New concepts in the pathogenesis and treatment of noninsulin-dependent diabetes mellitus

DeFronzo, Ralph A.; Ferrannini, Eleuterio; Koivisto, Veikko A.

doi:10.1016/0002-9343(83)90654-x

Cited by 275 publications

(122 citation statements)

References 261 publications

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“…Both normal control subjects and patients with type II diabetes have been shown to have a 30-35% increase in insulin-stimulated glucose disposal after physical training when studied by the hyperinsulinemic-euglycemic clamp technique (7,76,77). This increase in insulin sensitivity correlates well with the training-induced increase in Vo 2max (8,78,79) and is thought to be primarily due to increased glucose uptake by muscle because no changes have been observed in hepatic glucose production rates.…”

Section: Exercise In Type II Diabetesmentioning

confidence: 99%

Role and Management of Exercise in Diabetes Mellitus

Horton

1988

Diabetes Care

110

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As more is understood about the physiology of exercise, in both normal and diabetic subjects, its role in the treatment of diabetes is becoming better defined. Whereas people with diabetes may derive many benefits from regular physical exercise, there are also several hazards that make exercise difficult to manage. In type I (insulin-dependent) diabetes, there are risks of hypoglycemia during or after exercise or of worsening metabolic control if insulin deficiency is present. Type II (non-insulin-dependent) diabetic patients treated with sulfonylureas are also at some increased risk of developing hypoglycemia during or after exercise, although this poses less of a problem than with insulin treatment. In individuals treated by diet alone, regulation of blood glucose during exercise is usually not a significant problem and exercise can be used as an adjunct to diet to achieve weight loss and improved insulin sensitivity. When obese type II diabetic patients are treated with very low calorie diets, adequate amounts of carbohydrate must be provided to ensure maintenance of normal muscle glycogen content, particularly if individuals wish to participate in highintensity exercise that places a heavy workload on specific muscle groups. On the other hand, moderateintensity exercise such as vigorous walking can be tolerated by individuals on very low calorie, carbohydrate-restricted diets after an appropriate period of adaptation. A number of strategies can be employed to avoid hypoglycemia in type I diabetic patients, and both type I and II diabetic patients should be examined carefully for long-term complications of their disease, which may be made worse by exercise. These considerations have led many diabetologists to consider exercise beneficial in the management of diabetes for

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Section: Exercise In Type II Diabetesmentioning

confidence: 99%

Role and Management of Exercise in Diabetes Mellitus

Horton

1988

Diabetes Care

110

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“…It is characterized by defects in both insulin secretion and tissue sensitivity to insulin (1,2), leading to hyperglycemia. It is well accepted that part of this hyperglycemia results from the abnormal persistence of hepatic glucose production during the absorptive state and by an increase to excessive levels of hepatic glucose production in the postabsorptive state (3).…”

mentioning

confidence: 99%

Intrinsic Gluconeogenesis Is Enhanced in Renal Proximal Tubules of Zucker Diabetic Fatty Rats

Eid

Bodin²,

Ferrier³

et al. 2006

Journal of the American Society of Nephrology

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Recent studies indicate that renal gluconeogenesis is substantially stimulated in patients with type 2 diabetes, but the mechanism that is responsible for such stimulation remains unknown. Therefore, this study tested the hypothesis that renal gluconeogenesis is intrinsically elevated in the Zucker diabetic fatty rat, which is considered to be an excellent model of type 2 diabetes. For this, isolated renal proximal tubules from diabetic rats and from their lean nondiabetic littermates were incubated in the presence of physiologic gluconeogenic precursors. Although there was no increase in substrate removal and despite a reduced cellular ATP level, a marked stimulation of gluconeogenesis was observed in diabetic relative to nondiabetic rats, with near-physiologic concentrations of lactate (38%), glutamine (51%) and glycerol (66%). This stimulation was caused by a change in the fate of the substrate carbon skeletons resulting from an increase in the activities and mRNA levels of the key gluconeogenic enzymes that are common to lactate, glutamine, and glycerol metabolism, i.e., mainly of phosphoenolpyruvate carboxykinase and, to a lesser extent, of glucose-6-phosphatase and fructose-1,6-bisphosphatase. Experimental evidence suggests that glucocorticoids and cAMP were two factors that were responsible for the long-term stimulation of renal gluconeogenesis observed in the diabetic rats. These data provide the first demonstration in an animal model that renal gluconeogenesis is upregulated by a long-term mechanism during type 2 diabetes. Together with the increased renal mass (38%) observed, they lend support to the view so far based only on in vivo studies performed in humans that renal gluconeogenesis may be stimulated by and crucially contribute to the hyperglycemia of type 2 diabetes.

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“…Although presently available data suggest the presence ofan impairment in intracellular glucose metabolism, the possibility that reduced oxidative and nonoxidative glucose metabolism simply may be secondary to a reduced rate of glucose transport into a cell remains to be elucidated. Both hyperglycemia and hyperinsulinemia can increase glucose utilization and normalize total body glucose flux in NIDDM subjects ( 15,16). It has been suggested that elevation in the plasma concentrations of glucose and insulin may play a compensatory role in maintaining adequate glucose uptake in the presence of insulin resistance ( 15,16).…”

mentioning

confidence: 99%

“…Both hyperglycemia and hyperinsulinemia can increase glucose utilization and normalize total body glucose flux in NIDDM subjects ( 15,16). It has been suggested that elevation in the plasma concentrations of glucose and insulin may play a compensatory role in maintaining adequate glucose uptake in the presence of insulin resistance ( 15,16). More recently, Baron and his co-workers have extensively analyzed the metabolic effect ofvarious combinations ofplasma insulin and glucose concentrations on whole-body glucose disposal ( 17,18).…”

mentioning

confidence: 99%

Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus.

Prato¹,

Bonadonna²,

Bonora³

et al. 1993

J. Clin. Invest.

161

110

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IntroductionSeven non-insulin-dependent diabetes mellitus (NIDDM) patients participated in three clamp studies performed with 13-3HI-and [U-14CIglucose and indirect calorimetry: study I, euglycemic (5.2±0.1 mM) insulin (269±39 pM) clamp; study II, hyperglycemic (14.9±1.2 mM) insulin (259±19 pM) clamp; study III, euglycemic (5.5±0.3 mM) hyperinsulinemic (1650±529 pM) clamp. Seven control subjects received a euglycemic (5.1±0.2 mM) insulin (258±24 pM) clamp. Glycolysis and glucose oxidation were quantitated from the rate of appearance of 3H20 and '4CO2; glycogen synthesis was calculated as the difference between body glucose disposal and glycolysis. In study I, glucose uptake was decreased by 54% in NIDDM vs. controls. Glycolysis, glycogen synthesis, and glucose oxidation were reduced in NIDDM patients (P < 0.05-0.001). Nonoxidative glycolysis and lipid oxidation were higher. In studies II and III, glucose uptake in NIDDM was equal to controls (40.7±2.1 and 40.7±1.7 gmol/min * kg fat-free mass, respectively). In study II, glycolysis, but not glucose oxidation, was normal (P < 0.01 vs. controls). Nonoxidative glycolysis remained higher (P < 0.05). Glycogen deposition increased (P < 0.05 vs. study I), and lipid oxidation remained higher (P < 0.01). In study III, hyperinsulinemia normalized glycogen formation, glycolysis, and lipid oxidation but did not normalize the elevated nonoxidative glycolysis or the decreased glucose oxidation. Lipid oxidation and glycolysis (r = -0.65; P < 0.01), and glucose oxidation (r = -0.75; P < 0.01) were inversely correlated. In conclusion, in NIDDM: (a) insulin resistance involves glycolysis, glycogen synthesis, and glucose oxidation; (b) hyperglycemia and hyperinsulinemia can normalize total body glucose uptake; (c) marked hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and nonoxidative glycolysis; (d)

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New concepts in the pathogenesis and treatment of noninsulin-dependent diabetes mellitus

Cited by 275 publications

References 261 publications

Role and Management of Exercise in Diabetes Mellitus

Role and Management of Exercise in Diabetes Mellitus

Intrinsic Gluconeogenesis Is Enhanced in Renal Proximal Tubules of Zucker Diabetic Fatty Rats

Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus.

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