 or insulin treatment alone in controlling blood glucose, inhibiting platelet aggregation and decreasing TxA2 production.

Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients

Schorah C.J.; Downing C.; Piripitsi A.; Gallivan L.; Al-Hazaa A.H.; Sanderson M.J.; Bodenham A.
Division of Clinical Sciences, Old Medical School, University of Leeds, Leeds LS2 9JT United Kingdom
American Journal of Clinical Nutrition (USA), 1996, 63/5 (760-765)

Plasma concentrations of the antioxidant vitamin ascorbic acid were measured by high-performance liquid chromatography in critically ill patients in whom the excessive generation of reactive oxygen species could compromise antioxidant defense mechanisms. Median concentrations of both total vitamin C (ascorbic acid and dehydroascorbic acid) and ascorbic acid in these patients were < 25% (P < 0.001) of the values found in healthy control subjects and in subjects in two other disease groups (diabetes, gastritis) in which reactive oxygen species are reported to be increased. The low values could not be explained by age, sex, intake, or treatment differences, but were associated with the severity of the illness and were not prevented by the use of parenteral nutrition containing ascorbic acid. In addition, the vitamin was less stable in blood samples taken from critically ill patients than in similar samples from subjects in the other groups. The findings indicate that antioxidant defenses could be considerably compromised in these very sick patients. If this reduces the patient's capacity to scavenge reactive species, then the potential of these species to damage DNA and lipid membranes could be increased and compromise recovery.

Clinical study of vitamin influence in diabetes mellitus

Hashizume N.
Dept. of Laboratory Medicine, Ohashi Hosp., Toho Univ. Sch. of Med., 2-17-6 Ohashi, Meguro, Tokyo Japan
Journal of the Medical Society of Toho University (Japan), 1996, 42/6 (577-581)

Vitamin deficiency is a result of an inadequale diet. Education on the importance of trace nutrients in diabetic patients with poor blood sugar control is examined. Those who prepare meals must consider the loss of vitamins in the process of cooking. Our study also suggested that marginal vitamin deficiency plays an indirect but important role in the development of diabetic complications. Vitamin C as altering total cholesterol (T-ch) and vitamin E as altering triglyceride (TG) could modify diabetic angiopathy. Pharmacologically, niacin might be responsible for the decrease in Lipoprotein (a) and vitamin C would inhibit the influence of rapid blood glucose control on diabetic retinopathy.

Vitamins and metals: Potential dangers for the human being

Ballmer P.E.
Departement Innere Medizin, Inselspital, Universitat Bern, CH-3010 Bern Switzerland
Schweizerische Medizinische Wochenschrift (Switzerland), 1996, 126/15 (607-611)

Administration of vitamins or metals may cause severe side effects. Retinoids (derivatives of vitamin A) used for the treatment of various skin disorders are teratogenic, hepatotoxic and may induce a substantial increase in serum lipids. A case report demonstrates that vitamin D supplementation in a patient under total parenteral nutrition can cause hypercalcemia. The isolated administration of vitamin B1, without concomitant vitamin B6 and nicotinamide may precipitate potentially life-threatening pellagra encephalopathy. Repeat blood transfusions may produce clinically overt organ hemosiderosis, e.g. cirrhosis of the liver, diabetes mellitus or myocardiopathy. The literature contains reports on a few cases of sarcoma associated with orthopedic metal implants. The controversial issue of the potential dangers of dental amalgams is briefly mentioned.

Leukocyte lipid peroxidation, superoxide dismutase, glutathione peroxidase and serum and leukocyte vitamin C levels of patients with type II diabetes mellitus

Akkus I.; Kalak S.; Vural H.; Caglayan O.; Menekse E.; Can G.; Durmus B.
Selcuk University, School of Medicine, Department of Biochemistry, Konya Turkey
Clinica Chimica Acta (Netherlands), 1996, 244/2 (221-227)

In the present study, leukocyte lipid peroxidation, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and serum and leukocyte vitamin C levels of patients with type II diabetes mellitus and healthy controls were investigated. Patients consisted of 53 cases (23 male, 30 female) aged 35-75 years and controls of 34 subjects (15 male, 19 female) aged 34-66 years. Leukocyte lipid peroxidation of diabetics was significantly increased (P < 0.05) whereas vitamin C level was decreased (P < 0.05) compared to those of controls. There was no significant difference in the other parameters. Also, there was no correlation between the above parameters and HbA1c and glucose levels. Our results show that leukocytes of diabetics are affected by oxidative stress which might be a reason for decreased microbicidal activity.

Erythrocyte and plasma antioxidant activity in type I diabetes mellitus

Ndahimana J.; Dorchy H.; Vertongen F.
Laboratoire de Chimie Medicale, Hopital Saint-Pierre, 322, Rue Haute, 1000 Bruxelles Belgium
Presse Medicale (France), 1996, 25/5 (188-192)

Objectives: Some biologic parameters involved in cell defence against oxygen radicals (plasmatic vitamins C and E, erythrocyte glutathione peroxidase, glutathione reductase and superoxide dismutase) were measured in single blood samples from 119 diabetic infants, adolescents and young adults.

Methods: Data were studied in relation to residual insulin secretion determined by C peptide, level of metabolic control appreciated by glycosylated haemoglobin, lipid abnormalities and subclinical complications (retinopathy, neuropathy and nephropathy).

Results: There was no change in antioxidant parameters with insulin secretion. Patients with poor glycaemic control and high plasma lipids had higher levels of plasma vitamin E. Patients with nephropathy had lower plasma vitamin C levels and those with neuropathy showed lower erythrocyte glutathione peroxidase activity. Plasma vitamin C concentrations and erythrocyte glutathione reductase activities were negatively correlated with the age of the patients and the duration of the disease.

Conclusion: Higher transport capacity of vitamin E probably explains the elevated levels of vitamin E observed in patients with high lipid levels and long lasting illness. The lower levels of vitamin C in the presence of nephropathy may be due to an increased renal excretion of this vitamin. The reduction of glutathione peroxidase, glutathione reductase activities and vitamin C levels confirms the existence of an oxidative stress in type 1 diabetes.

Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus

Ting H.H.; Timimi F.K.; Boles K.S.; Creager S.J.; Ganz P.; Creager M.A.
Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115 USA
Journal of Clinical Investigation (USA), 1996, 97/1 (22-28)

Endothelium-dependent vasodilation is impaired in humans with diabetes mellitus. Inactivation of endothelium-derived nitric oxide by oxygen-derived free radicals contributes to abnormal vascular reactivity in experimental models of diabetes. To determine whether this observation is relevant to humans, we tested the hypothesis that the antioxidant, vitamin C, could improve endothelium-dependent vasodilation in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus. We studied 10 diabetic subjects and 10 age-matched, nondiabetic control subjects. Forearm blood flow was determined by venous occlusion plethysmography. Endothelium-dependent vasodilation was assessed by intraarterial infusion of methacholine (0.3-10 microg/min). Endothelium-independent vasodilation was measured by intraarterial infusion of nitroprusside (0.3-10 microg/min) and verapamil (10-300 microg/min). Forearm blood flow dose-response curves were determined for each drug before and during concomitant intraarterial administration of vitamin C (24 mg/min). In diabetic subjects, endothelium-dependent vasodilation to methacholine was augmented by simultaneous infusion of vitamin C (P = 0.002); in contrast, endothelium-independent vasodilation to nitroprusside and to verapamil were not affected by concomitant infusion of vitamin C (P = 0.9 and P = 0.4, respectively). In nondiabetic subjects, vitamin C administration did not alter endothelium-dependent vasodilation (P = 0.8). We conclude that endothelial dysfunction in forearm resistance vessels of patients with non- insulin-dependent diabetes mellitus can be improved by administration of the antioxidant, vitamin C. These findings support the hypothesis that nitric oxide inactivation by oxygen-derived free radicals contributes to abnormal vascular reactivity in diabetes.

Effects of aspirin or basic amino acids on collagen cross-links and complications in NIDDM.

Contreras I; Reiser KM; Martinez N; Giansante E; Lopez T; Suarez N; Postalian S; Molina M; Gonzalez F; Sanchez MR; Camejo M; Blanco MC
Luis Razetti Medical School, Central University of Venezuela, Caracas, Venezuela.
Diabetes Care (United States) May 1997, 20 (5) p832-5

OBJECTIVE: To determine if long-term therapy with aspirin or basic amino acids for subjects with NIDDM reduces the severity of clinical complications and/or reduces tissue levels of markers of glycooxidative damage.

RESEARCH DESIGN AND METHODS: Subjects with NIDDM were administered either aspirin (100 mg/day) or a combination of basic amino acids consisting of L-arginine (2 g/day) plus L-lysine (0.5 g/day) for 1 year. The study was double-blind and placebo-controlled. The presence and severity of retinopathy, nephropathy, and neuropathy were assessed in all subjects at 4-month intervals, as were serum blood glucose, glycohemoglobin levels, and presence of albuminuria. Collagen cross-linking and collagen glycation were measured in skin collagen obtained by biopsy at the beginning and the end of the study. Skin biopsies were also obtained from age-matched control subjects.

RESULTS: Skin samples obtained from NIDDM subjects at the beginning of the study had significantly increased levels of glucitolyllysine, pentosidine, and hydroxypyridinium, as compared with age-matched control subjects. Pentosidine levels were significantly correlated with severity of retinopathy and neuropathy, but not nephropathy. Subjects receiving aspirin, but not amino acids or placebo, had significantly decreased levels of skin pentosidine after 1 year of therapy.

CONCLUSIONS: It is concluded that 1) low-dose aspirin may reduce glycooxidative damage in people with NIDDM, and 2) treatment may need to continue for more than 1 year before clinical status improves.

Acute and chronic response to vanadium following two methods of streptozotocin-diabetes induction.

Yao J; Battell ML; McNeill JH
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Can J Physiol Pharmacol (Canada) Feb 1997, 75 (2) p83-90

Controversial reports on the efficacy and possible toxicity of vanadium obtained from various studies may be attributed to differences in the method of diabetes induction and (or) to differences in animal strains. The objective of this study was to evaluate the contribution of these two factors to the effects of vanadium in the treatment of experimental diabetes. Two methods of streptozotocin induction of diabetes in rats have been used for studying the antidiabetic effects of vanadium. One involves a single intravenous injection of 60 mg/kg streptozotocin, and the other uses two subcutaneous injections of 40 mg/kg streptozotocin, to either Wistar or Sprague-Dawley rats. In a 7-week chronic study, Sprague-Dawley rats appeared to develop a more severe diabetes (indicated by higher plasma cholesterol and higher fasting plasma glucose levels) following the single intravenous injection of streptozotocin than rats made diabetic by two subcutaneous injections of streptozotocin. Irrespective of the method of diabetes induction, the responses of all the diabetic animals to chronic vanadyl sulphate treatment were similar. In an acute study, Wistar diabetic rats were more responsive than Sprague-Dawley diabetic rats to vanadyl sulphate and to lower doses (0.6 and 0.8 mmol/kg) of a new organic vanadium compound, bis(maltolato)oxovanadium(i.v.).

[Comparison of metabolism of water-soluble vitamins in healthy children and in children with insulin-dependent diabetes mellitus depending upon the level of vitamins in the diet]

Kodentsova VM; Pustograev NN; Vrzhesinskaia OA; Kharitonchik LA; Pereverzeva OG; Iakushina LM; Trofimenko LS; Spirichev VB
Vopr Med Khim (Russia) Apr-Jun 1996, 42 (2) p153-8

Metabolism of vitamins C, B2, B6 and niacin in children with insulin-dependent diabetes mellitus was distinctly different from that of healthy persons of the same age as shown by studies of the correlation between content of vitamins or their coenzyme forms in blood, excretion of the vitamins with urine and content of the vitamins in a diet. These data corroborated once again that in estimation of the vitamins consumption suitable for ill children, the criteria of healthy children requirements for vitamins should not be taken into consideration. Dissimilar metabolism in healthy and impaired persons may also demonstrate some differences in consumption of these vitamins. Preliminary data showed that requirements of the impaired children for vitamin C were slightly increased, for vitamin B2--similar or slightly decreased as compared with healthy children. These results suggest that additional investigations are required for evaluation of vitamins consumption in children with diabetes mellitus of the I type.

Spice constituents scavenging free radicals and inhibiting pentosidine formation in a model system.

Oya T; Osawa T; Kawakishi S
Department of Applied Biological Sciences, Nagoya University, Japan.
Biosci Biotechnol Biochem (Japan) Feb 1997, 61 (2) p263-6

Many antioxidants have been found in spices and herbs, and some of them are well known as strong scavengers of active oxygen radicals. We have isolated active products, which markedly inhibited the formation of malondialdehyde (MDA from 2-deoxyribose and the hydroxylation of benzoate with the hydroxyl radical, from methanol extracts of allspice and clove. Pimentol from allspice, and biflorin and its isomer, abbreviated as clove3, from clove were identified as the active principles. These revealed strong activity as hydroxyl radical scavengers at a concentration of 2.0 microM. The antioxidative activities in an in vitro model system involving the rabbit erythrocyte membrane ghost were as strong as those of alpha-tocopherol at 200 microM. Such advanced glycation end products (AGE) as pentosidine are biomarkers of diabetes mellitus, and active oxygens have been suggested to be involved in the formation of AGE. The above-mentioned free radical scavengers effectively inhibited the formation of pentosidine in a model system of N alpha-t-butoxycarbonyl-fructoselysine and N alpha-t-butoxycarbonyl-arginine.

L-Arginine reduces lipid peroxidation in patients with diabetes mellitus.

Lubec B; Hayn M; Kitzmuller E; Vierhapper H; Lubec G
Department of Paediatrics, University of Vienna, Austria.
Free Radic Biol Med (United States) 1997, 22 (1-2) p355-7

A current concept for the development of diabetic long-term complications is the involvement of oxidative stress, as, e.g., lipid peroxidation, in the diabetic state. Data published recently show also oxidative damage to DNA, which might be one factor for accelerated aging and diabetic microangiopathy. In our study we tested the hypothesis that L-arginine can reduce lipid peroxidation in patients with diabetes. We performed a blind placebo controlled study with crossing over two treatment periods for 3 months. Thirty patients with diabetes mellitus were randomly assigned to treatment group A (first treatment then placebo) and B (first placebo then treatment). Treatment consisted of two daily dosages of 1 g L-arginine free base. Lipid peroxidation as reflected by malondialdehyde was evaluated in urine using a standard HPLC assay. After 3 months of treatment there was a significant reduction in malondialdehyde levels in group A (p < .0032), whereas there was no difference compared to the baseline values after three months of placebo treatment in group B (p < .97). After crossing over, there was a significant reduction in malondialdehyde levels in group B (p < .0002). Group A showed a significant increase in malondialdehyde levels (p < .0063) returning to baseline values. L-Arginine treatment was able to reduce the lipid peroxidation product malondialdehyde. This provides evidence that treatment with L-arginine may counteract lipid peroxidation and thus reduce microangiopathic long-term complications in diabetes mellitus.

Short-term oral administration of L-arginine reverses defective endothelium-dependent relaxation and cGMP generation in diabetes.

Pieper GM; Siebeneich W; Dondlinger LA
Department of Transplant Surgery, Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital, Milwaukee WI 53226, USA.
Eur J Pharmacol (Netherlands) Dec 19 1996, 317 (2-3) p317-20

In the present study, we evaluated whether acute dietary supplementation with L-arginine in vivo could reverse the defective endothelium-dependent relaxation in diabetic blood vessels assessed ex vivo. At 8 weeks of diabetes, streptozotocin-induced diabetic rats were given 1.25% L-arginine in drinking water 3 days prior to isolation of aortic rings for evaluation ex vivo. Plasma arginine concentration was reduced by diabetes but restored to normal in diabetic rats receiving dietary L-arginine. In norepinephrine-contracted rings, relaxation to acetylcholine but not to nitroglycerin was reduced by diabetes. Dietary treatment with L-arginine restored relaxation to acetylcholine without altering relaxation to nitroglycerin and restored the defect in acetylcholine-stimulated cGMP generation. These data suggest that the substrate for nitric oxide synthesis by the endothelium is likely to be limited in diabetes but can be overcome by dietary supplementation with L-arginine.

A diet enriched in protein accelerates diabetes manifestation in NOD mice.

Schneider K; Laube H; Linn T
Department of Internal Medicine, Justus Liebig University, Giessen, Germany.
Acta Diabetol (Germany) Sep 1996, 33 (3) p236-40

Diet modifies the development of insulin-dependent diabetes mellitus in animals and in humans. We examined female non-obese-diabetic (NOD) mice, a diabetes-prone mouse strain with 70% spontaneous diabetes incidence and metabolic abnormalities in non-overtly diabetic litters. They were fed a diet containing 55% (n = 27) or 15% (n = 26) protein, respectively, after weaning. At an age of 30 weeks, non-diabetic NOD mice were submitted to an intravenous glucose tolerance test (0.5 g/kg body weight; blood samples were taken after 2, 4, 8, 10, 15, 20 and 30 min) and to perfusion of the pancreas (stimulation media were Krebs-Ringer-Hepes buffer with 5 mmol/l glucose, 30 mmol/l glucose and 5 mmol/l glucose plus 19 mmol/l arginine). Diabetic mice were removed from the experiment. Serum glucose concentration and body weight were monitored weekly. Food ingestion was checked at an age of 11 weeks. On average, the onset of diabetes was diagnosed in mice on a high-protein diet (19.7 +/- 1.3 weeks) 4 weeks earlier than in mice on a low-protein diet (23.5 +/- 1.1 weeks; P < 0.05). Non-diabetic NOD mice on a high-protein diet showed significantly better glucose tolerance (as determined by the glucose disappearance rate) and mean insulin secretion (at 30 mmol/l glucose). No difference in the serum glucose concentration between non-diabetic mice on the low-protein diet or high-protein diet could be proved. In non-diabetic mice on the high-protein diet the body weight and food ingestion exceeded those of mice on the low-protein diet (P < 0.05). High insulin secretion and glucose tolerance in non-diabetic mice may reflect the capacity of beta-cells to adapt; however, beta-cells tend to be destroyed under such circumstances. Thus, a high-protein diet promoted the onset of diabetes, but it did not increase significantly the incidence of the disease.

Metformin improves hemodynamic and rheological responses to L-arginine in NIDDM patients.

Marfella R; Acampora R; Verrazzo G; Ziccardi P; De Rosa N; Giunta R; Giugliano D
Department of Geriatrics and Metabolic Discases, Second University of Naples, Italy.
Diabetes Care (United States) Sep 1996, 19 (9) p934-9

OBJECTIVE: The endothelium plays a pivotal role in the regulation of vascular tone by releasing nitric oxide (NO). Increased availability of L-arginine, the natural precursor of NO, induces vasodilatation and inhibits platelet activity. We studied the effect of metformin on hemodynamic and rheological responses to L-arginine in patients with NIDDM.

RESEARCH DESIGN AND METHODS: Ten newly diagnosed NIDDM patients with mild fasting hyperglycemia (7.5 +/- 0.3 mmol/l) and without evidence of both micro- and macrovascular complications were investigated. They received an intravenous infusion of L-arginine (1 g/min for 30 min) with evaluation of plasma glucose and insulin, systolic (sBP) and diastolic (dBP) blood pressure, heart rate and plasma catecholamines, platelet aggregation, and blood viscosity and filterability. The L-arginine test was repeated after an 8-week treatment with metformin (850 mg b.i.d.).

RESULTS: Metformin treatment significantly reduced basal fasting plasma glucose, HbA1c, and platelet aggregation to ADP (P < 0.05); the other parameters did not change. During pretreatment test, L-arginine infusion decreased sBP (from 137 +/- 4.1 to 129 +/- 4.5 mmHg, P < 0.01) and dBP (from 79 +/- 1.9 to 75 +/- 1.2 mmHg, P < 0.01) without affecting heart rate or plasma catecholamines. Both platelet aggregation and blood viscosity showed significant decrements after L-arginine, while blood filterability did not change. After metformin treatment, the decrease in blood pressure after L-arginine infusion was significantly enhanced, with a maximal decrease of sBP of 12 +/- 3.4 mmHg (8 +/- 2.5 mmHg pretreatment, P < 0.05) and dBP of 9.5 +/- 2.4 mmHg (4.5 +/- 1.9 mmHg pretreatment, P < 0.01). Heart rate, plasma norepinephrine levels, and blood filterability also rose significantly (P < 0.05-0.01). The decrease in both platelet aggregation and blood viscosity after L-arginine was significantly amplified after metformin.

CONCLUSIONS: We conclude that L-arginine infusion in newly diagnosed NIDDM patients without vascular complications produces relevant hemodynamic and theological changes, which are amplified by an 8-week treatment with metformin. Whether these vascular effects of metformin will improve the poor cardiovascular outlook of the diabetic patient is still unknown.

Impairment of coronary blood flow regulation by endothelium-derived nitric oxide in dogs with alloxan-induced diabetes.

Matsunaga T; Okumura K; Ishizaka H; Tsunoda R; Tayama S; Tabuchi T; Yasue H
Division of Cardiology, Kumamoto University School of Medicine, Japan.
J Cardiovasc Pharmacol (United States) Jul 1996, 28 (1) p60-7

Diabetes mellitus is a major cause of ischemic coronary artery disease. Endothelial dysfunction is implicated in the pathogenesis of diabetic vascular disease. To examine coronary blood flow (CBF) regulation with endothelium-derived nitric oxide (EDNO) in the diabetic state, we compared the effects of both acetylcholine (ACh) and adenosine (Ado) on left circumflex coronary artery (LCX) blood flow in 12 vehicle-treated and 21 dogs made diabetic with alloxan anesthetized with pentobarbital. All dogs were pretreated with aspirin to inhibit endogenous prostaglandins. None of the hemodynamic parameters were significantly different in the two groups. The percent change in coronary vascular resistance (CVR) after ACh (100 ng/kg) infusion was significantly attenuated in diabetic dogs (-56.5 +/- 1.4%) as compared with vehicle-treated dogs (-64.5 +/- 1.2%) (p < 0.01), whereas the effect of Ado (1 microgram/kg) was not different between the two groups (-71.1 +/- 1.5% in vehicle, -67.0 +/- 1.3% in diabetes). After infusion of incremental doses of NG-nitro-L-arginine methyl ester (L-NAME) 10(-5)-10(-3)M, the effect of ACh was progressively inhibited in both groups and was different no longer between the two groups after the maximal dose. L-Arginine (L-ARG), but not D-ARG, significantly restored the effect of ACh in diabetic dogs but did not affect vehicle-treated dogs. The effect of Ado did not change after L- and D-ARG administration. Cu, Zn-superoxide dismutase (Cu, Zn-SOD) had no effect on any of the effects of ACh and Ado in diabetic dogs. Regulation of CBF with EDNO is impaired in dogs with alloxan-induced diabetes, and this impairment is partially restored by L-ARG.

Involvement of the L-arginine-nitric oxide pathway in hyperglycaemia-induced coronary artery dysfunction of isolated guinea pig hearts.

Wascher TC; Bachernegg M; Kickenweiz A; Stark G; Stark U; Toplak H; Graier WF
Diabetic Angiopathy Research Group, University of Graz, Austria.
Eur J Clin Invest (England) Aug 1996, 26 (8) p707-12

The effects of hyperglycaemia and L-arginine on flow-induced reduction of coronary artery resistance were investigated in isolated guinea pig hearts. In the presence of indomethacin, hyperglycaemia caused an increase in flow-induced vasodilatation (P < 0.05). Hyperosmotic controls failed to mimic this effect. Addition of L-arginine strongly enhanced this effect. Addition of D-arginine failed to mimic the effects of L-arginine. The effect of L-arginine was abolished by co-administration of NG-nitro-L-arginine. In the absence of indomethacin and L-arginine, the effect of hyperglycaemia was blunted, suggesting the formation of vasoconstrictive prostanoids. Addition of L-arginine again resulted in a significant increase in flow-induced vasodilatation. In conclusion our results suggest that increased flow-induced vasodilatation under hyperglycaemic conditions depends on an adequate supply of L-arginine to maintain sufficient formation of nitric oxide.

Deficient nitric oxide responsible for reduced nerve blood flow in diabetic rats: effects of L-NAME, L-arginine, sodium nitroprusside and evening primrose oil.

Omawari N; Dewhurst M; Vo P; Mahmood S; Stevens E; Tomlinson DR
Department of Pharmacology, Queen Mary and Westfield College, London.
Br J Pharmacol (England) May 1996, 118 (1) p186-90

1. This study examined the potential role of impaired nitric oxide production and response in the development of endoneurial ischaemia in experimental diabetes. Rats were anaesthetized (Na pentobarbitone 45 mg kg-1, diazepam 2 mg kg-1) for measurement of sciatic nerve laser Doppler flux and systemic arterial pressure. Drugs were administered into the sciatic endoneurium via a microinjector attached to a glass micropipette.

2. In two separate studies comparing diabetic rats (streptozotocin-induced; 8-10 wk duration) with controls, nerve Doppler flux in diabetic rats (Study 1, 116.6 +/- 40.4 and Study 2, 90.1 +/- 34.7 (s.d.) in arbitrary units) was about half that measured in controls (219.6 +/- 52.4 and 212.8 +/- 95.5 respectively; P < 0.005 for both). There were no significant differences between the two in systemic arterial pressure.

3. Inhibition of nitric oxide production by microinjection of 1 nmol L-NAME into the endoneurium halved flux in controls (to 126.3 +/- 41.3 in Study 1 and 102.1 +/- 38.9 in Study 2; both P < 0.001), with no significant effect in diabetic rats, indicating markedly diminished tonic nitric oxide production in the latter. D-NAME was without effect on nerve Doppler flux.

4. L-Arginine (100 nmol), injected after L-NAME, markedly increased flux in controls (by 65.8% (P < 0.03) and 97.8% (P < 0.01) in the two studies) and by proportionally similar amounts in diabetic rats [75.8% (P < 0.001) and 60.2% (P < 0.02)]. The nitro-donor, sodium nitroprusside (SNP; 10 nmol) had similar effects to L-arginine in both groups (increases of 66.0% in controls and 77.5% in diabetics; both P < 0.002).

5. A second diabetic group, treated with evening primrose oil performed exactly like control rats in respect of responses to L-NAME, L-arginine and SNP.

6. These findings implicate deficient nitric oxide in nerve ischaemia of diabetes and suggest correction thereof as a mechanism of action of evening primrose oil.

Interactions between essential fatty acid, prostanoid, polyol pathway and nitric oxide mechanisms in the neurovascular deficit of diabetic rats.

Cameron NE; Cotter MA; Hohman TC
Department of Biomedical Sciences, University of Aberdeen, Scotland, UK.
Diabetologia (Germany) Feb 1996, 39 (2) p172-82

Impaired omega-6 essential fatty acid metabolism and exaggerated polyol pathway flux contribute to the neurovascular abnormalities in streptozotocin-diabetic rats. The potential interactions between these mechanisms were examined by comparing the effects of threshold doses of aldose reductase inhibitors and evening primrose oil, alone and in combination, on neurovascular deficits. In addition, high-dose aldose reductase inhibitor and evening primrose oil treatment effects were challenged by co-treatment with the cyclo-oxygenase inhibitor, flurbiprofen, or the nitric oxide synthase inhibitor, NG-nitro-L-arginine. Eight weeks of diabetes caused an 18.9% reduction in sciatic motor conduction velocity (p < 0.001). This was only modestly ameliorated by a 0.1% dietary supplement of evening primrose oil or the aldose reductase inhibitors ZD5522 (0.25 mg.kg-1.day-1 and WAY121 509 (0.2 mg.kg-1.day-1 for the final 2 weeks. However, joint treatment with primrose oil and ZD5522 or WAY121 509 caused marked 71.5 and 82.4% corrections, respectively, of the conduction deficit. Sciatic nutritive blood flow was 43.1% reduced by diabetes (p < 0.001) and this was corrected by 67.8% with joint ZD5522 and primrose oil treatment (p < 0.001). High-dose WAY121 509 (10 mg. kg-1.day-1 and primrose oil (10% dietary supplement) prevented sciatic conduction velocity and nutritive blood flow deficits in 1-month diabetic rats (p < 0.001). However, these effects were abolished by flurbiprofen (5 mg.kg(-1).day-1 and NG-nitro-L-arginine (10 mg.kg-1.day-1) co-treatment (p < 0.001). Thus, the data provide evidence for synergistic interactions between polyol pathway/nitric oxide and essential fatty acid/cyclo-oxygenase systems in the control of neurovascular function in diabetic rats, from which a potential therapeutic advantage could be derived.

Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non-insulin-dependent diabetes mellitus.

Boden G; Chen X; Ruiz J; van Rossum GD; Turco S
Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Temple University Schools of Medicine and Pharmacy, Philadelphia, PA, USA.
Metabolism (United States) Sep 1996, 45 (9) p1130-5

The safety and efficacy of vanadyl sulfate (VS) was tested in a single-blind, placebo-controlled study. Eight patients (four men and four women) with non-insulin-dependent diabetes mellitus (NIDDM) received VS (50 mg twice daily orally) for 4 weeks. Six of these patients (four men and two women) continued in the study and were given a placebo for an additional 4 weeks. Euglycemic-hyperinsulinemic clamps were performed before and after the VS and placebo phases. VS was associated with gastrointestinal side effects in six of eight patients during the first week, but was well tolerated after that. VS administration was associated with a 20% decrease in fasting glucose concentration (from 9.3 +/- 1.8 to 7.4 +/- 1.4 mmol/L, P < .05) and a decrease in hepatic glucose output (HGO) during hyperinsulinemia (from 5.0 +/- 1.0 pre-VS to 3.1 +/- 0.9 micromol/kg x min post-VS, P < .02). The improvement in fasting plasma glucose and HGO that occurred during VS treatment was maintained during the placebo phase. VS had no significant effects on rates of total-body glucose uptake, glycogen synthesis, glycolysis, carbohydrate (CHO) oxidation, or lipolysis during euglycemic-hyperinsulinemic clamps. We conclude that VS at the dose used was well tolerated and resulted in modest reductions of fasting plasma glucose and hepatic insulin resistance. However, the safety of larger doses and use of vanadium salts for longer periods remains uncertain.

Contraction and relaxation of aortas from diabetic rats: effects of chronic anti-oxidant and aminoguanidine treatments.

Archibald V; Cotter MA; Keegan A; Cameron NE
Department of Biomedical Sciences, University of Aberdeen, Marischal College, Scotland, UK.
Naunyn Schmiedebergs Arch Pharmacol (Germany) Apr 1996, 353 (5) p584-91

We examined whether chronic treatment with the free radical scavengers butylated hydroxytoluene (1 g kg-1 day-1) and N-acetyl-L-cysteine (250 mg kg-1 day-1), or the inhibitor of advanced glycosylation reactions, aminoguanidine (1 g kg-1 day-1), could prevent the development of relaxation and contraction abnormalities in aorta from 2 month streptozotocin-diabetic rats. Diabetes caused a 24% deficit in maximal endothelium-dependent relaxation to acetylcholine for phenylephrine precontracted aortas (P < 0.01). This was unaffected by tissue-bath glucose concentration (5.5 or 40 mM), or by addition of 1 mM L-arginine. Butylated hydroxytoluene, N-acetyl-L-cysteine and aminoguanidine treatments gave substantial protection, maximum relaxation remaining in the non-diabetic range. Neither diabetes nor treatment affected endothelium-independent relaxation to glyceryl trinitrate. To test the suggestion that aminoguanidine could act as an inhibitor of constitutive nitric oxide synthase, acute aminoguanidine effects on endothelium-dependent relaxation to acetylcholine were also examined. No inhibition was noted. A modest increase in phenylephrine sensitivity with diabetes (P < 0.05) was unaffected by butylated hydroxytoluene or N-acetyl-L-cysteine, but partially prevented by aminoguanidine (P < 0.05). The data, therefore, provide evidence for the involvement of reactive oxygen species and the advanced glycosylation process particularly for impaired endothelium-dependent relaxation in experimental diabetes.

[Erythrocyte and plasma antioxidant activity in diabetes mellitus type I]

Ndahimana J; Dorchy H; Vertongen F
Service de Chimie medicale, Universite Libre de Bruxelles, Belgique.
Presse Med (France) Feb 10 1996, 25 (5) p188-92

OBJECTIVES: Some biologic parameters involved in cell defence against oxygen radicals (plasmatic vitamins C and E, erythrocyte glutathione peroxidase, glutathione reductase and superoxide dismutase) were measured in single blood samples from 119 diabetic infants, adolescents and young adults.

METHODS: Data were studied in relation to residual insulin secretion determined by C peptide, level of metabolic control appreciated by glycosylated haemoglobin, lipid abnormalities and subclinical complications (retinopathy, neuropathy and nephropathy).

RESULTS: There was no change in antioxidant parameters with insulin secretion. Patients with poor glycaemic control and high plasma lipids had higher levels of plasma vitamin E. Patients with nephropathy had lower plasma vitamin C levels and those with neuropathy showed lower erythrocyte glutathione peroxidase activity. Plasma vitamin C concentrations and erythrocyte glutathione reductase activities were negatively correlated with the age of the patients and the duration of the disease.

CONCLUSION: Higher transport capacity of vitamin E probably explains the elevated levels of vitamin E observed in patients with high lipid levels and long lasting illness. The lower levels of vitamin C in the presence of nephropathy may be due to an increased renal excretion of this vitamin. The reduction of glutathione peroxidase, glutathione reductase activities and vitamin C levels confirms the existence of an oxidative stress in type I diabetes.

Hyperglycemia-induced latent scurvy and atherosclerosis: the scorbutic-metaplasia hypothesis.

Price KD; Price CS; Reynolds RD
University of Illinois at Chicago, College of Medicine 60612, USA.
Med Hypotheses (England) Feb 1996, 46 (2) p119-29

Latent scurvy is characterized by a reversible atherosclerosis that closely resembles the clinical form of this disease. Acute scurvy is characterized by microvascular complications such as widespread capillary hemorrhaging. Vitamin C (ascorbate) is required for the synthesis of collagen, the protein most critical in the maintenance of vascular integrity. We suggest that in latent scurvy, large blood vessels use modified LDL--in particular lipoprotein(a)--in addition to collagen to maintain macrovascular integrity. By this mechanism, collagen is spared for the maintenance of capillaries, the sites of gas and nutrient exchange. The foam-cell phenotype of atherosclerosis is identified as a mesenchymal genetic program, regulated by the availability of ascorbate. When vitamin C is limited, foam cells develop and induce oxidative modification of LDL, thereby stabilizing large blood vessels via the deposition of LDL. The structural similarity between vitamin C and glucose suggests that hyperglycemia will inhibit cellular uptake of ascorbate, inducing local vitamin C deficiency. (136 Refs.)

Oral vanadyl sulfate improves insulin sensitivity in NIDDM but not in obese nondiabetic subjects.

Halberstam M; Cohen N; Shlimovich P; Rossetti L; Shamoon H
Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Diabetes (United States) May 1996, 45 (5) p659-66

We compared the effects of oral vanadyl sulfate (100 mg/day) in moderately obese NIDDM and nondiabetic subjects. Three-hour euglycemic-hyperinsulinemic (insulin infusion 30 mU / m / min) clamps were performed after 2 weeks of placebo and 3 weeks of vanadyl sulfate treatment in six nondiabetic control subjects (age 37 +/- 3 years; BMI 29.5 +/- 2.4 kg/m2 ) and seven NIDDM subjects (age 53 +/- 2 years; BMI 28.7 +/-1.8 kg/m2). Glucose turnover ([3-3 H]glucose), glycolysis from plasma glucose, glycogen synthesis, and whole-body carbohydrate and lipid oxidation were evaluated. Decreases in fasting plasma glucose (by approximately 1.7 mmol/l) and HbAlc (both P < 0.05) were observed in NIDDM subjects during treatment; plasma glucose was unchanged in control subjects. In the latter, the glucose infusion rate (GIR) required to maintain euglycemia (40.1 +/- 5.7 and 38.1 +/- 4.8 micromol / kg fat-free mass FFM / min) and glucose disposal (Rd) (41.7 +/- 5.7 and 38.9 +/-4.7 micromol / kg FFM / min were similar during placebo and vanadyl sulfate administration, respectively. Hepatic glucose output (HGO) was completely suppressed in both studies. In contrast, in NIDDM subjects, vanadyl sulfate increased GIR approximately 82% (17.3 +/- 4.7 to 30.9 +/- 2.7 micromol / kg FFM / min, P < 0.05); this improvement in insulin sensitivity was due to both augmented stimulation of Rd (26.0 +/-4.0 vs. 33.6 +/- 2.22 micromol / kg FFM / min, P < 0.05) and enhanced suppression of HGO (7.7 +/- 3.1 vs. 1.3 +/- 0.9 micromol / kg FFM / min, P < 0.05). Increased insulin-stimulated glycogen synthesis accounted for >80% of the increased Rd with vanadyl sulfate (P < 0.005), but plasma glucose flux via glycolysis was unchanged. In NIDDM subjects, vanadyl sulfate was also associated with greater suppression of plasma free fatty acids (FFAs) (P < 0.01) and lipid oxidation (P < 0.05) during clamps. The reduction in HGO and increase in Rd were both highly correlated with the decline in plasma FFA concentrations during the clamp period (P < 0.001). In conclusion, small oral doses of vanadyl sulfate do not alter insulin sensitivity in nondiabetic subjects, but it does improve both hepatic and skeletal muscle insulin sensitivity in NIDDM subjects in part by enhancing insulin's inhibitory effect on lipolysis. These data suggest that vanadyl sulfate may improve a defect in insulin signaling specific to NIDDM.

Continued on the next page...

McCarty MF
Nutrition 21, San Diego, CA 92109.
Med Hypotheses (England) Oct 1993, 41 (4) p316-24

The insulin-sensitizing drug phenformin, in addition to its clinical utility in type II diabetes, has been reported to lower blood lipids, reduce body fat, enhance cellular immunity, and--in rodents--to increase mean lifespan and retard the development of growth of cancer. Initial studies with the insulin-sensitizing nutrient chromium picolinate indicate that it aids glucose tolerance in type II diabetes, lowers elevated LDL cholesterol, reduces body fat while increasing lean mass, and-- in rats--increases median lifespan. These effects are thus analogous to those reported for phenformin; chromium picolinate should be tested to determine whether it likewise has a favorable impact on cellular immunity and cancer risk. The ability of both phenformin and chromium picolinate to increase lifespan suggests that age-related insulin resistance may play a profound role in the aging process. It may not be coincidental that caloric restriction--the best documented technique for increasing lifespan--markedly increases insulin sensitivity. Safe, appropriate measures for promoting lifelong insulin sensitivity include a low-fat diet, exercise training, and supplemental chromium picolinate. (75 Refs.)

[The effect of chromium picolinate on the liver levels of trace elements]

Aguilar MV; Jorge AM; Mateos CJ; Garcia J; Laborda JM; Meseguer I; Martinez-Para MC; Gonzalez MJ
Departamento de Nutricion y Bromatologia, Facultad de Farmacia, Universidad de Alcala de Henares, Espana.
Nutr Hosp (Spain) Nov-Dec 1995, 10 (6) p373-6

Chromium picolinate has been implicated as a lipid and carbohydrate reducing agent, and therefore it may be a valuable adjunct to the treatment and prevention of diabetes and heart disease. This compound is inexpensive and apparently nontoxic. In this work, we have determined the influence of its administration (100, 200, 500 micrograms Cr/ml, for 7 and 21 days) on hepatic content of Zn, Mn, Cu and Fe of male Wistar rats. The results show a variation of the levels of these elements after the administration of chromium picolinate, although the differences are only significantly (p < 0.01) in the case of Mn. This influence is dose-dependent, occurring a decrease of 72% in the group treated with 500 micrograms/ml (Pic-500) respect to the content of control group.

Anabolic effects of insulin on bone suggest a role for chromium picolinate in preservation of bone density.

McCarty MF
Med Hypotheses (England) Sep 1995, 45 (3) p241-6

Activation of osteoclasts by parathyroid hormone (PTH) is mediated by PTH stimulation of osteoblasts, and is dependent on a PTH-induced rise in protein kinase C activity. Physiological levels of insulin reduce the ability of PTH to activate protein kinase C in osteoblasts, suggesting that insulin may be a physiological antagonist of bone resorption. In addition, insulin is known to promote collagen production by osteoblasts. These findings imply that efficient insulin activity may exert an anabolic effect on bone, and rationalize the many clinical studies demonstrating reduced bone density in Type I diabetes. Recently, the insulin-sensitizing nutrient chromium picolinate has been found to reduce urinary excretion of hydroxyproline and calcium in postmenopausal women, presumably indicative of a reduced rate of bone resorption. This nutrient also raised serum levels of dehydroepiandrosterone-sulfate, which may play a physiological role in the preservation of postmenopausal bone density. The impact of chromium picolinate (alone or in conjunction with calcium and other micronutrients) on bone metabolism and bone density, merits further evaluation in controlled studies. (69 Refs.)

Longevity effect of chromium picolinate--'rejuvenation' of hypothalamic function?

McCarty MF
Nutrition 21, San Diego, California 92109.
Med Hypotheses (England) Oct 1994, 43 (4) p253-65

The first rodent longevity study with the insulin-sensitizing nutrient chromium picolinate has reported a dramatic increase in both median and maximal lifespan. Although the observed moderate reductions in serum glucose imply a decreased rate of tissue glycation reactions, it is unlikely that this alone can account for the substantial impact on lifespan; an effect on central neurohormonal regulation can reasonably be suspected. Recent studies highlight the physiological role of insulin as a modulator of brain function. I postulate that aging is associated with a reduction of effective insulin activity in the brain, and this contributes to age-related alterations of hypothalamic functions that result in an 'older' neurohormonal milieu; consistent with this possibility, diabetes leads to changes of hypothalamic regulation analogous to those seen in normal aging. Conversely, promoting brain insulin activity with chromium picolinate may help to maintain the hypothalamus in a more functionally youthful state; increased hypothalamic catecholamine activity, sensitization of insulin-responsive central mechanisms regulating appetite and thermogenesis, and perhaps trophic effects on brain neurons may play a role in this regard. Since both the pineal gland and thymus are dependent on insulin activity, chromium may aid their function as well. Thus, the longevity effect of chromium picolinate may depend primarily on delay or reversal of various age-related changes in the body's hormonal and neural milieu. A more general strategy of hypothalamic 'rejuvenation' is proposed for extending healthful lifespan.

Thiamine pyrophosphate and pyridoxamine inhibit the formation of antigenic advanced glycation end-products: comparison with aminoguanidine.

Booth AA; Khalifah RG; Hudson BG
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160-7421, USA.
Biochem Biophys Res Commun (United States) Mar 7 1996, 220 (1) p113-9

Nonenzymatic glycation of proteins by glucose leading to the formation of toxic and immunogenic advanced glycation end products (AGEs) may be a major contributor to the pathological manifestations of diabetes mellitus, aging, and, possibly, neurodegenerative diseases such as Alzheimer's. We tested the in vitro inhibition of antigenic AGE formation on bovine serum albumin, ribonuclease A, and human hemoglobin by various vitamin B1 and B6 derivatives. Among the inhibitors, pyridoxamine and thiamine pyrophosphate potently inhibited AGE formation and were more effective than aminoguanidine, suggesting that these two compounds may have novel therapeutic potential in preventing vascular complications of diabetes. An unexpected finding was that aminoguanidine inhibited the late kinetic stages of glycation much more weakly than the early phase.

Loss of glucose-induced insulin secretion and GLUT2 expression in transplanted beta-cells.

Ogawa Y; Noma Y; Davalli AM; Wu YJ; Thorens B; Bonner-Weir S; Weir GC
E.P. Joslin Laboratories, Joslin Diabetes Center, Boston, MA 02215.
Diabetes (United States) Jan 1995, 44 (1) p75-9

Either 200 or 400 syngeneic islets were transplanted under the kidney capsule of normal or streptozocin-induced diabetic B6/AF1 mice. The diabetic mice with 400 islets became normoglycemic, but those with 200 islets, an insufficient number, were still diabetic after the transplantation (Tx). Two weeks after Tx, GLUT2 expression in the islet grafts was evaluated by immunofluorescence and Western blots, and graft function was examined by perfusion of the graft-bearing kidney. Immunofluorescence for GLUT2 was dramatically reduced in the beta-cells of grafts with 200 islets exposed to hyperglycemia. However, it was plentiful in grafts with 400 islets in a normoglycemic environment. Densitometric analysis of Western blots on graft homogenates demonstrated that GLUT2 protein levels in the islets, when exposed to chronic hyperglycemia for 2 weeks, were decreased to 16% of those of normal recipients. Moreover, these grafts had defective glucose-induced insulin secretion, while the effects of arginine were preserved. We conclude that GLUT2 expression in normal beta-cells is promptly down-regulated during exposure to hyperglycemia and may contribute to the loss of glucose-induced secretion of diabetes.

Case report: amelioration of insulin resistance in diabetes with dehydroepiandrosterone.

Buffington CK; Pourmotabbed G; Kitabchi AE
Department of Medicine, University of Tennessee, Memphis.
Am J Med Sci (United States) Nov 1993, 306 (5) p320-4

In hyperandrogenic females, the ratio of dehydroepiandrosterone (DHEA) to testosterone may be an important determinant of insulin sensitivity. This study involved changes in insulin sensitivity and glucose metabolism with therapeutic manipulation of DHEA (S)/testosterone in a female patient with non-insulin-dependent diabetes and hyperandrogenism. Therapeutic intervention included 1-month treatment with 0.25 mg dexamethasone at bedtime and 1-month dexamethasone + DHEA. Insulin sensitivity and glucose tolerance were assessed before and after each treatment regimen by examining: 1) fasting and oral glucose tolerance test glucose and insulin levels, 2) hypoglycemic response to intravenous insulin, and 3) erythrocyte insulin receptor binding. With dexamethasone alone, DHEAS, testosterone, and their ratio were reduced with a concomitant increase (30%) in oral glucose tolerance test insulin levels and a decrease (33%) in erythrocyte insulin binding. With DHEA + dexamethasone, the ratio of DHEAS/testosterone increased 16-fold along with a marked improvement in insulin sensitivity, as determined by a more than 30% reduction in fasting and oral glucose tolerance test insulin levels, a threefold stimulation of the rate of glucose disappearance with intravenous insulin, and a 30% increase in insulin binding. DHEA improved insulin sensitivity and reduced fasting and oral glucose tolerance test glucose levels and ameliorated the diabetic state. The ratio of DHEAS/testosterone is an important regulator of insulin sensitivity and glucose tolerance and that DHEA therapy may be beneficial in the treatment of certain forms of insulin resistance.

Therapeutic effects of dehydroepiandrosterone metabolites in diabetes mutant mice (C57BL/KsJ-db/db).

Coleman DL; Leiter EH; Applezweig N
Endocrinology 1984 Jul;115(1):239-43

Dehydroepiandrosterone (DHEA) fed at 0.4% in the diet is known to exert strong antihyperglycemic effects in C57BL/KsJ genetically diabetic (db/db) mice. Three of the major metabolic products of DHEA; DHEA sulfate, alpha-hydroxyetiocholanolone (alpha-ET), and beta- hydroxyetiocholanolone (beta-ET) when fed at 0.1% in the diet, and one putative product, 17 beta-estradiol, when fed at 0.005% also prevented the development of severe diabetes while having little effect on the amount of food eaten or the rate of weight gain. When suboptimal doses (5-20 micrograms/week) of estradiol were injected in combination with diets containing either alpha-ET or beta-ET, marked potentiating effect was noted, normalization of the hyperglycemia being produced with as little as 0.025% of beta-ET and 0.05% of alpha-ET. The ability of the etiocholanolones to maintain islet integrity and prevent the development of most diabetes symptoms suggests that these metabolites are not merely inactive end products of steroid metabolism, but are physiological effectors in their own right.

The endocrine pancreas in pyridoxine deficient rats.

Toyota T; Kai Y; Kakizaki M; Ohtsuka H; Shibata Y; Goto Y Tohoku
Med (Japan) Jul 1981, 134 (3) p331-6

Because the supplementation of pyridoxine (vitamin B6) improves the glucose tolerance in gestational diabetes and adult onset diabetes, pyridoxine deficiency has been considered to be one of the factors that cause diabetes mellitus. We produced pyridoxine deficient rats by giving pyridoxine-free food with deoxypyridoxine which competitively the activity of pyridoxal phosphate. In these pyridoxine deficient rats plasma insulin during the glucose tolerance test was significantly low as compared with controls. In vitro experiments of pancreas perfusion showed that secretion of insulin and glucagon was impaired in the pyridoxine deficiency. Since the restriction of diet-calorie caused a decrease in arginine- nduced secretion of insulin and glucagon from the isolated pancreas, the impairment of the endocrine pancreas may depend on malnutrition. Pyridoxine deficiency is surely one of the factors that impair the endocrine pancreas by multifactorial derangement of metabolism besides the tryptophan-nicotinic acid pathway.

Vitamin B6 metabolism and diabetes.

Rogers KS; Mohan C
Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907.
Biochem Med Metab Biol (United States) Jun 1994, 52 (1) p10-7

No abstract.

A deficiency of vitamin B6 is a plausible molecular basis of the retinopathy of patients with diabetes mellitus.

Ellis JM; Folkers K; Minadeo M; VanBuskirk R; Xia LJ; Tamagawa H
Department of Medicine, Titus County Hospital, Mt. Pleasant, Texas.
Biochem Biophys Res Commun (United States) Aug 30 1991, 179 (1) p615-9

Eighteen patients with diabetes mellitus, some of whom had variously retinopathy, pregnancy, and the carpal tunnel syndrome, and were variously treated with steroids and vitamin B6, have been overviewed for periods of 8 months to 28 years. We have established an association of a deficiency of vitamin B6 with diabetes by monitoring the specific activity of the erythrocyte glutamic oxaloacetic transaminase and again by the association with the carpal tunnel syndrome (C.T.S.). It has been known for a decade that C.T.S. is caused by a B6 deficiency. The absence of retinopathy in vitamin B6-treated diabetic patients over periods of 8 months - 28 years appears monumental. These observations are like discovery and constitute a basis for a new protocol to establish the apparent relationship of a deficiency of vitamin B6 as a molecular cause of diabetic neuropathy. Blindness and vision are so important that the strength or weakness of the observations are not important; the conduct of a new protocol is important.

Erythrocyte O2 transport and metabolism and effects of vitamin B6 therapy in type II diabetes mellitus.

Solomon LR; Cohen K
Department of Medicine, Veterans Administration Medical Center, West Haven, CT 06516.
Diabetes (United States) Jul 1989, 38 (7) p881-6

The effects of vitamin B6 on erythrocyte metabolism, erythrocyte hemoglobin O2 affinity (P50), and nonenzymatic glycosylation were studied in 15 Caucasian men with type II (non-insulin-dependent) diabetes mellitus. A control group of 13 healthy Caucasian men was also evaluated. Before treatment, diabetic subjects had low mean cell hemoglobin concentration values and increases in both erythrocyte 2,3-diphosphoglycerate (2,3-DPG) levels and erythrocyte hexokinase activities. Although all three of these changes are associated with a decrease in hemoglobin O2 (Hb-O2) affinity, P50 values were normal in diabetic subjects. Moreover, P50 values normalized to pH 7.4 (P50(7.4] were inversely related to the level of glycosylated hemoglobin (HbA1c). Both erythrocyte 2,3-DPG and erythrocyte ATP were also inversely related to HbA1c. Vitamin B6 nutriture, as determined by erythrocyte aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, was normal in all diabetic subjects before vitamin B6 therapy. Nonetheless, HbA1c levels decreased after 6 wk of treatment with 150 mg/day pyridoxine and increased again during placebo administration. These changes were not explained by changes in fasting blood glucose. Pyridoxine therapy also decreased P50(7.4) values and increased erythrocyte AST and ALT activities but had no effect on 2,3-DPG, ATP, or the activities of hexokinase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase. These observations suggest that 1) nonenzymatic glycosylation may play a role in regulating both erythrocyte metabolism and Hb-O2 affinity in diabetic subjects, and 2) vitamin B6 therapy may modify nonenzymatic glycosylation of hemoglobin in this population.

Diabetes and adrenal disease.

Nestler JE; McClanahan MA
Division of Endocrinology and Metabolism, Medical College of Virginia, Richmond 23298-0111.
Baillieres Clin Endocrinol Metab (England) Oct 1992, 6 (4) p829-47

Disorders of the adrenal cortex and medulla can result in glucose intolerance or overt diabetes mellitus. Cushing's syndrome, characterized by excessive secretion of glucocorticoids, impairs glucose tolerance primarily by causing insulin resistance at the post-receptor level. On the other hand, phaeochromocytoma and hyperaldosteronism, via the respective actions of catecholamines and hypokalaemia on the pancreatic beta-cell, impair glucose tolerance primarily by inhibiting insulin release. The glucose intolerance associated with these adrenal disorders is usually only mild to moderate in severity. Marked hyperglycaemia, glycosuria, and polyuria are uncommon and ketosis is rare. Moreover, the late complications of diabetes mellitus are distinctly uncommon in patients with these disorders, and the prognosis for morbidity and death is usually that of the underlying disease and not that of diabetes mellitus. The impaired glucose tolerance induced by all three of these adrenal disorders usually return.

[Preventive treatment of diabetic microangiopathy: blocking the pathogenic mechanisms]

Guillausseau PJ
Service de Medecine B, Hopital Lariboisiere, Paris, France.
Diabete Metab (France) 1994, 20 (2 Pt 2) p219-28

The development of drugs in order to block metabolic pathway of glucose responsible for diabetic vascular dysfunction is in progress. Aldose reductase inhibitors prevent or reduce the different components of vascular dysfunction, cataract, neuropathy and nephropathy in animal models of diabetes. Promising results have been observed in diabetic patients concerning the prevention of neuropathy and of retinopathy. Larger scale studies with the second generation compounds are in progress. Glycation inhibitors, mainly aminoguanidine, have been shown to prevent or reduce vascular dysfunction and microvascular complications in animal models. Trials in diabetic patients with aminoguanidine are just beginning. Anti-oxidant therapy is also at its early stage of development (vitamin E, vitamin C, alpha lipoic acid). Antiplatelet agents (aspirin, ticlopidine) have been demonstrated to reduce the progression of non proliferative diabetic retinopathy. Angiotensin converting enzyme inhibitors are of particular interest in preventing diabetic glomerulopathy. (83 Refs.)

Alternative therapeutic principles in the prevention of microvascular and neuropathic complications.

Gries FA
Diabetesforschungsinstitut an der Heinrich-Heine-Universitat, Dusseldorf, Germany.
Diabetes Res Clin Pract (Ireland) Aug 1995, 28 Suppl pS201-7

Since the prevention of chronic diabetic complications by near normal metabolic control is not always achievable, alternative therapeutic principles have been developed. The specific intervention at metabolic abnormalities which seem to play a key role in the pathogenesis of complications has been shown to prevent the development of microangiopathy and neuropathy in experimental diabetes, e.g. inhibition of non-enzymatic glycation by aminoguanidine, inhibition of polyol pathway activity by aldose reductase inhibitors, prevention of hypoxia and oxidative stress by vasodilators and radical scavengers such as alpha-lipoic acid. Some of these drugs should soon be available for common clinical use. (12 Refs.)

Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid.

Jacob S; Henriksen EJ; Schiemann AL; Simon I; Clancy DE; Tritschler HJ; Jung WI; Augustin HJ; Dietze GJ
Department of Internal Medicine, City Hospital, Baden-Baden, Germany.
Arzneimittelforschung (Germany) Aug 1995, 45 (8) p872-4

Insulin resistance of skeletal muscle glucose uptake is a prominent feature of Type II diabetes (NIDDM); therefore pharmacological interventions should aim to improve insulin sensitivity. Alpha-lipoic acid (CAS 62-46-4, thioctic acid, ALA), a natural occurring compound frequently used for treatment of diabetic polyneuropathy, enhances glucose utilization in various experimental models. To see whether this compound also augments insulin mediated glucose disposal in NIDDM, 13 patients received either ALA (1000 mg/Thioctacid/500 ml NaCl, n = 7) or vehicle only (500 ml NaCl, n = 6) during a glucose-clamp study. Both groups were comparable in age, body-mass index and duration of diabetes and had a similar degree of insulin resistance at baseline. Acute parenteral administration of ALA resulted in a significant increase of insulin-stimulated glucose disposal; metabolic clearance rate (MCR) for glucose rose by about 50% (3.76 ml/kg/min = pre vs. 5.82 ml/kg/min = post, p < 0.05), whereas the control group did not show any significant change (3.57 ml/kg/min = pre vs. 3.91 ml/kg/min = post). This is the first clinical study to show that alpha-lipoic acid increases insulin stimulated glucose disposal in NIDDM. The mode of action of ALA and its potential use as an antihyperglycemic agent require further investigation.

Inhibition with N-acetylcysteine of enhanced production of tumor necrosis factor in streptozotocin-induced diabetic rats.

Sagara M; Satoh J; Zhu XP; Takahashi K; Fukuzawa M; Muto G; Muto Y; Toyota T
Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Clin Immunol Immunopathol (United States) Jun 1994, 71 (3) p333-7

We previously reported that the in vivo production of the tumor necrosis factor alpha (TNF) was significantly enhanced after the onset of diabetes in spontaneous type 1 and 2 diabetic animals. In this report we confirmed the enhanced production of TNF in streptozotocin (STZ)-induced diabetes and then attempted to suppress the enhanced TNF production with N-acetylcysteine (NAC), a precursor of glutathione synthesis. The lipopolysaccharide-induced serum TNF activities were significantly enhanced in STZ-induced diabetic rats (6-18 weeks of age) compared with those of nondiabetic rats throughout the 12-week experiment. A single, oral administration of NAC (200 or 1000 mg/kg body wt) significantly suppressed the enhanced TNF production in the diabetic rats compared with that in untreated rats in a dose-dependent manner. On the other hand, in the long-term (6 or 12 weeks) administrations, smaller doses of NAC (50 or 200 mg/kg/day) also significantly inhibited the enhanced production of TNF regardless of the dose of NAC. NAC administration, however, did not suppress the TNF production of nondiabetic rats. The long-term NAC administration affected neither body weight nor levels of serum glucose, fructosamine, albumin, and triglyceride. These results show that NAC administration significantly suppressed the enhanced TNF production in diabetic rats and indicate that NAC might be useful in preventing TNF-mediated pathological conditions in diabetes.

Effects of acetyl- and proprionyl-L-carnitine on peripheral nerve function and vascular supply in experimental diabetes.

Cotter MA; Cameron NE; Keegan A; Dines KC
Department of Biomedical Sciences, University of Aberdeen, Scotland, UK.
Metabolism (United States) Sep 1995, 44 (9) p1209-14

L-Carnitine metabolism is abnormal in diabetes mellitus, and treatment with acetyl-L-carnitine (ALC) improves the function of cardiac muscle, retina, and peripheral nerve in experimental models. The aim was to compare the effects of ALC and proprionyl-L-carnitine (PLC) on motor and sensory nerve conduction in streptozotocin-diabetic rats and to ascertain whether their action could be mediated by a vascular mechanism. ALC and PLC treatment for 2 months after diabetes induction attenuated the development of sciatic motor nerve conduction velocity (NCV) deficits by 59.4% +/- 4.4% and 46.9% +/- 3.2%, respectively. There was a similar level of protection for sensory saphenous NCV (42.9% +/- 6.6% and 47.8% +/- 6.0%, respectively). Neither ALC nor PLC prevented the development of resistance to hypoxic conduction failure (RHCF) in sciatic nerve from diabetic rats. A 46.5% +/- 3.4% deficit in sciatic endoneurial blood flow, measured by microelectrode polarography and hydrogen clearance, in diabetic rats was partially prevented by both ALC (48.7% +/- 6.4%) and PLC (69.4% +/- 10.1%). ALC had no significant effect on blood flow in nondiabetic rats. Thus, the data show that these L-carnitine derivatives have a similar efficacy in preventing nerve dysfunction, which depends on a neurovascular action.

Acetyl-L-carnitine for symptomatic diabetic neuropathy [letter]

Quatraro A; Roca P; Donzella C; Acampora R; Marfella R; Giugliano D
Diabetologia (Germany) Jan 1995, 38 (1) p123

No abstract.

Peptide alterations in autonomic diabetic neuropathy prevented by acetyl-L-carnitine.

Gorio A; Di Giulio AM; Tenconi B; Donadoni L; Germani E; Bertelli A; Mantegazza P; Maccari F; Ramacci MT
Department of Medical Pharmacology, Faculty of Medicine, University of Milan, Italy.
Int J Clin Pharmacol Res (Switzerland) 1992, 12 (5-6) p225-30

Autonomic neuropathy and gastrointestinal problems are among the most common complications of diabetes. In this report it is shown that a possible correlation between the two disorders might exist, since diabetes causes a profound alteration of the peptidergic innervation of the gut. It is reported that 14 weeks after diabetes induction with alloxan the levels of substance P and methionine-enkephalin are markedly reduced throughout the intestine, while vasoactive intestinal polypeptide content is dramatically increased. Therefore the enteric innervation of diabetic animals is completely disorganized, with some systems undergoing atrophy and others undergoing hypertrophy. Treatment of diabetic animals with acetyl-L-carnitine prevents the onset of the marked peptide changes described above. The results suggest a potential for acetyl-L-carnitine in the treatment of autonomic neuropathies.

Prevention of cardiovascular and renal pathology of aging by the advanced glycation inhibitor aminoguanidine.

Li YM; Steffes M; Donnelly T; Liu C; Fuh H; Basgen J; Bucala R; Vlassara H
Picower Institute for Medical Research, Manhasset, NY 11030, USA.
Proc Natl Acad Sci U S A (United States) Apr 30 1996, 93 (9) p3902-7

Human aging is impacted severely by cardiovascular disease and significantly but less overtly by renal dysfunction. Advanced glycation endproducts (AGEs) have been linked to tissue damage in diabetes and aging, and the AGE inhibitor aminoguanidine (AG) has been shown to inhibit renal and vascular pathology in diabetic animals. In the present study, the effects of AG on aging-related renal and vascular changes and AGE accumulation were studied in nondiabetic female Sprague-Dawley (S-D) and Fischer 344 (F344) rats treated with AG (0.1% in drinking water) for 18 mo. Significant increases in the AGE content in aged cardiac (P < 0.05), aortic (P < 0.005), and renal (P < 0.05) tissues were prevented by AG treatment (P < 0.05 for each tissue). A marked age-linked vasodilatory impairment in response to acetylcholine and nitroglycerine was prevented by AG treatment (P < 0.005), as was an age-related cardiac hypertrophy evident in both strains (P < 0.05). While creatinine clearance was unaffected by aging in these studies, the AGE/ creatinine clearance ratio declined 3-fold in old rats vs. young rats (S-D, P < 0.05; F344, P < 0.01), while it declined significantly less in AG-treated old rats (P < 0.05). In S-D but not in F344 rats, a significant (P < 0.05) age-linked 24% nephron loss was completely prevented by AG treatment, and glomerular sclerosis was markedly suppressed (P < 0.01). Age-related albuminuria and proteinuria were markedly inhibited by AG in both strains (S-D, P < 0.01; F344, P < 0.01). These data suggest that early interference with AGE accumulation by AG treatment may impart significant protection against the progressive cardiovascular and renal decline afflicting the last decades of life.

Prevention of long-term complications of non-insulin-dependent diabetes mellitus.

Nathan DM
Harvard Medical School, Diabetes Clinic, Massachusetts General Hospital, Boston, Mass., USA
Clin Invest Med (Canada) Aug 1995, 18 (4) p332-9

Non-insulin-dependent diabetes mellitus (NIDDM) may be the most rapidly-growing chronic disease in the world. Its long-term complications, including retinopathy, nephropathy, neuropathy, and accelerated macrovascular disease cause major morbidity and mortality. Although therapy that normalizes glycemia may prevent the development and delay the progression of long-term complications in NIDDM, as has been demonstrated in insulin-dependent diabetes mellitus (IDDM), no direct data exist to support the efficacy of "intensive therapy" in NIDDM. An alternative approach to preventing the development of long-term complications may be to intervene more distally, i.e., inhibit the mechanism(s) by which elevated glucose levels cause complications. Potential pathogenic mechanisms include the accumulation of sorbitol and other biochemical changes in tissues with aldose reductase, and the modification of proteins by glycation. Pharmacologic probes, including aldose reductase inhibitors and glycation inhibitors such as aminoguanidine, are currently under study and may provide an efficient means of preventing complications, independent of the ambient glycemic level. (44 Refs.)

Secondary intervention with aminoguanidine retards the progression of diabetic retinopathy in the rat model.

Hammes HP; Strodter D; Weiss A; Bretzel RG; Federlin K; Brownlee M
Third Medical Department, Justus-Liebig-University, Giessen, Germany.
Diabetologia (Germany) Jun 1995, 38 (6) p656-60

Primary prevention with aminoguanidine-an inhibitor of advanced glycation end product (AGE) formation--has been successfully employed to prevent diabetic retinopathy in the rat. However, it is unknown whether inhibition of AGE formation is still effective in a secondary intervention strategy. The present study addresses this question by comparing secondary intervention with aminoguanidine with syngeneic islet transplantation in the rat model. After 6 months of diabetes, one group was treated with aminoguanidine (50 mg/100 ml drinking water; D-AG) while another group received syngeneic transplantation of collagenase-ficoll isolated islets by intraportal injection (Tx). After an additional 4 months, both groups were compared to a normal (NC 10) and diabetic (DC 10) control group. Retinal autofluorescence was increased 2.5-fold after 6 months and increased 3.7-fold after 10 months of diabetes (p < 0.001). Aminoguanidine and islet Tx retarded the further accumulation of autofluorescence equally (p < 0.001 vs DC 10), although the values were higher than those observed in DC at 6 months (p < 0.001). Diabetes was associated with a 2.7-fold increase in acellular capillaries after 6 months and a 4.1-fold increase after 10 months. Treatment with aminoguanidine or islet Tx reduced but did not completely attenuate the progression of vascular occlusion (p < 0.001 vs DC 10; D-AG vs DC 6, p < 0.05; Tx vs DC 6, p < 0.01). Both treatments reduced endothelial proliferation (22.4% after 10 months; p < 0.001) and completely arrested pericyte dropout (40% after 10 months; p < 0.001).

Prevention of glomerular basement membrane thickening by aminoguanidine in experimental diabetes mellitus.

Ellis EN; Good BH
Department of Pediatrics, University of Arkansas for Medical Science, Little Rock.
Metabolism (United States) Oct 1991, 40 (10) p1016-9

The etiology of diabetic glomerulopathy appears to be related, at least in part, to the degree of hyperglycemia, the resultant nonenzymatic glycosylation of proteins, and the eventual formation of advanced glycosylation end products in long-lived structural proteins. To investigate the relationship between the glomerular basement membrane (GBM) changes of diabetic nephropathy and the formation of advanced glycosylation end products, we studied control rats, diabetic rats, and control and diabetic rats who received aminoguanidine, a compound that pharmacologically inhibits formation of advanced glycosylation end products. After 9 months, rat weight was smaller and kidney weight larger in both diabetic groups compared with both control groups. GBM width was increased in the diabetic group compared with the control group. Aminoguanidine administration to diabetic rats ameliorated this increase in GBM. Thus, aminoguanidine administration from the onset of experimental diabetes prevented the widening of the GBM that is typical of diabetes.

Can metformin reduce insulin resistance in polycystic ovary syndrome?

Acbay O; Gundogdu S
Department of Internal Medicine, Cerrahpasa Medical Faculty of Istanbul University, Turkey.
Fertil Steril (United States) May 1996, 65 (5) p946-9

OBJECTIVE: To examine whether metformin is able to reduce insulin resistance in polycystic ovary syndrome (PCOS).

DESIGN: Single-blind study comprising two successive periods of treatment: 8 weeks of placebo and 10 weeks of metformin (orally, 850 mg twice daily).

SETTING: Clinic of endocrinology and metabolism of Cerrahpasa Medical Faculty at Istanbul University, Istanbul, Turkey.

PATIENTS: Sixteen insulin-resistant women with PCOS.

INTERVENTIONS: Insulin sensitivity (with an IV insulin tolerance test), plasma glucose and insulin levels during an oral glucose tolerance test (OGTT), serum androgens, and lipids were measured at baseline and after each treatment period.

RESULTS: Insulin sensitivity, the mean fasting serum levels of glucose, insulin, total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total T, free T, androstenedione, DHEAS, and LH:FSH ratio, and the areas under the curve for plasma glucose and insulin during OGTT were not changed.

Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women.

Crave JC; Fimbel S; Lejeune H; Cugnardey N; Dechaud H; Pugeat M
Hospices Civils de Lyon, Laboratoire de la Clinique Endocrinologique, Hopital de l'Antiquaille, France.
J Clin Endocrinol Metab (United States) Jul 1995, 80 (7) p2057-62

Evidence suggests that hyperinsulinemic insulin resistance may increase serum levels of ovarian androgens and reduce sex hormone-binding globulin (SHBG) levels in humans. The present study was conducted to assess the effect of administration of the biguanide metformin, a drug commonly used in the treatment of diabetes mellitus, on androgen and insulin levels in 24 hirsute patients. The patients selected for the study were obese, with a body mass index higher than 25 kg/m2 and high fasting insulin (> 90 pmol/L) and low SHBG levels (< 30 nmol/L). All patients were given a low calorie diet (1500 Cal/day) and randomized for either metformin administration at a dose of 850 mg or a placebo, twice daily for 4 months, in a double blind study. In the placebo group, diet resulted in a significant decrease in body mass index (30.8 +/- 1.0 vs. 32.7 +/- 1.5 kg/m2; P < 0.0001), fasting insulin (127 +/- 11 vs. 156 +/- 14 pmol/L; P < 0.01), non-SHBG-bound testosterone (0.19 +/- 0.02 vs. 0.28 +/- 0.03 nmol/L; P < 0.02), androstenedione (5.8 +/- 0.5 vs. 9.0 +/- 1.1 nmol/L; P < 0.03), and 3 alpha-diolglucuronide (8.6 +/- 1.1 vs. 11.7 +/- 1.9; P < 0.005) plasma concentrations and a significant increase in the glucose/insulin ratio (0.047 +/- 0.005 vs. 0.035 +/- 0.003; P < 0.001) and plasma concentrations of SHBG (26.0 +/- 3.3 vs. 19.1 +/- 1.9 nmol/L; P < 0.001) and dehydroepiandrosterone sulfate (8.7 +/- 1.5 vs. 8.4 +/- 1.3; P < 0.05). Beneficial effects of diet were not significantly different in the patients who were given metformin instead of placebo. These results confirm that weight loss induced by a low calorie diet is effective in improving hyperinsulinemia and hyperandrogenism in obese and hirsute women. With our study design, metformin administration had no additional benefit over the effect of diet.

[The value of metformin in therapy of type 2 diabetes: effect on insulin resistance, diabetic control and cardiovascular risk factors]

Schernthaner G
Medizinische Abteilung, Krankenanstalt Rudolfstiftung, Wien.
Wien Klin Wochenschr (Austria) 1994, 106 (24) p793-802

In this review article recently published controlled clinical studies of metformin treatment in type-2 diabetic patients are summarized. Several studies demonstrate that body weight decreases and insulin resistance improves--as evaluated by peripheral glucose utilisation--under metformin treatment. HbA1c is lowered by approximately 20% (absolute decrease of HbA1c: 1.0%-1.5%). Since plasma lipid values and plasminogen-activator-inhibitor (PAI-1) concentrations are also lowered under metformin therapy, it currently represents the treatment of choice for the obese group of type-2 diabetic patients. (104 Refs.)

Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus.

Cohen N; Halberstam M; Shlimovich P; Chang CJ; Shamoon H; Rossetti L
Department of Medicine, Albert Einstein College of Medicine, New York 10461, USA.
J Clin Invest (United States) Jun 1995, 95 (6) p2501-9

We examined the in vivo metabolic effects of vanadyl sulfate (VS) in non-insulin-dependent diabetes mellitus (NIDDM). Six NIDDM subjects treated with diet and/or sulfonylureas were examined at the end of three consecutive periods: placebo for 2 wk, VS (100 mg/d) for 3 wk, and placebo for 2 wk. Euglycemic hyperinsulinemic (30 mU/m2.min) clamps and oral glucose tolerance tests were performed at the end of each study period. Glycemic control at baseline was poor (fasting plasma glucose 210 +/- 19 mg/dl; HbA1c 9.6 +/- 0.6%) and improved after treatment (181 +/- 14 mg/dl [P < 0.05], 8.8 +/- 0.6%, [P < 0.002]); fasting and post-glucose tolerance test plasma insulin concentrations were unchanged. After VS, the glucose infusion rate during the clamp was increased (by approximately 88%, from 1.80 to 3.38 mg/kg.min, P < 0.0001). This improvement was due to both enhanced insulin-mediated stimulation of glucose uptake (rate of glucose disposal [Rd], +0.89 mg/kg.min) and increased inhibition of HGP (-0.74 mg/kg.min) (P < 0.0001 for both). Increased insulin-stimulated glycogen synthesis (+0.74 mg/kg.min, P < 0.0003) accounted for > 80% of the increased Rd after VS, and the improvement in insulin sensitivity was maintained after the second placebo period. The Km of skeletal muscle glycogen synthase was lowered by approximately 30% after VS treatment (P < 0.05). These results indicate that 3 wk of treatment with VS improves hepatic and peripheral insulin sensitivity in insulin-resistant NIDDM humans. These effects were sustained for up to 2 wk after discontinuation of VS.

Toxicity studies on one-year treatment of non-diabetic and streptozotocin-diabetic rats with vanadyl sulphate.

Dai S; Thompson KH; Vera E; McNeill JH
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Pharmacol Toxicol (Denmark) Nov 1994, 75 (5) p265-73

Streptozotocin-diabetic and non-diabetic rats were given vanadyl sulphate in drinking water at concentrations of 0.5-1.5 mg/ml for one year. It was found that vanadyl treatment did not produce persistent changes in plasma aspartate aminotransferase, alanine aminotransferase, and urea, specific morphological abnormalities in the brain, thymus, heart, lung, liver, spleen, pancreas, kidney, adrenal, or testis, or abnormal organ weight/body weight ratio for these organs in either non-diabetic or diabetic animals. Treatment significantly reduced the incidence of the occurrence of urinary stones in non-diabetic rats. In diabetic animals vanadyl treatment significantly reduced the mortality rate and prevented the elevation of plasma levels of alanine aminotransferase and urea, the increases in organ size, and the occurrence of megacolon but did not affect the development of renal and testicular tumours. Plasma and tissue concentrations of vanadium were determined and found to have the following order of distribution: bone > kidney > testis > liver > pancreas > plasma > brain. Vanadium was retained in these organs at 16 weeks following vanadyl withdrawal while the plasma levels were beneath detection limits. It is concluded that vanadyl sulphate at antidiabetic doses is not significantly toxic to rats following a one-year administration in drinking water, but vanadium may be retained in various organs for months after cessation of treatment.

Antidiabetic action of vanadyl in rats independent of in vivo insulin-receptor kinase activity.

[No author listed]
Diabetes (United States) Apr 1991, 40 (4) p492-8

The effects of oral vanadyl sulfate administration for 9-12 days on carbohydrate and lipid metabolism in the basal state and on glucose dynamics during submaximal hyperinsulinemic clamps were investigated in nondiabetic and streptozocin-induced diabetic rats. Decreases in growth rate and water and food consumption were the only significant alterations noted in control animals receiving vanadyl. Administration of vanadyl to diabetic rats resulted in weight loss; a significant decrease in plasma glucose, triglyceride, and cholesterol levels; and decreases in food and water intake, without a concomitant change in plasma insulin concentrations. Vanadyl treatment did not modify either peripheral glucose utilization or hepatic glucose production in control rats during submaximal insulin clamps. In contrast, vanadyl therapy increased insulin-induced glucose utilization significantly and had a small but nonsignificant effect on insulin-mediated suppression of glucose production in diabetic rats. The tyrosine kinase activity of liver- and muscle-derived insulin receptors from diabetic rats that underwent clamp study, which reflected the in vivo phosphorylation state of insulin receptor, was not altered by vanadyl treatment. In conclusion, these results show that augmentation of peripheral glucose utilization is the major determinant of the antidiabetic action of vanadyl and support the notion that the action of vanadyl is independent of insulin-receptor kinase activity.

A high biotin diet improves the impaired glucose tolerance of long-term spontaneously hyperglycemic rats with non-insulin-dependent diabetes mellitus

Zhang H.; Osada K.; Maebashi M.; Ito M.; Komai M.; Furukawa Y.
H. Zhang, Laboratory of Nutrition, Dept. Applied Biological Chemistry, Faculty of Agriculture, Sendai 981 Japan
Journal of Nutritional Science and Vitaminology (Japan), 1996, 42/6 (517-526)

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat, serving as a spontaneously diabetic model with non-insulin-dependent diabetes mellitus (NIDDM),exhibits impaired glucose tolerance (IGT) at about 16 weeks of age. In this study, we investigated whether or not biotin, a water-soluble vitamin, improved the IGT of OLETF rats. To this end, we administered diets containing one of three levels of biotin, a high-biotin diet (BH), a normal-biotin diet (BN) and a basal-biotin diet (BB), to OLETF rats up to 24 weeks of age. An oral glucose tolerance test (OGTT) was performed four times between 13 and 22 weeks of age. The administration of a BH corrected the IGT of OLETF rats. Upon further investigation, we found that insulin secretion in the OLETF-BH rats was decreased to a significant extent, signaling that the hyperinsulinemia typical to the OLETF-BH rats had clearly improved. Body weights were significantly lower in the OLETF-BH group than in the other OLETF groups, even though the OLETF-BH rats showed a significantly higher average daily food intake. The body weight gain of the OLETF-BH rats followed the same tendency as the control-LETO (Long Evans Tokushima Otsuka) rats (LETO-BB and LETO-BN). These results demonstrate that a high-level biotin diet can improve the glucose handicap in NIDDM rats.

Oral glucose tolerance test after high-dose i.v. biotin administration in normoglucemic hemodialysis patients

Koutsikos D.; Fourtounas C.; Kapetanaki A.; Agroyannis B.; Tzanatos H.; Rammos G.; Kopelias I.; Bosiolis B.; Bovoleti O.; Darema M.; Sallum G.
Aretaieon University Hospital, 76, Vas. Sofias AVE, 115 28 Athens Greece
Renal Failure (USA), 1996, 18/1 (131-137)

Abnormal glucose metabolism in uremia may result from a complex interplay between decreased insulin secretion and insulin resistance. Recent studies report beneficial effect of biotin administration in glucose metabolism in diabetic animals and in a small number of patients with diabetes mellitus. The aim of the present study was to evaluate the response of oral glucose tolerance test (OGTT) to the i.v. administration of large doses of biotin in hemodialysis patients. Eleven hemodialysis patients aged 56.90 plus or minus 11.20 (32- 76) years on regular hemodialysis thrice a week for 2.72 plus or minus 1.79 (1-7) years were studied. Fasting venous plasma glucose, glucosylated hemoglobin (%GH), and plasma glucose concentration 2 h after the administration of a 75-g glucose load were measured before, and 2 weeks and 2 months after administration of 50 mg of biotin i.v. postdialysis, and after a 2-month washout period. During the study, dialysis schedule and patients' medication, diet, and dry weight were kept unchanged. OGTT was abnormal in 4 patients before biotin administration and became normal in 3 patients (75%). Our results offer support to the findings of other studies about the beneficial effect of biotin in experimental or clinical diabetes mellitus, and argue for the involvement of biotin in glucose metabolism.

Transcriptional regulation of liver phosphoenolpyruvate carboxykinase by biotin in diabetic rats

Dakshinamurti K.; Li W.
Biochemistry/Molecular Biology Dept., University of Manitoba, Winnipeg, Man. R3E OW3 Canada
Mol Cell Biochem 1994 Mar 30;132(2):127-32

Rat liver phosphoenolpyruvate carboxykinase (PEPCK) activity was followed over a time period of 5 h following administration of biotin to streptozotocin-induced diabetic rats. In parallel with the decrease in enzyme activity liver PEPCK mRNA decreased by 85% at 3 h after injection of biotin to diabetic rats. There was no significant change in the accumulation of kidney PEPCK mRNA. Parallel studies with insulin indicated that biotin had a regulatory effect similar to that of insulin on liver PEPCK mRNA. The administration of biotin did not change the insulin status of the diabetic rat indicating that biotin did not act via insulin. The transcriptional activity of the hepatic PEPCK gene, as measured by nuclear run-on assay; was decreased by 57% within 30 min of biotin administration. The results suggest that biotin regulates hepatic, but not renal, PEPCK mRNA concentration at the transcriptional level in diabetic rats.

Effect of biotin on the regulation of glucokinase in the intact rat

Hsieh Y.T.L.; Mistry S.P.
Department of Poultry/Avian Sciences, Institute of Food Science, Cornell University, Ithaca, NY 14853-5601 USA
Nutr. Res. (USA), 1992, 12/6 (787-799)

Glucokinase activity was affected by hormones, dietary state, and dietary sources (e.g., glucose). Therefore, various factors (such as glucose, insulin, and biotin) affecting glucokinase activity in the rat liver were investigated. The activity of glucokinase was low in diabetic, fasting, and/or biotin-deficient rats. In the present study, the de novo synthesis of the glucokinase induced by the insulin and biotin in the intact rat was proposed. The first induction of glucokinase was activated by insulin. The second phase of enzyme activity could be induced by biotin. In addition, supplementation of cGMP with glucose and insulin to biotin deficient rats fully restored the enzyme activity as did biotin, showing that cGMP induction of glucokinase was dependent on the biotin status of the animal.

Biotin supplementation improves glucose and insulin tolerances in genetically diabetic KK mice

Reddi A.; DeAngelis B.; Frank O.; Lasker N.; Baker H.
Department of Medicine, Division of Nephrology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07107-3006 USA
Life Sci 1988;42(13):1323-30

Because biotin treatment may lower blood glucose in insulin-dependent diabetes, we chose to study such an effect in non-insulin dependent diabetes. Twenty-six diabetic KK mice, moderately hyperglycemic and insulin resistant, were treated for 10 weeks: 9 animals with 2 mg of biotin/Kg, 8 with 4 mg of biotin/Kg, and 9 with saline (controls). Blood glucose levels, oral glucose tolerance, insulin response to oral glucose, and blood glucose decrease in response to insulin were quantitated. Compared to controls, biotin treatment lowered post-prandial glucose levels, and improved tolerance to glucose and insulin resistance. Serum immunoreactive insulin levels in biotin-treated mice were like the controls.

Biotin administration improves the impaired glucose tolerance of streptozotocin-induced diabetic Wistar rats.

Zhang H, Osada K, Sone H, Furukawa Y
Department of Applied Biological Chemistry, Faculty of Agriculture Tohoku University Sendai Japan.
J Nutr Sci Vitaminol (Tokyo) 1997 Jun;43(3):271-80

The effect of biotin administration on the glucose tolerance of streptozotocin (STZ)-induced diabetic Wistar rats was investigated. STZ-induced diabetes was induced by intraperitoneal injection of streptozotocin (45 mg/kg body weight as a single dose). The impaired glucose tolerance in response to an oral glucose load (1.8g per kg body weight) in STZ-induced diabetic rats (STZ-rat) was partially improved by intraperitoneal administration of biotin for 15 days (100 micrograms/rat/day). However, a recovery in the STZ-rat's insulin secretion was not found after biotin administration. To help clarify the mechanism underlying the improvement in glucose tolerance seen with biotin treatment, glucokinase and hexokinase activities were determined in the liver and pancreas. In STZ-rats that had received biotin (STZ-biotin rats), glucokinase activity was higher by 3.4-fold in liver and by 2.4-fold in pancreas than in the STZ-rats. The biotin level of STZ-rats was significantly lower in the liver and pancreas than that of the control rats (no STZ administration); but in STZ-biotin rats, the level in these organs recovered to the control level. These results demonstrate that injected biotin can improve glucose handling without increasing insulin secretion in STZ-rats.

Biotin for diabetic peripheral neuropathy.

Koutsikos D, Agroyannis B, Tzanatos-Exarchou H
University of Athens, Aretaieon University Hospital Greece.
Biomed Pharmacother 1990;44(10):511-4

Biotin in high doses was given for 1-2 years to three diabetic patients suffering from severe diabetic peripheral neuropathy. Within 4-8 weeks there was a marked improvement in clinical and laboratory findings. It is suggested that in diabetes may exist a deficiency, inactivity or unavailability of Biotin, resulting in disordered activity of biotin-dependent enzyme, pyruvate carboxylase, leading to accumulation of pyruvate and/or depletion of aspartate, both of which play a significant role in nervous system metabolism. Based on our good results, regular biotin administration could be suggested for every diabetic patient for the prevention and management of peripheral neuropathy although extensive randomised clinical trials are required.

Tissue concentrations of water-soluble vitamins in normal and diabetic rats.

Reddi AS, Jyothirmayi GN, DeAngelis B, Frank O, Baker H
Department of Medicine, UMDNJ-New Jersey Medical School Newark 07103.
Int J Vitam Nutr Res 1993;63(2):140-4

Changes in circulating and tissue concentrations of several vitamins have been reported in diabetic animals and human subjects. In this study, the effect of short-term (2 weeks) streptozotocin diabetes on folate, B6, B12, thiamin, nicotinate, pantothenate, riboflavin and biotin in liver, kidney, pancreas, heart, brain and skeletal muscle of rats was investigated. The tissue distribution of vitamins varied widely in normal rats. Diabetes significantly lowered folate in kidney, heart, brain, and muscle; B6 in brain; B12 in heart; thiamin in liver and heart; nicotinate in liver, kidney, heart and brain; pantothenate in all tissues; riboflavin in liver, kidney, heart, and muscle. These results indicate that experimental diabetes causes a depression of several water-soluble vitamins in various tissues of rats.