Metabolic consequences of prolonged hyperinsulinemia in humans. Evidence for induction of insulin insensitivity

Marangou, Andreas G.; Weber, Kathryn M.; Boston, Raymond C.; Aitken, P.; Heggie, J. C.; Kirsner, R. L.; Best, J. D.; Alford, F. P.

doi:10.2337/diabetes.35.12.1383

Cited by 57 publications

(39 citation statements)

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“…Excess insulin in animals and man has been shown to induce insulin resistance and fat accumulation (Cusin et al, 1990 andMarangou et al, 1986). Experimental reduction of insulinemia in hyperinsulinemic, obese, insulin resistant animal models of type 2-diabetes (leptin-deficient ob/ob mice and fa/fa rats) significantly reduced body weight, hepatic and adipose tissue lipogenesis, circulating triglyceride levels, and improved insulin sensitivity ( AssimacopoulosLin et al: Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats Neuropharmacology 51(7--8): 1129--1136, 2006Jeannet and Jeanrenaud, 1976and Standridge et al, 2000.…”

Section: Effect Of Haloperidol or Risperidone On Body Tissue Compositionmentioning

confidence: 99%

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats

et al. 2006

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Antipsychotic drugs have been used effectively for the treatment of schizophrenia symptoms, but they are often associated with metabolic side effects such as weight gain and endocrine disruptions. To investigate the possible mechanisms of antipsychotic-induced metabolic effects, we studied the impact of chronic administration of a typical antipsychotic drug (haloperidol) and an atypical antipsychotic (risperidone) to male rats on food intake, body weight, adiposity, and the circulating concentrations of hormones and metabolites that can influence energy homeostasis. Chronic (28 days) haloperidol administration had no effect on food intake, weight gain or adiposity in male rats, whereas risperidone treatment resulted in a transient reduction in food intake and significantly reduced body weight gain compared to vehicle-treated control rats. Whereas neither antipsychotic had any effect on serum lipid profiles, glucose tolerance or the circulating concentrations of hormones controlled by the hypothalamo-pituitary-thyroid (free T4), -adrenal (corticosterone), -somatotropic (IGF-1), orgonadotropic axes (testosterone), haloperidol increased circulating insulin levels and risperidone increased serum glucagon levels. This finding suggests that haloperidol or risperidone induce distinct metabolic effects. Since metabolic disorders such as obesity and type 2 diabetes mellitus represent serious health issues, understanding antipsychotic-induced endocrine and metabolic effects may ultimately allow better control of these side effects.

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Section: Effect Of Haloperidol or Risperidone On Body Tissue Compositionmentioning

confidence: 99%

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats

et al. 2006

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“…It generally is thought that insulin resistance represents the primary disturbance, while hyperinsulinaemia is a compensatory response by the beta cells to offset the defect in insulin action and maintain a normal flux of glucose into the cell. However, recent evidence suggests that hyperinsulinaemia per se may lead to the development of insulin resistance [13][14][15][16][17][18].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, chronic hyperinsulinaemia has been shown to induce insulin resistance in some [13][14][15][16][17][18], but not all [19][20][21] studies. Little information is available concerning the effect of chronic hyperinsulinaemia on insulinmediated glucose metabolism in man [16,17] and the intracellular metabolic pathway(s) responsible for the reduction in insulin-mediated glucose disposal following chronic exposure to the hormone have not been examined. If chronic, sustained elevated plasma insulin levels are, indeed, a cause of insulin resistance, then the "compensatory" hyperinsulinaemia in NIDDM can no longer be viewed as an adaptive mechanism responsible for the maintenance of normal glucose tolerance, but rather as a self-perpetuating cause of the diabetic condition.…”

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confidence: 99%

Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man

et al. 1994

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SummaryTwo study protocols to examine the effects of chronic (72-96 h) physiologic euglycaemic hyperinsulinaemia (+ 72 pmol/1) and chronic hyperglycaemic (+ 1.4 mmol/1) hyperinsulinaemia (+ 78 pmol/1) on insulin sensitivity and insulin secretion were performed in 15 healthy young subjects. Subjects received a three-step euglycaemic insulin (insulin infusion rates = 1.5, 3, and 6 nmol. kg -1 9 min -1) clamp and a hyperglycaemia (6.9 mmol/1) clamp before and after chronic insulin or glucose infusion. Following 4 days of sustained euglycaemic hyperinsulinaemia whole body glucose disposal decreased by 2040 %. During each insulin clamp step, the defect in insulin action was accounted for by impaired non-oxidative glucose disposal (p < 0.01). Chronic euglycaemic hyperinsulinaemia did not alter insulin-mediated suppression of hepatic glucose production. Following insulin infusion the ability of hyperglycaemia to stimulate insulin secretion was significantly diminished. Following 72 h of chronic glucose infusion (combined hyperglycaemic hyperinsulinaemia), there was no change in whole body glucose disposal. However, glucose oxidation during each insulin clamp step was significantly increased and there was a reciprocal decline in non-oxidative glucose disposal by 25-39 % (p < 0.01); suppression of hepatic glucose production by insulin was unaltered by chronic hyperglycaemic hyperinsulinaemia. Chronic glucose infusion increased the plasma insulin response to acute hyperglycaemia more than twofold. These results demonstrate that chronic, physiologic hyperinsulinaemia, whether created by exogenous insulin infusion or by stimulation of endogenous insulin secretion, leads to the development of insulin resistance, which is characterized by a specific defect in the non-oxidative (glycogen synthetic) pathway. These findings indicate that hyperinsulinaemia should be considered, not only as a compensatory response to insulin resistance, but also as a self-perpetuating cause of the defect in insulin action. [Diabetologia (1994[Diabetologia ( ) 37: 1025[Diabetologia ( -1035

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“…We speculated that the marked chronic hyperinsulinemia in the LIRKO mice might have led to secondary insulin resistance in muscle and fat (20)(21)(22) and perhaps limited insulin action on these extrahepatic tissues. We therefore treated a second group of LIRKO mice with streptozotocin (LIRKO+STZ mice) to reduce hyperinsulinemia in an We and others have suggested that insulin predominantly acts indirectly to inhibit hepatic glucose production (HGP) via suppression of gluconeogenic precursors, FFAs, and glucagon.…”

Section: Introductionmentioning

confidence: 99%

Insulin signaling is required for insulin’s direct and indirect action on hepatic glucose production

Fisher¹,

Kahn²

2003

J. Clin. Invest.

196

132

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IntroductionThe failure of insulin to inhibit hepatic glucose production (HGP) is a cardinal feature of insulin resistance in the liver and a major factor contributing to hyperglycemia in diabetic states. Classically, the HGP-suppressing effect of insulin is thought to occur via signaling through the hepatic insulin receptor to inhibit glycogenolysis and gluconeogenesis. This classical paradigm has been challenged by in vivo studies suggesting that much of insulin's action on the liver may be indirect, and related to systemic, rather than hepatic, insulin effects (1-6). Thus, extrahepatic actions of insulin on muscle and adipose tissue to inhibit release of gluconeogenic substrates (e.g., lactate, alanine, and glycerol) and gluconeogenic energy substrates (e.g., FFAs) result in a subsequent inhibition of HGP (7-10). These mechanisms may be particularly important in the diabetic state, in which gluconeogenesis is considerably increased (11)(12)(13)(14), and in which hyperglycemia per se has been shown to potentiate the indirect actions of insulin (15). Furthermore, since up to 75% of basal HGP is driven by glucagon (16), insulin-induced suppression of glucagon release may be another indirect mechanism by which insulin suppresses HGP (2, 3, 17, 18).We have recently developed a unique model to investigate direct versus indirect insulin actions. Liver-specific insulin receptor knockout (LIRKO) mice have an approximately 95% reduction in insulin receptor content in the liver, and only in the liver (19). Since the Alb-Cre transgene is only expressed in hepatocytes, and since hepatocytes make up only about 85% of the total number of cells in the liver, it is likely that the knockout of insulin receptor in LIRKO hepatocytes is essentially complete. LIRKO mice have an absence of insulin-stimulated receptor tyrosine phosphorylation and insulin signaling in the hepatocyte (19). Since the livers of LIRKO mice cannot respond directly to insulin, any effect of insulin administered in vivo must be mediated by indirect actions of insulin on extrahepatic tissues.In this study, in an attempt to clarify indirect effects of insulin on the suppression of HGP, we assessed the regulation of HGP in both control and LIRKO mice by performing high-dose hyperinsulinemic-euglycemic clamps to maximally stimulate insulin-sensitive peripheral tissues. We speculated that the marked chronic hyperinsulinemia in the LIRKO mice might have led to secondary insulin resistance in muscle and fat (20)(21)(22) and perhaps limited insulin action on these extrahepatic tissues. We therefore treated a second group of LIRKO mice with streptozotocin (LIRKO+STZ mice) to reduce hyperinsulinemia in an We and others have suggested that insulin predominantly acts indirectly to inhibit hepatic glucose production (HGP) via suppression of gluconeogenic precursors, FFAs, and glucagon. To test that hypothesis, we performed high-dose hyperinsulinemic-euglycemic clamps using [3-3 H]-glucose in liver-specific insulin receptor knockout (LIRKO) mice, LIRKO mice treated with ...

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Metabolic consequences of prolonged hyperinsulinemia in humans. Evidence for induction of insulin insensitivity

Cited by 57 publications

References 0 publications

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats

Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man

Insulin signaling is required for insulin’s direct and indirect action on hepatic glucose production

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