Conditional ablation of Gsk-3β in islet beta cells results in expanded mass and resistance to fat feeding-induced diabetes in mice.
Conditional ablation of Gsk-3β in islet beta cells results in expanded mass and resistance to fat feeding-induced diabetes in mice.
复制标题
DOI：
10.1007/s00125-010-1882-x
复制
发表时间：
2010-12
期刊：
影响因子：
8.2
通讯作者：
Permutt, M. A.
中科院分区：
文献类型：
--
作者：
Liu, Y.;Tanabe, K.;Baronnier, D.;Patel, S.;Woodgett, J.;Cras-Meneur, C.;Permutt, M. A.
糖原合成酶-3β(GSK-3β)是一种被胰岛素抑制的酶，当胰岛素升高时，会导致骨骼肌和糖尿病的胰岛素抵抗。它在β细胞发育和功能中的作用鲜为人知。由于这种酶的抗增殖和促凋亡特性，这里要检验的假设是，小鼠中缺乏β细胞特异性的GSK-3β会导致β细胞质量和功能的增强。在大鼠胰岛素2基因启动子的控制下，用高表达Cre重组酶基因的小鼠(β(β-β−/−)饲养GSK-3βFLOX/FLOX小鼠，获得β细胞缺陷小鼠，检测葡萄糖耐量、胰岛素分泌、胰岛质量、细胞增殖和细胞凋亡。用免疫印迹法检测胰岛蛋白的变化。在正常饮食下，β-GSK-3β−/−小鼠的糖耐量和葡萄糖诱导的胰岛素分泌略有改善，β细胞质量增加，伴随着增殖增加和细胞凋亡减少。在高脂饮食下，β-GSK-3β−/−小鼠表现出糖耐量的改善和β细胞质量的增加，与对照组相比，增殖增加，从而抵抗脂肪喂养的糖尿病。导致这些表型变化的分子机制包括胰岛IRS1和IRS2蛋白和磷酸化Akt水平的增加，这表明通过磷脂酰肌醇3-激酶(PI3K)/Akt途径的信号增强，以及胰岛/十二指肠同源盒蛋白1(PDX1)的水平增加。抑制体外培养的MIN6细胞中的GSK3通过抑制蛋白酶体的降解而导致IRS1和IRS2蛋白水平的升高。这些结果与内源性GSK-3β活性通过反馈抑制胰岛素受体/PI3K/Akt信号通路来控制胰岛β细胞生长的机制一致。
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 proapoptotic 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. Mice with beta cell deficiency of GSK-3β (β-Gsk-3β [also known as Gsk3b]−/−) were generated by breeding Gsk-3βflox/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. On a normal diet β-Gsk-3β−/− 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 β-Gsk-3β−/− 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. These results are consistent with a mechanism whereby endogenous GSK-3β activity controls islet beta cell growth by feedback inhibition of the insulin receptor/PI3K/Akt signalling pathway.
登录
查看更多内容
影响因子：
7.7
作者：
Liu H;Remedi MS;Pappan KL;Kwon G;Rohatgi N;Marshall CA;McDaniel ML
通讯作者：
McDaniel ML
影响因子：
4.8
作者：
Buteau, Jean;Shlien, Adam;Accili, Domenico
通讯作者：
Accili, Domenico
影响因子：
8.2
作者：
Rao, R.;Hao, C. -M.;Breyer, M. D.
通讯作者：
Breyer, M. D.
影响因子：
15.9
作者：
Kushner, JA;Ye, J;White, MF
通讯作者：
White, MF
影响因子：
5.3
作者：
Patel, Satish;Doble, Bradley W.;Woodgett, James R.
通讯作者：
Woodgett, James R.