Oral Vanadyl Sulfate Improves Insulin Sensitivity in NIDDM but Not in Obese Nondiabetic Subjects
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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−2 · min−1) 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 ([3-3H]glucose), glycolysis from plasma glucose, glycogen synthesis, and whole-body carbohydrate and lipid oxidation were evaluated. Decreases in fasting plasma glucose (by ∼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 μmol · kg fat-free mass [FFM]−1 · min−1) and glucose disposal (Rd) (41.7 ± 5.7 and 38.9 ±4.7 μmol · kg FFM−1 · min−1) 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 ∼82% (17.3 ± 4.7 to 30.9 ± 2.7 μmol · kg FFM−1 · min−1, 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 μmol · kg FFM−1 · min−1, P < 0.05) and enhanced suppression of HGO (7.7 ± 3.1 vs. 1.3 ± 0.9 μmol · kg FFM−1 · min−1, 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.Keywords:
Carbohydrate Metabolism
Glucose clamp technique
Obesity and insulin resistance are associated with altered brain glucose metabolism. Here, we studied brain glucose metabolism in 22 morbidly obese patients before and 6 months after bariatric surgery. Seven healthy subjects served as control subjects. Brain glucose metabolism was measured twice per imaging session: with and without insulin stimulation (hyperinsulinemic-euglycemic clamp) using [18F]fluorodeoxyglucose scanning. We found that during fasting, brain glucose metabolism was not different between groups. However, the hyperinsulinemic clamp increased brain glucose metabolism in a widespread manner in the obese but not control subjects, and brain glucose metabolism was significantly higher during clamp in obese than in control subjects. After follow-up, 6 months postoperatively, the increase in glucose metabolism was no longer observed, and this attenuation was coupled with improved peripheral insulin sensitivity after weight loss. We conclude that obesity is associated with increased insulin-stimulated glucose metabolism in the brain and that this abnormality can be reversed by bariatric surgery.
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NO one has so far produced anything approaching a clear picture of either fat or carbohydrate metabolism and the interactions of the two are still more involved and elusive although they clearly exist. Plants and animals build up reserves of fat from carbohydrate, but the reverse process (fat into carbohydrate), proved in plant seeds, is still unproven in animals, although theoretically possible.In normal human metabolism fat-carbohydrate interactions are almost hidden. The disturbances shown in the metabolism of a diabetic seem to give us the clearest indications of these interactions. Either carbohydrate or fat can be used as the main source of body fuel, but their metabolic course is very different, both as regards chemistry and function. It is only whep carbohydrate is not available, either in starvation or severe diabetes, that fat provides the fuel of the body; this contrast is also manifest in the blood and internal organs, especially the liver. Under the commonest normal conditions of diet carbohydrate is predominantly and preferentially used for metabolism. The liver is rich in glycogen, poor in fat; the blood fat is minimal and ketone bodies, although perhaps present in small amount in the blood at most times, are absent on common tests. As soon as carbohydrate is insufficiently available for the needs of metabolism, depot fat flows to the liver and is there catabolized to ketone bodies which recent proof has shown to be burned peripherally in the muscles independent of carbohydrate metabolism. This is a normal process, harmful only in diabetes, and especially harmful when it occurs suddenly, e.g. when insulin is cut off from a fat diabetic dog or human patient. A diabetic supports with ease a prolonged severe ketosis but suffers from one of sudden onset, although of milder severity. Insulin in the diabetic and sugar in the starved switches metabolism from fat to carbohydrate usage very quickly and ketonuria usually disappears in three to six hours."Diabetic obesity" is very common and is often seen in the earliest stages and again after insulin treatment. It seems probable that hyperglycaemia causes this obesity and this has been clearly established by observations on an unusual case of lipaemia, diabetes and lipodystrophy.Lipaecmia may occur in two opposite phases of metabolism, one anabolic-when fat is on its way to storage, the other catabolic-when it is flowing from stores to the liver. The latter is the usual condition obvious in disease.Work has also been done which suggests that other lipotropic factors-choline, lipocaic, &c., exert an influence on carbohydrate-fat balance, more specifically the glycogen-fat balance in the liver.In America attention has been drawn to the frequent and persistenzt occurrence of fatty enlargement of the liver in diabetic children. The author has seen many diabetic children (usually in a state of chronic ketosis) with enlarged livers, but such enlargement has rapidly disappeared with better management of the diabetes. Only two out of some 500 diabetic children have clearly shown the unmistakable syndrome of "hepatomegalic dwarfism ". In these two cases choline and lipocaic were given over prolonged periods without any effect: the liver, however, of one of these cases has since become normal by the addition of zinc protamine insulin.
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Classifying the glycemic responses of carbohydrate foods using the glycemic index (GI) requires standardized methodology for valid results. Dietary carbohydrates influence metabolism by at least four mechanisms: nature of the monosaccharides absorbed, amount of carbohydrate consumed, rate of absorption, and colonic fermentation. Reducing glycemic responses by reducing carbohydrate intake increases postprandial serum free-fatty acids (FFA) and does not improve overall glycemic control in diabetic subjects. By contrast, low-GI diets reduce serum FFA and improve glycemic control. Thus, current evidence supports FAO/WHO recommendations to maintain a high-carbohydrate diet and choose low-GI starchy foods.
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HbAIc and FA were investigated as markers in the diagnosis of early carbohydrate metabolic derangements. A group with normal TSH and a high concentration for glycosylation products was singled out. Carbohydrate metabolic derangements in 89 per cent showed a tendency to progression. Interrelationship between glycemia and PH was noted. The diagnostic and prognostic importance of HbAIc and FA was determined, and their combined use for single investigation of carbohydrate metabolism was recommended, making it possible to exclude "accidental" latent transitory hyperglycemia. TSH determination at early stages can be of low informative value, whereas HbAIc and FA measurements can detect disorders of carbohydrate metabolism early enough.
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The ratio of nutrients which might impair carbohydrate metabolism was studied using male albino rats fed with various kind of diet. It was clarified that both the increased ratio of fat and the decreased ratio of carbohydrate + protein in the total calory consumed were the important dietary factor for the impairment of carbohydrate metabolism. The importance of this dietary ratio was discussed. Several authors have demonstrated that the amounts of circulating glucose in rats fed on a high-fat diet was increased, and these amounts were higher than those in animals fed on a diet rich in carbohydrates 1> 2>. A reduction in carbohydrate in the diet has been reported to cause the tissues to use up less carbohydrate and increase gluconeogenesis from protein 3>. Generally because high fat diet unevitably decreases the content of not only carbohydrate, but also protein in the diets, the role of protein and carbohydrate must be explored. The object of this study was to clarify the effect of carbohydrate and protein in the diet on the impaired carbohydrate metabolism of rats fed on a high fat diet, and also to investigate the ratio of nutrient imparing carbohydrate metabolism.
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We compared estimates of in vivo insulin action derived from insulin tolerance tests (ITT) and euglycemic and hyperglycemic glucose clamp studies in 17 normal subjects and 19 patients with various diseases characterized by insulin resistance. Fifteen subjects underwent an ITT and a euglycemic clamp study, 17 subjects underwent an ITT and a hyperglycemic clamp study, and 4 subjects underwent all 3 tests. The ITT consisted of a bolus iv injection of regular insulin (0.1 U/kg BW). The plasma glucose disappearance rate during the 3- to 15-min period following the insulin injection was taken as a measure of insulin action. In both euglycemic and hyperglycemic clamp studies, which were carried out with standard techniques, the ratio between the amount of glucose infused to maintain glycemia at the desired level and the mean plasma insulin concentration from 60-120 min (M) (euglycemic clamp studies) or 20-120 min (I) (hyperglycemic clamp studies) was used as a measure of insulin action. A close correlation was found between plasma glucose disappearance rate and the M/I ratio during either the euglycemic (r = 0.811; P less than 0.001) or the hyperglycemic (r = 0.826; P less than 0.001) clamp studies. These results suggest that the 15-min ITT is suitable as a simple and rapid estimation of in vivo insulin action when glucose clamp studies are not feasible, as in large series of subjects or serial studies.
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Glucose clamp technique
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