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Conditional ablation of Gsk-3? in islet beta cells results in expanded mass and resistance to fat feeding-induced diabetes in mice.

ABSTRACT: AIMS/HYPOTHESIS:Glycogen synthase kinase 3? (GSK-3?) is an enzyme that is suppressed by insulin and when elevated results in insulin resistance in skeletal muscle and diabetes. Its role in beta cell development and function is little known. Because of the enzyme's anti-proliferative and pro-apoptotic properties, the hypothesis to be tested here was that beta cell specific deficiency of GSK-3? in mice would result in enhanced beta cell mass and function. METHODS:Mice with beta cell deficiency of GSK-3? (?-Gsk-3? [also known as Gsk3b](-/-)) were generated by breeding Gsk-3? (flox/flox) mice with mice overexpressing the Cre recombinase gene under the control of the rat insulin 2 gene promoter (RIP-Cre mice), and glucose tolerance, insulin secretion, islet mass, proliferation and apoptosis were measured. Changes in islet proteins were investigated by western blotting. RESULTS:On a normal diet ?-Gsk-3? ( -/- ) mice were found to have mild improvement of glucose tolerance and glucose-induced insulin secretion, and increased beta cell mass accompanied by increased proliferation and decreased apoptosis. On a high-fat diet ?-Gsk-3? (-/-) mice exhibited improved glucose tolerance and expanded beta cell mass with increased proliferation relative to that in control mice, resisting fat-fed diabetes. Molecular mechanisms accounting for these phenotypic changes included increased levels of islet IRS1 and IRS2 proteins and phospho-Akt, suggesting enhanced signalling through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and increased islet levels of pancreas/duodenum homeobox protein 1 (PDX1). Inhibition of GSK3 in MIN6 cells in vitro led to increased IRS1 and IRS2 protein levels through inhibition of proteosomal degradation. CONCLUSIONS/INTERPRETATION:These results are consistent with a mechanism whereby endogenous GSK-3? activity controls islet beta cell growth by feedback inhibition of the insulin receptor/PI3K/Akt signalling pathway.

SUBMITTER: Liu Y

PROVIDER: S-EPMC2991091 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Conditional ablation of Gsk-3β in islet beta cells results in expanded mass and resistance to fat feeding-induced diabetes in mice.

Liu Y Y Tanabe K K Baronnier D D Patel S S Woodgett J J Cras-Méneur C C Permutt M A MA

Diabetologia 20100907 12

<h4>Aims/hypothesis</h4>Glycogen synthase kinase 3β (GSK-3β) is an enzyme that is suppressed by insulin and when elevated results in insulin resistance in skeletal muscle and diabetes. Its role in beta cell development and function is little known. Because of the enzyme's anti-proliferative and pro-apoptotic properties, the hypothesis to be tested here was that beta cell specific deficiency of GSK-3β in mice would result in enhanced beta cell mass and function.<h4>Methods</h4>Mice with beta cell ...[more]

PMID: 20821187

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Project description:Mesenchymal stem cells offer a promising approach to the treatment of myocardial infarction and prevention of heart failure. However, in the clinic, cells will be isolated from patients who may be suffering from comorbidities such as obesity and diabetes, which are known to adversely affect progenitor cells. Here we determined the effect of a high-fat diet (HFD) on mesenchymal stem cells from cardiac and adipose tissues. Mice were fed a HFD for 4 months, after which cardiosphere-derived cells (CDCs) were cultured from atrial tissue and adipose-derived mesenchymal cells (ADMSCs) were isolated from epididymal fat depots. HFD raised body weight, fasted plasma glucose, lactate, and insulin. Ventricle and liver tissue of HFD-fed mice showed protein changes associated with an early type 2 diabetic phenotype. At early passages, more ADMSCs were obtained from HFD-fed mice than from chow-fed mice, whereas CDC number was not affected by HFD. Migratory and clonogenic capacity and release of vascular endothelial growth factor did not differ between cells from HFD- and chow-fed animals. CDCs from chow-fed and HFD-fed mice showed no differences in surface marker expression, whereas ADMSCs from HFD-fed mice contained more cells positive for CD105, DDR2, and CD45, suggesting a high component of endothelial, fibroblast, and hematopoietic cells. Both Noggin and transforming growth factor ?-supplemented medium induced an early stage of differentiation in CDCs toward the cardiomyocyte phenotype. Thus, although chronic high-fat feeding increased the number of fibroblasts and hematopoietic cells within the ADMSC population, it left cardiac progenitor cells largely unaffected.Mesenchymal cells are a promising candidate cell source for restoring lost tissue and thereby preventing heart failure. In the clinic, cells are isolated from patients who may be suffering from comorbidities such as obesity and diabetes. This study examined the effect of a high-fat diet on mesenchymal cells from cardiac and adipose tissues. It was demonstrated that a high-fat diet did not affect cardiac progenitor cells but increased the number of fibroblasts and hematopoietic cells within the adipose-derived mesenchymal cell population.

Dataset Information

Conditional ablation of Gsk-3? in islet beta cells results in expanded mass and resistance to fat feeding-induced diabetes in mice.

Publications

Conditional ablation of Gsk-3β in islet beta cells results in expanded mass and resistance to fat feeding-induced diabetes in mice.

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