Insulin receptor down-regulation and impaired antilipolytic action of insulin in diabetic patients after pancreas/kidney transplantation.

Boden, Guenther; Chen, Xinhua; Ruiz, J.; Heifets, Michael; Morris, Michael; Badosa, Francisco

doi:10.1210/jcem.78.3.8126138

Cited by 24 publications

(20 citation statements)

References 24 publications

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“…This leads to increased fatty acids in the serum and ectopic fat accumulation resulting in impaired insulin signaling in non-adipose tissues. 24 We found that stevioside treatment improved adipogenesis and glucose uptake in visceral adipose tissue, evidenced by higher expressions of Lxra, Fabp4 and Glut4. 25,26 The Glut4 27 and Fabp4 28 are direct transcriptional targets for the LXR/retinoid X-receptor heterodimer.…”

Section: Discussionmentioning

confidence: 66%

Stevioside inhibits atherosclerosis by improving insulin signaling and antioxidant defense in obese insulin-resistant mice

et al. 2009

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Objective: Stevioside is a non-caloric natural sweetener that does not induce a glycemic response, making it attractive as sweetener to diabetics and others on carbohydrate-controlled diets. Obesity is frequently associated with insulin resistance and increased inflammation and oxidative stress. Therefore, we investigated its effects on insulin resistance, inflammation and oxidative stress related to atherosclerosis in obese insulin-resistant mice.Research design: Twelve-week-old mice were treated with stevioside (10 mg kg À1 , n ¼ 14) or placebo (n ¼ 20) for 12 weeks. Results: Stevioside had no effect on weight and triglycerides, but lowered glucose and insulin. Stevioside treatment improved adipose tissue maturation, and increased glucose transport, insulin signaling and antioxidant defense in white visceral adipose tissues. Together, these increases were associated with a twofold increase of adiponectin. In addition, stevioside reduced plaque volume in the aortic arch by decreasing the macrophage, lipid and oxidized low-density lipoprotein (ox-LDL) content of the plaque. The higher smooth muscle cell-to-macrophage ratio was indicative for a more stable plaque phenotype. The decrease in ox-LDL in the plaque was likely due to an increase in the antioxidant defense in the vascular wall, as evidenced by increased Sod1, Sod2 and Sod3. Circulating adiponectin was associated with improved insulin signaling and antioxidant defense in both the adipose tissue and the aorta of stevioside-treated mice. Conclusion: Stevioside treatment was associated with improved insulin signaling and antioxidant defense in both the adipose tissue and the vascular wall, leading to inhibition of atherosclerotic plaque development and inducing plaque stabilization.

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Section: Discussionmentioning

confidence: 66%

Stevioside inhibits atherosclerosis by improving insulin signaling and antioxidant defense in obese insulin-resistant mice

et al. 2009

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“…Not all previous studies have demonstrated an impairment of insulin's antilipolytic action in KPT-S recipients versus healthy subjects (9,51). Despite the total-body insulin resistance in the KPT-S group, there was no difference in endogenous glucose production during fasting in KPT-S versus KPT-P. We showed a greater suppression of endogenous glucose production during both low-dose and high-dose insulin infusion in the KPT-S group compared with the KPT-P group.…”

Section: Discussionmentioning

confidence: 91%

“…Consequently, transplant recipients who undergo this procedure become hyperinsulinemic and have reduced total-body insulin sensitivity (4 -9), even when compared with nondiabetic kidney transplant recipients on a similar antirejection drug regimen (7,8). Furthermore, these patients have a reduction in insulin's antilipolytic activity in peripheral tissues, another feature of systemic insulin resistance (9).…”

mentioning

confidence: 99%

The Effect of Systemic Versus Portal Insulin Delivery in Pancreas Transplantation on Insulin Action and VLDL Metabolism

Carpentier¹,

Patterson

Uffelman³

et al. 2001

Diabetes

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Combined kidney-pancreas transplantation (KPT) with anastomosis of the pancreatic vein to the systemic circulation (KPT-S) or to the portal circulation (KPT-P) provides a human model in which the chronic effects of portal versus systemic insulin delivery on glucose and VLDL metabolism can be examined. Despite similar plasma glucose and C-peptide levels, KPT-S (n ‫؍‬ 9) had an approximate twofold elevation of fasting and intravenous glucose-stimulated plasma insulin levels compared with both KPT-P (n ‫؍‬ 7) and healthy control subjects (n ‫؍‬ 15). The plasma free fatty acid (FFA) levels were elevated in both transplant groups versus control subjects, but the plasma insulin elevation necessary to lower plasma FFA by 50% was approximately two times higher in KPT-S versus KPT-P and control subjects. Endogenous glucose production was similar in KPT-S and KPT-P, despite ϳ35% higher hepatic insulin levels in the latter, and was suppressed to a greater extent during a euglycemic-hyperinsulinemic clamp in KPT-S versus KPT-P. Total-body glucose utilization during the euglycemic-hyperinsulinemic clamp was ϳ40% lower in KPT-S versus KPT-P, indicating peripheral tissue but not hepatic insulin resistance in KPT-S versus KPT-P. Both transplant groups had an approximate twofold elevation of triglyceride (TG)-rich lipoprotein apolipoprotein B (apoB) and lipids versus control subjects. Elevation of VLDL-apoB and VLDL-TG in both transplant groups was entirely explained by an ϳ50% reduction in clearance of VLDL compared with healthy control subjects. In the presence of increased FFA load but in the absence of hepatic overinsulinization and marked hepatic insulin resistance, there was no elevation of VLDL secretion in KPT-S versus KPT-P and control subjects. These findings suggest that chronic systemic hyperinsulinemia and peripheral tissue insulin resistance with the consequent elevation of plasma FFA flux are insufficient per se to cause VLDL overproduction and that additional factors, such as hepatic hyperinsulinemia and/or gross insulin resistance, may be an essential prerequisite in the pathogenesis of VLDL overproduction in the common form of the insulin resistance syndrome.

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“…Intraperitoneal studies have yielded somewhat conflicting results, with either improved [23,24,26,29] or unchanged [25,27,28] insulin sensitivity. Similarly pancreas transplantation has been shown by many [30][31][32][34][35][36][37], but not all groups [33,38] to cause a deterioration in insulin responsiveness.…”

Section: : 1125-1134]mentioning

confidence: 98%

“…Metabolic control after pancreas transplantation and in chronic liver disease, when the portal-systemic gradient is lost, has also been the subject of investigation [29][30][31][32][33][34][35][36][37][38][39][40]. Intraperitoneal studies have yielded somewhat conflicting results, with either improved [23,24,26,29] or unchanged [25,27,28] insulin sensitivity.…”

Section: : 1125-1134]mentioning

confidence: 99%

The effect of portal and peripheral insulin delivery on carbohydrate and lipid metabolism in a miniature pig model of human IDDM

et al. 1997

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The normal portal-peripheral insulin gradient is absent in patients with insulin-dependent diabetes mellitus (IDDM) managed on conventional insulin therapy. The effect of this on intermediary metabolism has been studied widely in man and animals. However, results have been conflicting and considerable uncertainty still exists regarding the importance of the gradient for the maintenance of overall metabolic homeostasis.In animal models the metabolic importance of the portal-systemic gradient has been examined using a variety of techniques including direct cannulation combined with exogenous insulin infusion, islet and pancreatic transplantation, and diversion of pancreatic venous drainage . In some studies control of hepatic glucose output or blood glucose concentrations was superior with the portal route of insulin delivery, [3,8,15,16,18,20] while in others no Diabetologia (1997Diabetologia ( ) 40: 1125Diabetologia ( -1134 The effect of portal and peripheral insulin delivery on carbohydrate and lipid metabolism in a miniature pig model of human IDDM Summary A pig model of insulin-dependent diabetes was used to examine the importance of the portal-systemic insulin gradient for whole-body metabolic control. Six pigs had jugular vein, portal vein, and carotid artery cannulae implanted before being made diabetic (150 mg kg − 1 streptozotocin). Each animal received 4 weeks of portal and 4 weeks of peripheral insulin delivery in random order. The blood glucose target range was 5-10 mmol ⋅ l − 1 , and serum fructosamine and fasting and postprandial blood glucose concentrations were not different between peripheral and portal insulin infusion. Insulin requirement was not different between the 4 week infusion periods, but fasting peripheral insulin levels after peripheral delivery (124 ± 16 (mean ± SEM) pmol ⋅ l − 1 ) were significantly higher (p < 0.05) than in portally infused (73.8 ± 5.4 pmol ⋅ l − 1 ) or pre-diabetic control animals (68.4 ± 3.6 pmol ⋅ l − 1 ). Basal hepatic glucose output was also higher (p < 0.05) in peripherally (4.2 ± 0.4 mg ⋅ kg − 1 ⋅ min − 1 ) than in portally infused animals (2.9 ± 0.4 mg ⋅ kg). Clamp glucose metabolic clearance rate was, however, not different between the peripheral and portal insulin delivery routes (8.1 ± 1.0 vs 9.0 ± 0.7 ml ⋅ kg), although both were significantly lower (p < 0.05) than that measured in prediabetic control animals (11.7 ± 1.0 ml ⋅ kg. Lipid profiles and subfractions were similar in all three groups. It is concluded that the portal route of delivery is superior to the peripheral in maintaining more appropriate insulin concentrations and control of hepatic glucose output, although in the absence of euglycaemia it is still associated with significant metabolic abnormalities. [Diabetologia (1997[Diabetologia ( ) 40: 1125[Diabetologia ( -1134

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Insulin receptor down-regulation and impaired antilipolytic action of insulin in diabetic patients after pancreas/kidney transplantation.

Cited by 24 publications

References 24 publications

Stevioside inhibits atherosclerosis by improving insulin signaling and antioxidant defense in obese insulin-resistant mice

Stevioside inhibits atherosclerosis by improving insulin signaling and antioxidant defense in obese insulin-resistant mice

The Effect of Systemic Versus Portal Insulin Delivery in Pancreas Transplantation on Insulin Action and VLDL Metabolism

The effect of portal and peripheral insulin delivery on carbohydrate and lipid metabolism in a miniature pig model of human IDDM

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