Downregulation of Insulin Receptors in Obese Man

Wigand, James P.; Blackard, William G.

doi:10.2337/diab.28.4.287

Cited by 54 publications

(22 citation statements)

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“…We found that diazoxide had no demonstrable effect on insulin binding in either the normal subjects or the patients with NIDDM. Wigand and Blackard (1979) studied the effects of diazoxide on insulin receptors in obese hyperinsuhnaemic subjects. They showed an increase in insulin receptor number that was secondary to the suppression of plasma insulin levels by diazoxide.…”

Section: Discussionmentioning

confidence: 99%

Post-Receptor Insulin Resistance after Diazoxide in Non-Insulin Dependent Diabetes

Sa¹,

Rh²,

Cn³

1986

Horm Metab Res

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Insulin binding to monocytes and the counterregulatory hormone response to intravenous insulin was determined in six normal subjects and eight patients with non-insulin dependent diabetes mellitus (NIDDM), before and after seven days treatment with oral diazoxide. In the normal subjects diazoxide had no effect on insulin binding or sensitivity. In the patients with NIDDM diazoxide caused resistance to intravenous insulin with no change in the counterregulatory hormone response or in insulin binding to account for this. Diazoxide appears to cause post-receptor insulin resistance in NIDDM, and it may be a useful tool for studying post-receptor binding events.

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Section: Discussionmentioning

confidence: 99%

Post-Receptor Insulin Resistance after Diazoxide in Non-Insulin Dependent Diabetes

Sa¹,

Rh²,

Cn³

1986

Horm Metab Res

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“…Evidence is, however, given both in animals [29] and in humans [30,31] that decrease in the number of insulin receptors is secondary to hyperinsulinism and is not the primary cause of insulin resistance in obesity. In most patients it appears to be caused by a metabolic abnormality beyond the receptor levels [32,33].…”

Section: Discussionmentioning

confidence: 99%

Glucose storage and oxidation in different degrees of human obesity measured by continuous indirect calorimetry

Felber¹,

Meyer²,

Curchod

et al. 1981

Diabetologia

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Summary. Glucose disposal of a 100 g glucose load has been determined in 26 obese compared with 10 non-obese subjects by means of a new application of continuous indirect calorimetry. The obese subjects were divided into 4 groups, according to their degree of glucose intolerance and their insulin response to the glucose load. Through this division it appeared that subjects with no glucose intolerance were moderately obese while the groups with glucose intolerance showed a higher degree of obesity, glucose intolerance increasing with age. The 10 obese subjects with no glucose intolerance (group A) presented values for glucosedisposal similar to those of the control subjects. The 4 obese subjects with impaired glucose tolerance. (group B) showed no significant changes in glucose storage and in basal oxidation, but a significant decrease in oxidation in response to the load (11 _+ 2g vs 19 _-2 lg in the control group, p <0.02). The 6 obese subjects with overt diabetes and elevated insulin response to the glucose load (group C) showed a significant decrease in glucose storage (34 _.+ 6 g vs 63 --_ I g, p < 0.001) but not in oxidation. The 6 obese subjects With overt diabetes and decreased insulin response (group D) showed a significant decrease in glucose storage (25 +4 g vs 63 -+ 1 g, p < 0.001) and oxidation (12 +__ i g, vs 19 + 1 g, p < 0.005). These observations show that in obese diabetics, glucose intolerance results primarily from decreased glucose storage and to a lesser extent from a decrease in glucose oxidation.

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“…By doing so, we further explored the impact of mild insulin resistance on endothelial function. Notably, the IRKO mouse displays a metabolic phenotype that mirrors the abnormalities of insulin signaling described in insulin-resistant humans, including reduced insulin receptor numbers (56), reduced insulin receptor tyrosine kinase activity (14), and impaired intracellular insulin signaling (9).…”

mentioning

confidence: 99%

Accelerated endothelial dysfunction in mild prediabetic insulin resistance: the early role of reactive oxygen species

Duncan¹,

Walker²,

Ezzat³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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AM, Kearney MT. Accelerated endothelial dysfunction in mild prediabetic insulin resistance: the early role of reactive oxygen species. Am J Physiol Endocrinol Metab 293: E1311-E1319, 2007. First published August 28, 2007; doi:10.1152/ajpendo.00299.2007.-Insulin resistance is well established as an independent risk factor for the development of type 2 diabetes and cardiovascular atherosclerosis. Most studies have examined atherogenesis in models of severe insulin resistance or diabetes. However, by the time of diagnosis, individuals with type 2 diabetes already demonstrate a significant atheroma burden. Furthermore, recent studies suggest that, even in adolescence, insulin resistance is a progressive disorder that increases cardiovascular risk. In the present report, we studied early mechanisms of reduction in the bioavailability of the antiatheroscerotic molecule nitric oxide (NO) in very mild insulin resistance. Mice with haploinsufficiency for the insulin receptor (IRKO) are a model of mild insulin resistance with preserved glycemic control. We previously demonstrated that 2-moold (Young) IRKO mice have preserved vasorelaxation responses to ACh. This remained the case at 4 mo of age. However, by 6 mo, despite no significant deterioration in glucose homeostasis (Adult), IRKO mice had marked blunting of ACh-mediated vasorelaxation [IRKO maximum contraction response (Emax) 66 Ϯ 5% vs. wild type 87 Ϯ 4%, P Ͻ 0.01]. Despite the endothelial dysfunction demonstrated, aortic endothelial nitric oxide synthase (eNOS) mRNA levels were similar in Adult IRKO and wild-type mice, and, interestingly, aortic eNOS protein levels were increased, suggesting a compensatory upregulation in the IRKO. We then examined the potential role of reactive oxygen species in mediating early endothelial dysfunction. The superoxide dismutase mimetic Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP) restored ACh relaxation responses in the Adult IRKO (Emax to ACh with MnTMPyP 85 Ϯ 5%). Dihydroethidium fluorescence of aortas and isolated coronary microvascular endothelial cells confirmed a substantial increase in endothelium-derived reactive oxygen species in IRKO mice. These data demonstrate that mild insulin resistance is a potent substrate for accelerated endothelial dysfunction and support a role for endothelial cell superoxide production as a mechanism underlying the early reduction in NO bioavailability. insulin resistance; endothelial function; superoxide; enos INSULIN RESISTANCE is a central pathogenic feature of type 2 diabetes mellitus (42), the incidence of which is rising substantially (24). The principal cause of death in type 2 diabetes is premature cardiovascular atherosclerosis (23), and patients with type 2 diabetes have a similar risk of fatal cardiovascular events as nondiabetic patients who have sustained a myocardial infarction (19). We recently demonstrated that, despite contemporary therapies, patients with type 2 diabetes who have sustained an acute myocardial infarction have not benefited from the impr...

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Downregulation of Insulin Receptors in Obese Man

Cited by 54 publications

References 0 publications

Post-Receptor Insulin Resistance after Diazoxide in Non-Insulin Dependent Diabetes

Post-Receptor Insulin Resistance after Diazoxide in Non-Insulin Dependent Diabetes

Glucose storage and oxidation in different degrees of human obesity measured by continuous indirect calorimetry

Accelerated endothelial dysfunction in mild prediabetic insulin resistance: the early role of reactive oxygen species

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