Analysis of molecular mechanisms for impaired insulin secretion and beta-cell hyperplasia caused by lipotoxicity

脂毒性导致胰岛素分泌受损和β细胞增生的分子机制分析

• 批准号: 15390285
• 负责人: TERAUCHI Yasuo
• 金额: $ 9.47万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390285/
• 关键词: PPARγ; islet triglyceride content; insulin secretion; SREBP-1c; AMP kinase; high-fat diet; glucokinase; IRS-2; DNA microarray

On a high-fat diet, glucose-induced insulin secretion in PPARγ^<+/-> mice was impaired. The tissue triglyceride content of the white adipose tissue, skeletal muscle, and liver was decreased in PPARγ^<+/-> mice, but it was increased in the islets. Administration pioglitazone reduced the islet triglyceride content in PPARγ^<+/-> mice on a high-fat diet and ameliorated the impaired insulin secretion.Despite reduced body weight, serum leptin level was significantly higher in PPARγ^<+/-> mice on the high-fat diet than in wild-type mice. To determine the impact of a lack of leptin action on PPARγ^<+/-> mice, we generated PPARγ^<+/-> mice on the ob/ob genetic background. At 16 weeks, PPARγ^<+/-> ob/ob mice showed worse glucose tolerance than ob/ob mice. Insulin secretion from islets was markedly impaired in PPARγ^<+/-> ob/ob mice as compared with ob/ob mice. Thus, leptin plays a role in the protection from high-fat diet-induced glucose intolerance in PPARγ^<+/-> mice.We overexpressed a consti … More tutively active form of SREBP-1c in INS-1 cells with an adenoviral vector. This treatment activated transcription of the genes involved in fatty acid biosynthesis, increased cellular triglyceride content, and blunted glucose-stimulated insulin secretion. Exposure of AICAR increased free fatty acid oxidation, partially reversed the triglyceride accumulation, phosphorylated AMPK and acetyl-coenzyme A carboxylase, and improved the impaired glucose-stimulated insulin secretion. Mice overexpressing SREBP-1c in. β-cells developed diabetes with decreased insulin secretion.On a high-fat diet, wild-type mice showed marked β-cell hyperplasia, whereas Gck^<+/-> mice failed to show such compensatory β-cell hyperplasia in association with decreased β-cell replication, despite the presence of a similar degree of insulin resistance. DNA chip analysis revealed decreased levels of expression of IGF-1-receptor (2.4-fold) and Irs2 (25-fold) in the islets of Gck^<+/-> mice on the high-fat diet, compared with the islets of wild-type mice on the high-fat diet. Western blot and RT-PCR analyses confirmed up-regulation of IGF-1-receptor and Irs2 expression in the islets of the wild-type mice on the high-fat diet, compared with wild-type mice fed standard chow, and their reduced expression in the islets of Gck^<+/-> mice on the high-fat diet, compared with the islets of wild-type mice on the high-fat diet. Moreover, Irs2^<+/-> mice on the high-fat diet failed to show a sufficient increase in β-cell mass. Less

在高脂肪饮食中，PPARγ^<+/->小鼠葡萄糖诱导的胰岛素分泌受损。PPARγ^<+/->小鼠白色脂肪组织、骨骼肌和肝脏组织甘油三酯含量降低，而胰岛组织甘油三酯含量升高。吡格列酮降低高脂饮食PPARγ^<+/->小鼠胰岛甘油三酯含量，改善胰岛素分泌受损。尽管体重减轻，但高脂饮食的PPARγ^<+/->小鼠的血清瘦素水平显著高于野生型小鼠。为了确定缺乏瘦素作用对PPARγ^<+/->小鼠的影响，我们在ob/ob遗传背景下产生了PPARγ^<+/->小鼠。16周时，PPARγ^<+/-> ob/ob小鼠的葡萄糖耐量低于ob/ob小鼠。与ob/ob小鼠相比，PPARγ^<+/-> ob/ob小鼠胰岛胰岛素分泌明显受损。因此，瘦素在PPARγ^<+/->小鼠高脂肪饮食诱导的葡萄糖耐受不良中起保护作用。我们用腺病毒载体在INS-1细胞中过表达了一种更有效的SREBP-1c。这种治疗激活了参与脂肪酸生物合成的基因的转录，增加了细胞甘油三酯含量，减弱了葡萄糖刺激的胰岛素分泌。暴露于AICAR增加游离脂肪酸氧化，部分逆转甘油三酯积累，磷酸化AMPK和乙酰辅酶A羧化酶，改善葡萄糖刺激的胰岛素分泌受损。过表达SREBP-1c的小鼠β细胞发生糖尿病，胰岛素分泌减少。在高脂肪饮食中，野生型小鼠表现出明显的β细胞增生，而Gck^<+/->小鼠没有表现出这种与β细胞复制减少相关的代偿性β细胞增生，尽管存在类似程度的胰岛素抵抗。DNA芯片分析显示，与高脂肪饮食的野生型小鼠相比，高脂肪饮食的Gck^<+/->小鼠胰岛中igf -1受体表达水平（2.4倍）和Irs2表达水平（25倍）降低。Western blot和RT-PCR分析证实，与标准饲料的野生型小鼠相比，高脂肪饮食的野生型小鼠胰岛中igf -1受体和Irs2表达上调，而与高脂肪饮食的野生型小鼠相比，高脂肪饮食的Gck^<+/->小鼠胰岛中igf -1受体和Irs2表达降低。此外，高脂肪饮食的Irs2^<+/->小鼠β细胞质量没有显示出足够的增加。少

项目成果

Terauchi Y, et al.: "Impact of genetic background and ablation of IRS-3 on IRS-2 knockout mice."J.Biol.Chem.. 278. 14284-14290 (2003)

Terauchi Y 等人：“遗传背景和 IRS-3 消融对 IRS-2 敲除小鼠的影响。”J.Biol.Chem.. 278. 14284-14290 (2003)

Pioglitazone reduces islet triglyceride content and restores impaired glucose-stimulated insulin secretion in heterozygous peroxisome proliferator-activated receptor-gamma-deficient mice on a high-fat diet.

在高脂肪饮食的杂合过氧化物酶体增殖物激活受体γ缺陷小鼠中，吡格列酮可降低胰岛甘油三酯含量并恢复受损的葡萄糖刺激的胰岛素分泌。

• 发表时间: 2004
• 期刊: Diabetes 53
• 作者: Matsui J;et al.
• 通讯作者: et al.

Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus.

• DOI: 10.1172/jci21484
• 发表时间: 2004-10
• 期刊: The Journal of clinical investigation
• 作者: N. Kubota;Y. Terauchi;K. Tobe;Wataru Yano;R. Suzuki;K. Ueki;Iseki Takamoto;H. Satoh;Toshiyuki Maki;Tetsuya Kubota;M. Moroi;Miki Okada-Iwabu;O. Ezaki;R. Nagai;Y. Ueta;T. Kadowaki;T. Noda

Pdx1 expression in Irs2 deficient mouse beta-cells is regulated in a strain-dependent manner.

Irs2 缺陷型小鼠 β 细胞中的 Pdx1 表达以菌株依赖性方式受到调节。

• 发表时间: 2003
• 期刊: J.Biol.Chem. 278
• 作者: Suzuki R;et al.
• 通讯作者: et al.

Suzuki R, et al.: "Pdx1 expression in Irs2 deficient mouse β-cells is regulated in a strain-dependent manner."J.Biol.Chem.. 278. 43691-43698 (2003)

Suzuki R 等人：“Irs2 缺陷型小鼠 β 细胞中的 Pdx1 表达以菌株依赖性方式受到调节。”J.Biol.Chem.. 278. 43691-43698 (2003)