Reduced hepatic insulin clearance in rats with dietary-induced obesity

Strömblad, G; Björntorp, Per

doi:10.1016/0026-0495(86)90148-4

Cited by 115 publications

(52 citation statements)

References 11 publications

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“…Studies in isolated rat hepatocytes showed a concentration-dependent FFA -m e d iated decrease in binding and degradation of insulin (43). This effect was also shown ex vivo in rat liver (43)(44)(45)(46). We have recently shown that heparin-Intralipid infusion in dogs reduces hepatic insulin extraction in vivo (47).…”

Section: Discussionmentioning

confidence: 71%

Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes.

et al. 2000

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Our recent in vivo observations in healthy nonobese humans have demonstrated that prolonged elevation of plasma free fatty acids (FFAs) results in diminished glucose-stimulated insulin secretion (GSIS) when the F FA-mediated decrease in insulin sensitivity is taken into account. In the present study, we investigated whether obese individuals and patients with type 2 diabetes are more sensitive than healthy control subjects to the inhibitory effect of prolonged elevation of plasma FFAs on GSIS. In seven patients with type 2 diabetes and seven healthy nondiabetic obese individuals, we assessed GSIS with a programmed graded intravenous glucose infusion on two occasions, 6-8 weeks apart, with and without a prior 48-h infusion of heparin and Intralipid, which was designed to raise plasma FFA concentration approximately twofold over basal. The nondiabetic obese subjects had a significant 21% decrease in GSIS (P = 0.0008) with the heparin and Intralipid infusion, associated with a decrease in whole body insulin clearance. The impairment in GSIS was evident at low (<11 mmol/l) but not at higher plasma glucose concentrations. In contrast, the patients with t y p e 2 diabetes had a slight increase in GSIS (P = 0.027) and no change in insulin clearance, although there was marked interindividual variability in response. Plasma proinsulin concentrations measured in a subset of subjects were not altered in either group by the infusion of heparin and Intralipid. In summary, 1) obese nondiabetic individuals are susceptible to a desensitization of GSIS with heparin and Intralipid infusion, and 2) patients with type 2 diabetes do not demonstrate such susceptibility when FFAs are elevated approximately twofold above basal with heparin and Intralipid. Our results suggest that FFAs could play an important role in the development of -cell failure in obese individuals who are at risk for developing t y p e 2 diabetes. They do not, however, seem to further deteriorate the -cell function of patients who already have established type 2 diabetes and may even result in a slight increase in GSIS in this latter group. D i a b e t e s 4 9 :3 9 9-408, 2000 I t is well accepted that type 2 diabetes is characterized by defects in both insulin action and insulin secretion (1,2), with a specific defect in glucose-stimulated insulin secretion (GSIS) early in the evolution of this disease (3,4). Over the past decade, several investigators have focused their attention on the possible role of free fatty acids (FFAs), which are often elevated in states of insulin resistance, in selectively desensitizing the -cell to glucose (5-9). The concept of FFA-induced -cell desensitization has received support from prospective epidemiological studies, which show that elevated plasma FFA levels are a risk marker for the long-term development of glucose intolerance and progression toward type 2 diabetes both in Caucasians (10) and in Pima Indians (11).The acute stimulating effect of FFAs on GSIS has been well described both in vitro (12,13) and in vivo (14-16), and...

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Section: Discussionmentioning

confidence: 71%

Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes.

et al. 2000

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“…After secretion, insulin is removed from the plasma, mainly by the liver [28], in a process called insulin clearance, which is altered in obesity [29] and type 2 diabetes [2,30,31] animal models, and is also commonly associated with obesity [32,33] and type 2 diabetes in human patients [2,3,34]. It is well accepted that, in type 2 diabetes, insulin clearance is usually impaired and associated with insulin resistance and loss of beta cell mass.…”

Section: Discussionmentioning

confidence: 99%

Ciliary neurotrophic factor (CNTF) protects non-obese Swiss mice against type 2 diabetes by increasing beta cell mass and reducing insulin clearance

et al. 2012

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Aims/hypothesis Ciliary neurotrophic factor (CNTF) improves metabolic variables of obese animals with characteristics of type 2 diabetes, mainly by reducing insulin resistance. We evaluated whether CNTF was able to improve other metabolic variables in mouse models of type 2 diabetes, such as beta cell mass and insulin clearance, and whether CNTF has any effect on non-obese mice with characteristics of type 2 diabetes. Methods Neonatal mice were treated with 0.1 mg/kg CNTF or citrate buffer via intraperitoneal injections, before injection of 250 mg/kg alloxan. HEPG2 cells were cultured for 3 days in the presence of citrate buffer, 1 nmol/l CNTF or 50 mmol/l alloxan or a combination of CNTF and alloxan. Twenty-one days after treatment, we determined body weight, epididymal fat weight, blood glucose, plasma insulin, NEFA, glucose tolerance, insulin resistance, insulin clearance and beta cell mass. Finally, we assessed insulin receptor and protein kinase B phosphorylation in peripheral organs, as well as insulin-degrading enzyme (IDE) protein production and alternative splicing in the liver and HEPG2 cells. Results CNTF improved insulin sensitivity and beta cell mass, while reducing glucose-stimulated insulin secretion and insulin clearance in Swiss mice, improving glucose handling in a non-obese type 2 diabetes model. This effect was associated with lower IDE production and activity in liver cells. All these effects were observed even at 21 days after CNTF treatment. Conclusions/interpretation CNTF protection against type 2 diabetes is partially independent of the anti-obesity actions of CNTF, requiring a reduction in insulin clearance and increased beta cell mass, besides increased insulin sensitivity. Furthermore, knowledge of the long-term effects of CNTF expands its pharmacological relevance.

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“…Previous studies have shown a reduction in the insulin clearance in obese humans (Erdmann et al 2009(Erdmann et al , 2012 and in DIO animal models (Strömblad & Björntorp 1986, Brandimarti et al 2013, and a downregulation in the expression and/or activity of liver IDE seems to play an important role in the impairment of insulin clearance. In cafeteria diet-fed mice, the reduced insulin clearance was related to a downregulation of hepatic expression of IDE (Brandimarti et al 2013), a phenomenon also observed in our DIO mice.…”

Section: Figurementioning

confidence: 92%

Acute exercise restores insulin clearance in diet-induced obese mice

Kurauti

Costa-Júnior

Ferreira

et al. 2016

Journal of Endocrinology

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The aim of this study was to investigate the insulin clearance in diet-induced obese (DIO) mice submitted to acute endurance exercise (3h of treadmill exercise at 60–70% VO2max). Glucose-stimulated insulin secretion in isolated islets; ipGTT; ipITT; ipPTT;in vivoinsulin clearance; protein expression in liver, skeletal muscle, and adipose tissue (insulin degrading enzyme (IDE), insulin receptor subunitβ(IRβ), phospho-Akt (p-Akt) and phospho-AMPK (p-AMPK)), and the activity of IDE in the liver and skeletal muscle were accessed. In DIO mice, acute exercise reduced fasting glycemia and insulinemia, improved glucose and insulin tolerance, reduced hepatic glucose production, and increased p-Akt protein levels in liver and skeletal muscle and p-AMPK protein levels in skeletal muscle. In addition, insulin secretion was reduced, whereas insulin clearance and the expression of IDE and IRβ were increased in liver and skeletal muscle. Finally, IDE activity was increased only in skeletal muscle. In conclusion, we propose that the increased insulin clearance and IDE expression and activity, primarily, in skeletal muscle, constitute an additional mechanism, whereby physical exercise reduces insulinemia in DIO mice.

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Reduced hepatic insulin clearance in rats with dietary-induced obesity

Cited by 115 publications

References 11 publications

Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes.

Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes.

Ciliary neurotrophic factor (CNTF) protects non-obese Swiss mice against type 2 diabetes by increasing beta cell mass and reducing insulin clearance

Acute exercise restores insulin clearance in diet-induced obese mice

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