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.

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