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

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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