[Reappraisal of metformin : less restrictions and more potential indications]. / La metformine revisitée : moins de restrictions et davantage d'indications.

While commercialized since over 60 years, metformin is still the first-line drug recommended for the management of type 2 diabetes and is thus today the first glucose-lowering agent used worldwide. Despite this long experience, metformin retains its mysteries, especially regarding the underlying mechanisms responsible for its antidiabetic activity and other potential beneficial effects. During the last years, some contra-indications of metformin use have been at least partially withdrawn while new indications have been recognized. Furthermore, interesting prospects have been reported in important, although unexpected, medical areas such as cancer and neurodegenerative diseases. However, promising results in animal studies and observational human studies have now to be confirmed in well conducted randomized controlled trials.

Commercialisée depuis plus de 60 ans, la metformine est recommandée en première intention dans le traitement du diabète de type 2, ce qui en fait, aujourd'hui, le médicament anti-hyperglycémiant le plus prescrit à travers le monde. Malgré cette longue expérience, la metformine garde ses mystères, notamment quant aux mécanismes qui sous-tendent son action antidiabétique et d'autres effets potentiels. Au cours des dernières années, certaines contre-indications à l'utilisation de la metformine ont été, au moins partiellement, levées tandis que de nouvelles indications apparaissent avec, par ailleurs, des perspectives intéressantes dans des domaines aussi importants qu'inattendus, comme le cancer ou les maladies neurodégénératives. Les résultats prometteurs des études animales et des études observationnelles humaines doivent cependant être vérifiés dans des essais d'intervention contrôlés bien conduits.

[Clinical approach of a suspicion of hypoglycaemic malaise in a nondiabetic adult]. / La vignette diagnostique de l'étudiant Mise au point d'une suspicion de malaise hypoglycémique chez une personne adulte non diabétique.

Malaises are often attributed to hypoglycaemia in nondiabetic people who don't have any other serious medical problem. However, such a diagnosis is often overused, because not really demonstrated in most instances. The diagnosis of hypoglycaemia should be structured, based upon the Whipple triad. First, the anamnesis must search for adrenergic and neuroglucopenic symptoms that suggest hypoglycaemia. Afterwards, hypoglycaemia must be authentified by a measurement of a low glucose level at the time of a malaise. Finally, if the malaise is due to a hypoglycaemia, it should resume rapidly after the administration of sugar. When the diagnosis is made based upon this triad, the medical interview should precise the severity of the symptoms and focus on the chronology of the malaises, after meal or in the fasting state, which is crucial to differentiate functional reactice hypoglycaemia from hypoglycaemia due to an insulinoma. Finally, additional medical examinations may be performed, first based upon clinical biology followed, if necessary, by medical imaging. They will not only confirm the diagnosis of hypoglycaemia, but also contribute to find the cause of hypoglycaemia, which will help in choosing the therapeutic strategy.

Résumé : La survenue de malaises est souvent attribuée à une hypoglycémie chez des personnes non diabétiques et, a priori, sans autre problème de santé. Ce diagnostic est, cependant, souvent galvaudé, car habituellement non clairement démontré. Le diagnostic d'hypoglycémie doit se faire de façon structurée en se basant sur la triade de Whipple. Tout d'abord, l'anamnèse doit rechercher les symptômes évocateurs d'hypoglycémie, adrénergiques et neuroglucopéniques. Ensuite, l'hypoglycémie doit être authentifiée par une mesure d'une valeur basse au moment d'un malaise. Enfin, s'il s'agit bien d'une hypoglycémie, le malaise doit disparaître rapidement après resucrage. Une fois le diagnostic posé sur la base de cette triade, l'anamnèse doit faire préciser, outre la sévérité des malaises, leur chronologie, après les repas ou à jeun, ce qui oriente vers une hypoglycémie réactive, fonctionnelle, ou vers une hypoglycémie d'origine organique (insulinome). Des examens complémentaires, faisant d'abord appel à la biologie clinique, ensuite éventuellement à l'imagerie médicale, permettront de, non seulement confirmer le diagnostic d'hypoglycémie, mais aussi d'en préciser l'origine, ce qui orientera la stratégie thérapeutique.

Inhibiting or antagonizing glucagon: making progress in diabetes care.

Absolute or relative hyperglucagonaemia has been recognized for years in all experimental or clinical forms of diabetes. It has been suggested that excess secretion of glucagon by the islet α cells is a direct consequence of intra-islet insulin secretory defects. Recent studies have shown that knockout of the glucagon receptor or administration of a monoclonal specific glucagon receptor antibody make insulin-deficient type 1 diabetic rodents thrive without insulin. These observations suggest that glucagon plays an essential role in the pathophysiology of diabetes and that targeting the α cell and glucagon are innovative approaches in the management of diabetes. Despite active research and identification of promising compounds, no one selective glucagon antagonist is presently used in the treatment of diabetes. Interestingly, besides insulin, several drugs used today in the management of diabetes appear to exert their effects, in part, by inhibiting glucagon secretion (glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors and, possibly, sulphonylureas) or glucagon action (metformin). The potential risks associated with total glucagon suppression include α-cell hyperplasia, increased mass of the pancreas, increased susceptibility to hepatosteatosis and hepatocellular injury and increased risk of hypoglycaemia, and these should be considered in the search and development of new compounds reducing glucagon receptor signalling. More than 40 years after its initial description, hyperglucagonaemia in diabetes can no longer be ignored or minimized, and its correction represents an attractive way to improve diabetes management.

Early milestones in glucagon research.

As an introduction to the Symposium, we have reviewed the early steps in glucagon research from its discovery in 1923 to the establishment of the basics of the physiology and pathophysiology of the hormone after the description of a sensitive and specific radioimmunoassay by Unger and his co-workers in 1959.

[Cardiovascular prevention: could the polypill reduce the risk of clinical inertia and poor compliance?]. / Prévention cardio-vasculaire: la "polypill", une solution pour vaincre l'inertie clinique et le manque d'observance?

The concept of "polypill" for cardiovascular prevention was introduced in 2003 in a landmark paper of the British Medical Journal. A model based on results provided by evidence-based medicine suggested that a "polypill", that contains a statin, three blood pressure lowering drugs (each at half standard dose), aspirin and folic acid, would result in an 80% reduction in the incidence of coronary and cerebrovascular events, while being associated with a good tolerance profile and offering a favourable cost-effectiveness ratio. The present paper aims at presenting the new advances dealing with this new paradigm in cardiovascular prevention. We will present the progresses of the "polypill" concept since 2003, the results of a first controlled clinical trial, the pharmaceutical feasibility for routine clinical use and the potential pharmaco-economical impacts of such a strategy. The "polypill" may offer a solution to avoid physician's clinical inertia and reduce patients's lack of compliance, two drawbacks in the field of cardiovascular prevention.

[Insulin glargine and cancer: a storm in a glass of water?]. / Insuline glargine et cancer: une tempête dans un verre d'eau?

Insulin glargine is widely used as basal insulin in the treatment of type 1 and type 2 diabetes mellitus. However, this insulin analogue has been recently suspected to be associated with an increased risk of cancer, especially breast cancer, in patients with type 2 diabetes. The present article aims at briefly presenting the state of the art based upon currently available data. We will first summarize the observations reported in recent publications, then we will present a critical analysis of these in fact non-conclusive findings, and finally we will conclude with some practical recommendations.

[United Kingdom Prospective Diabetes Study (UKPDS): 10 years later]. / L'étude clinique du mois. "United Kingdom Prospective Diabetes Study": 10 ans plus tard.

A 10-year post-trial monitoring of patients with newly diagnosed type 2 diabetes randomised in the "United Kingdom Prospective Diabetes Study" (UKPDS) demonstrated a continued reduction in microvascular risk (-24%, p = 0.001) and emergent risk reductions for myocardial infarction (-15%, p = 0.01) and death from any cause (-13%, p = 0.007), despite an early loss of glycaemic differences ("legacy effect"). A continued benefit after metformin therapy was evident during the ten-year post-trial follow-up among overweight patients (-33%, p = 0.005 for myocardial infarction and -27%, p = 0.002 for death from any cause). In contrast, the benefits of previously improved blood pressure control were not sustained when between-groups differences in blood pressure were lost during follow-up, except for a reduced risk for peripheral vascular disease. These observations are strong arguments in favour of an early optimisation of blood glucose control and of a sustained control of blood pressure in patients with type 2 diabetes.

[Brain, a gluco-dependent organ: toxic effects of hypoglycaemia and hyperglycaemia]. / Le cerveau, un organe gluco-dépendant. Effets délétères de l'hypoglycémie et de l'hyperglycémie.

Glucose is almost the only energy substrate for the brain. Such glucose dependence explains why any large variation of plasma glucose levels could lead to cerebral dysfunction, which may be severe and progress to a coma. Hypoglycaemic coma, the most common one, has a pure metabolic origin (neuroglucopenia) whereas hyperglycaemic coma is more complex and mainly due to osmotic disturbances. Besides acute changes of plasma glucose concentrations, it is generally recognized that more subtle chronic or recurrent glucose abnormalities could also result in brain dysfunction. However, such clinical consequences are more difficult to assess in clinical practice. Nevertheless, learning perturbations in young patients with type 1 diabetes and memory losses, sometimes severe and subject to progress to dementia ("diabetic encephalopathy") in older type 1 or type 2 diabetic patients, have been reported, although with some controversy. The present paper summarizes the current knowledge of both acute and chronic cerebral dysfunctions following perturbations of blood glucose levels in diabetic patients.

Factors controlling gastric-glucagon release.

A system consisting of an isolated dog stomach perfused with whole blood has been designed to study gastric glucagon secretion. Under basal conditions, gastric glucagon release was 0.0-3.1 ng glucagon/100g of stomach per min. Arginine, at an arterial plasma concentration averaging 10 mM, elicited a rapid glucagon release. This gastric glucagon release was almost completely abolished by somatostatin (100 ng/ml). The release of gastric glucagon was not affected by hyperglycemia alone but was reduced by about 40% when hyperglycemia was concomitant with an hyperinsulinemia within the physiological range. These observations support the concept that adequate concentrations of insulin are necessary in order for hyperglycemia to inhibit gastric glucagon secretion. Furthermore, it is suggested that the isolated perfused dog stomach might provide a unique tool permitting investigation of alpha-cell function in the absence of endogenously released insulin.

[How to explore...the metabolic syndrome by its new IDF definition]. / Comment j'explore...le syndrome métabolique par sa nouvelle définition dite de "consensus".

The International Diabetes Federation recently proposed a so-called consensus definition of metabolic syndrome. According to this new definition, a subject has the metabolic syndrome if he/she has abdominal obesity (considered as a prerequisite and assessed, in the European population, by a waist circumference > 80 cm in women and > 94 cm in men) and, in addition, at least two other risk factors among 1) elevated fasting triglycerides > or = 150 mg/dl; 2) low HDL cholesterol HDL < 50 mg/dl in women and < 40 mg/dl in men; 3) increased arterial blood pressure > or = 130/ 85 mm Hg; and 4) elevated fasting plasma glucose concentration > or = 100 mg/dl. We will discuss the advantages and limitations of this new definition as well as the consequences of its use on the prevalence of the metabolic syndrome in the Belgian population.

Neurotransmitters and glucagon release from the isolated, perfused canine stomach.

The isolated, perfused, canine stomach was used to investigate the effect of three neurotransmitters--norepinephrine, acetylcholine (or its analogue carbamylcholine), and VIP (vasoactive intestinal peptide)--on gastric glucagon release. Norepinephrine at the two concentrations tested (3.10-8 and 7.10-7 M) did not influence gastric glucagon release. In contrast, acetylcholine or carbamylcholine (5.10-6 M) as well as VIP (46-60 ng/ml) unequivocally stimulated gastric glucagon release, an effect apparently independent of the changes in blood flow. These results are in sharp contrast with the previously reported lack of effect of an electric stimulation of the vagus nerves on the release of glucagon from the dog stomach. An absence of innervation of the canine gastric A-cell would probably best explain this situation.

Similar metabolic effects of pulsatile versus continuous human insulin delivery during euglycemic, hyperinsulinemic glucose clamp in normal man.

Seven normal volunteers were studied on two different occasions during which 4-h pulsatile (PULS: 0.8 mU X kg-1 X min-1, 7.5 min of 15) and continuous (CONT: 0.4 mU X kg-1 X min-1) intravenous (i.v.) infusions of human insulin (Actrapid HM, Novo) were randomly compared. A euglycemic glucose clamp was performed and a 3-3H-glucose infusion was used for determination of endogenous glucose production (EGP) and metabolic clearance rate (MCR) of glucose. Plasma glucose was similar in both conditions; plasma insulin was stable at about 29 mU/L (CONT) and fluctuated between 10 and 45 mU/L (mean: 28, PULS). Exogenous glucose infused was 1.137 +/- 0.058 and 1.088 +/- 0.099 g X kg-1 X 4 h-1 in CONT and PULS, respectively (NS). EGP was totally suppressed in both conditions. Glucose MCR increased similarly to a maximum of 6.71 +/- 0.19 (CONT) and 6.79 +/- 0.59 (PULS) ml X kg-1 X min-1 during the fourth hour. C-peptide plasma levels remained stable, whereas plasma glucagon, free fatty acids, and 3-hydroxybutyrate were similarly suppressed in both tests. Thus, under these conditions, pulsatile and continuous insulin infusions have similar metabolic effects. These data contrast with those of Matthews et al. (1983) who reported that, at lower plasma concentrations (5-19 mU/L), pulsatile insulin had greater hypoglycemic effect than did continuous delivery. It is concluded that pulsatile insulin shows no greater activity under normoglycemic, moderately hyperinsulinemic conditions in man.

Greater efficacy of pulsatile insulin in type I diabetics critically depends on plasma glucagon levels.

The aim of this study was to investigate the role of plasma glucagon levels on the blood glucose response to intravenous insulin administered continuously or in a pulsatile manner. Six type I diabetic patients proven to have no residual insulin secretion were investigated. Endogenous glucagon secretion was inhibited by a continuous intravenous infusion of somatostatin (100 micrograms/h) and replaced by exogenous infusions of the hormone at three different rates (7.5, 4.5, and 2.5 micrograms/h), resulting in three different plasma glucagon steady-state levels (i.e., approximately equal to 200, approximately equal to 130, and approximately equal to 75 pg/ml, respectively). Each subject, in random order and on different days, was infused intravenously with regular human insulin either continuously (0.17 mU X kg-1 X min-1) or with the same amount of insulin infused in a pulsatile manner (0.85 mU X kg-1 X min-1 during 2 min followed by 8 min during which no insulin was infused). At plasma glucagon levels approximately equal to 200 pg/ml, blood glucose rose from approximately 10 to approximately 13 mM without any difference between the two modalities of insulin infusion. For plasma glucagon levels approximately equal to 130 pg/ml, plasma glucose remained steady throughout the experiments, but during the last 40 min, plasma glucose levels were significantly lower when insulin was administered intermittently. This greater blood glucose-lowering effect of pulsatile insulin occurred earlier and was more pronounced for plasma glucagon levels averaging 75 pg/ml. We conclude that the greater hypoglycemic effect of insulin administered intravenously in a pulsatile manner in type I diabetics critically depends on plasma glucagon circulating levels.

Utilization of oral sucrose load during exercise in humans. Effect of the alpha-glucosidase inhibitor acarbose.

We investigated the hormonal and metabolic response to a 100-g sucrose load given 15 min after adaptation to moderate-intensity (50% VmaxO2) long-duration (4-h) exercise in healthy volunteers. The effect of a 100-mg dose of the alpha-glucosidase inhibitor Acarbose ingested with the sucrose load was also investigated. "Naturally labeled [13C] sucrose" was used to follow the conversion to expired-air CO2 of the sugar ingested by isotope-ratio mass spectrometry. Circulating hormone and metabolite data were obtained in nine subjects, and indirect calorimetry and stable isotope methodology were applied to six of them. Under placebo, 93 +/- 4 g sucrose were entirely oxidized during the 4 h of exercise, total carbohydrate utilization was 235 +/- 14 g, endogenous carbohydrate utilization was 142 +/- 13 g, and total lipid oxidation was 121 +/- 7 g. A single oral dose of 100 mg Acarbose ingested with the sucrose load did not significantly modify total carbohydrate (239 +/- 2 g/4 h) or lipid (122 +/- 6 g/4 h) oxidation. In contrast, sucrose oxidation was reduced to 53 +/- 6 g/4 h and endogenous carbohydrate utilization increased to 186 +/- 7 g/4 h. Reduction of the rises in blood glucose and fructose and of the increases in plasma insulin and C peptide under Acarbose confirmed these effects, whereas lower circulating levels of alanine suggested a higher rate of gluconeogenesis. These data show that a 100-g glucose load ingested soon after initiation of exercise is a perfect available metabolic substrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Cryptocrine signaling in the thymus network and T cell education to neuroendocrine self-antigens.

Both during phylogeny and ontogeny the thymus appears as a nodal point between the two major systems of cell-to-cell signaling, the neuroendocrine and immune systems. This review presents the experimental observations which support a dual role in T cell selection played by the thymic repertoire of neuroendocrine polypeptide precursors. Through the mode of cryptocrine intercellular signaling thymic neuroendocrine-related precursors synthesized in thymic epithelial cells have been shown to influence the early steps in T cell differentiation. In addition, thymic neuroendocrine-related polypeptides are a source of self-antigens which are presented by the major histocompatibility system of the thymic epithelium. Preliminary data also suggest that the intrathymic T cell education to neuroendocrine self-antigens is not strictly superimposible to the antigen presentation by dedicated presenting cells. Insulin-like growth factor-II (IGF-II) was identified as one dominant member of the insulin family expressed by thymic epithelial and nurse cells. The intrathymic presentation of IGF-II or IGF-II derived self-antigens is under current investigation. If further confirmed, the central tolerogenic properties of IGF-II could be considered in the elaboration of a strategy for an efficient and safe prevention of insulin-dependent diabetes.

Troglitazone: antihyperglycemic activity and potential role in the treatment of type 2 diabetes.

Insulin resistance is a major component of type 2 diabetes; therefore, an insulin sensitizer agent like the thiazolidinedione compound troglitazone is considered a very promising drug. Troglitazone exerts an antihyperglycemic activity in a dose-dependent manner between 200 and 600 mg/day in type 2 diabetic patients treated with diet alone, sulfonylureas, or insulin. Additive antihyperglycemic effect may also be obtained by combining troglitazone and metformin. The antihyperglycemic effect of troglitazone as monotherapy is rather modest (reduction of HbA1c by 0.5-1.0%), but it appears to be somewhat greater when it is combined with other antidiabetic drugs. No double-blind studies have directly compared the activity of troglitazone with that of sulfonylureas or metformin. Troglitazone has been shown to exert additional beneficial effects on serum lipid profile and arterial blood pressure. It may be considered as a valuable alternative in insulin-resistant (obese and hyperinsulinemic) diabetic patients who appear to be the best responders to the drug. However, the efficacy of troglitazone is challenged by its safety profile, and the risk of hepatotoxicity still remains a major concern in clinical practice.

Improvement of insulin-induced glucose disposal in obese patients with NIDDM after 1-wk treatment with d-fenfluramine.

OBJECTIVE: To study the short-term effects of the serotoninergic anorectic drug d-fenfluramine on insulin-induced glucose disposal. RESEARCH DESIGN AND METHODS: A randomized double-blind placebo-controlled crossover trial with 1-wk treatment periods (2 x 15 mg/day d-fenfluramine) was conducted. Twenty obese subjects, 10 with normal oral glucose tolerance and 10 with non-insulin-dependent diabetes mellitus (NIDDM), were all treated with a weight-maintaining diet. Euglycemic-hyperinsulinemic glucose clamps with measurement of glucose kinetics with D-[3-3H]glucose were performed at either two (patients without NIDDM, 0.05 and 0.10 U.kg-1.h-1) or three (patients with NIDDM, 0.05, 0.10, and 0.50 U.kg-1.h-1) insulin delivery rates. RESULTS: In the nondiabetic subjects, no significant changes in any metabolic or hormonal parameter were measured in the basal state or during the clamp despite a slight reduction in body weight (-1.2 +/- 0.5 kg, P less than 0.05). In the diabetic patients, no significant changes in body weight or basal plasma insulin levels were observed, but fasting blood glucose levels (8.0 +/- 0.8 vs. 9.4 +/- 1.1 mM, P less than 0.005) and plasma free fatty acid concentrations (1150 +/- 227 vs. 1640 +/- 184 microM, P less than 0.05) were significantly reduced after d-fenfluramine compared with placebo. During the clamp, insulin metabolic clearance rate (MCR) was similar after both placebo and d-fenfluramine; endogenous (hepatic) glucose production was similarly and almost completely suppressed, whereas glucose disposal was remarkably enhanced after d-fenfluramine (average increase of glucose MCR 35 +/- 12%, P less than 0.02). CONCLUSIONS: Whatever the mechanism(s) involved, a 1-wk treatment with d-fenfluramine induces better blood glucose control and improves insulin sensitivity in obese patients with NIDDM independent of significant weight reduction; this last effect is not present in obese subjects with normal oral glucose tolerance.

Risk of developing retinopathy in Diabetes Control and Complications Trial type 1 diabetic patients with good or poor metabolic control.

OBJECTIVE: The study goal was to assess and predict the risk of developing retinopathy in type 1 diabetic patients with extreme metabolic control. RESEARCH DESIGN AND METHODS: Based on material from the Diabetes Control and Complications Trial (DCCT) study (n = 1,441 patients), patients without retinopathy at baseline (DCCT primary cohort) were considered under good or poor metabolic control if the mean HbA(1c) level (until the last visit) fell in the lower or upper 20% of the overall HbA(1c) distribution, respectively. Retinopathy was recorded as either absent or present. Logistic regression was used to predict retinopathy from covariates used in the DCCT retinopathy study. RESULTS: Among the 153 DCCT patients with "good metabolic control" (mean HbA(1c) < or = 6.87%), three-step change retinopathy developed in 15 (9.8%), and 138 (90%) remained free of retinopathy. Conversely, among the 166 patients with "poor metabolic control" (mean HbA(1c) > or = 9.49%), the complication did not develop in 71 (43%) and did develop in 95 (57%). Whereas occurrence of diabetic retinopathy was primarily due to metabolic control (P < 0.0001) and duration of participation in the study (P < 0.0001), two other covariates were found to be significant prognostic factors of the complication: HbA(1c) at baseline (OR 1.37, P < 0.001) and BMI (OR 1.11, P < 0.05). CONCLUSIONS: This study confirms that retinopathy develops in approximately 10% of patients with type 1 diabetes under good metabolic control, whereas > 40% of patients with type 1 diabetes remain free of retinopathy despite poor metabolic control. After adjusting for metabolic control and duration of participation in the study, it was found that previous glycemic exposure (HbA(1c)) and BMI may provide a possible explanation to such paradoxical clinical situations.

U-100 insulin gives some protection against metabolic deterioration due to CSII interruption.

We investigated the influence of insulin concentration within the insulin pump on the metabolic and plasma free-insulin changes induced by a 6-h nocturnal interruption of continuous subcutaneous insulin infusion (CSII) in five C-peptide-negative insulin-dependent diabetic patients with low circulating levels of anti-insulin antibodies. We compared the changes in blood glucose, plasma free fatty acids, 3-hydroxybutyrate, and free insulin during the interruption from 2300 to 0500 h of the Nordisk Infuser loaded with either U-100 or U-20 regular insulin. The decrease in plasma free-insulin levels was slower, resulting in a significantly delayed and smaller increase in blood glucose levels (2.4 +/- 1.6 vs. 7.6 +/- 2.9 mM, P less than .025) when the pump contained U-100 instead of U-20 insulin. Although the increases in levels of plasma free fatty acids were similar in both tests, the rise in plasma 3-hydroxybutyrate levels tended to be reduced with U-100 insulin (414 +/- 139 vs. 639 +/- 67 microM, P less than .10). Thus, our observations indicate that U-100 insulin gives some protection against the metabolic deterioration due to the interruption of CSII so that diabetic patients may be able to remain without the pump for longer periods with concentrated rather than diluted insulin.

Vitamin E reduction of protein glycosylation in diabetes. New prospect for prevention of diabetic complications?

OBJECTIVE: This study evaluated the possibility of inhibiting protein glycosylation in vivo with vitamin E. RESEARCH DESIGN AND METHODS: Two groups of 10 insulin-requiring diabetic patients, matched for duration of disease and metabolic control, received daily vitamin E supplementation of 1200 and 600 mg, respectively, for 2 mo. A third group of 10 diabetic patients, matched for duration of disease and metabolic control, served as the control group and received placebo. Fasting plasma glucose, mean daily plasma glucose, fasting labile HbA1, and glycosylated proteins were measured in the basal state and after 1 and 2 mo of treatment. In addition, hyperglycemic clamp studies were performed in basal state and after 1 mo of vitamin E administration in all patients. RESULTS: Glycemic indices did not show any significant changes during the study, whereas fasting labile HbA, and glycosylated proteins decreased significantly after 1 and 2 mo in patients on vitamin E administration. Stable HbA1 decreased after 2 mo. Mean glycemic incremental area in the hyperglycemic clamp procedure was similar before and after treatment, whereas a significant reduction in mean labile HbA1 incremental area was found after vitamin E supplementation. A significant difference was also found in both fasting and incremental labile HbA1 levels, stable HbA1, and glycosylated proteins between the two groups of diabetic patients on the two doses of vitamin E; the diabetic patients who received the higher dose of vitamin E showed the greater reduction. No significant changes in these parameters were observed in diabetic patients on placebo administration. CONCLUSIONS: These results demonstrate that vitamin E administration may reduce protein glycosylation in diabetic subjects independently of changes in plasma glucose, an effect that may be due to the inhibition of labile glycosylation, the first step of the Maillard reaction. Long-term studies will help establish the usefulness of vitamin E administration for the prevention of diabetic complications.