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

在高脂饮食中，葡萄糖诱导的γ^&lt；/-&gt；小鼠的胰岛素分泌受到损害。PPARγ^&lt；/-&gt；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。服用吡格列酮可降低高脂饮食PPARγ^&lt；/-&gt；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PPARγ；/-&gt；小鼠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^&lt；/-&gt；小鼠的影响，我们在ob/ob遗传背景上培育了PPARγ^&lt；/-&gt；小鼠。16周时，PPARγ；&lt；/-&ob/ob小鼠表现出比ob/ob小鼠更差的糖耐量。与ob/ob小鼠相比，PPARγ^&lt；/-&gt；ob/ob小鼠的胰岛胰岛素分泌明显受损。因此，瘦素在保护PPARγ^&lt；/-&gt；小鼠免受高脂饮食诱导的糖耐量异常中起作用。我们超量表达了一段…。用腺病毒载体在INS-1细胞中表达更具活性的SREBP-1c。这种治疗激活了与脂肪酸生物合成有关的基因的转录，增加了细胞甘油三酯的含量，并抑制了葡萄糖刺激的胰岛素分泌。暴露于AICAR可增加游离脂肪酸的氧化，部分逆转甘油三酯的蓄积，磷酸化AMPK和乙酰辅酶A羧基酶，改善葡萄糖刺激的胰岛素分泌受损。高表达SREBP-1c的小鼠。β细胞患上糖尿病，胰岛素分泌减少。在高脂饮食中，野生型小鼠表现出明显的β细胞增殖，而尽管存在类似程度的胰岛素抵抗，但GCK^&lt；/-&gt；小鼠没有表现出与β细胞复制减少相关的代偿性β细胞增殖。DNA芯片分析显示，与高脂饮食的野生型小鼠相比，高脂饮食组小鼠胰岛中IGF-1受体(2.4倍)和irs2(25倍)的表达水平降低。Western印迹和RT-PCR分析证实，与喂标准饲料的野生型小鼠相比，高脂饮食的野生型小鼠胰岛中IGF-1受体和Irs2的表达上调，而与高脂饮食的野生型小鼠相比，它们在GCK^&lt；/-&gt；；小鼠的胰岛中的表达降低。此外，高脂饮食的Irs2^&lt；/-&gt；小鼠没有表现出足够的β细胞质量的增加。较少

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