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.