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.

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