The onset of type 2 diabetes is characterized by transition from successful to failed insulin secretory compensation to obesity-related insulin resistance and dysmetabolism. Energy-rich diets in rodents are commonly studied models of compensatory increases in both insulin secretion and β cell mass. However, the mechanisms of these adaptive responses are incompletely understood, and it is also unclear why these responses eventually fail. We measured the temporal trends of glucose homeostasis, insulin secretion, β cell morphometry, and islet gene expression in C57BL/6NTac mice fed a 60% high-fat diet (HFD) or control diet for up to 16 weeks. A 2-fold increased hyperinsulinemia was maintained for the first 4 weeks of HFD feeding and then further increased through 16 weeks. β cell mass increased progressively starting at 4 weeks, principally through nonproliferative growth. Insulin sensitivity was not significantly perturbed until 11 weeks of HFD feeding. Over the first 8 weeks, we observed two distinct waves of increased expression of β cell functional and prodifferentiation genes. This was followed by activation of the unfolded protein response at 8 weeks and overt β cell endoplasmic reticulum stress at 12-16 weeks. In summary, β cell adaptation to an HFD in C57BL/6NTac mice entails early insulin hypersecretion and a robust growth phase along with hyperexpression of related genes that begin well before the onset of observed insulin resistance. However, continued HFD exposure results in cessation of gene hyperexpression, β cell functional failure, and endoplasmic reticulum stress. These data point to a complex but not sustainable integration of β cell-adaptive responses to nutrient overabundance, obesity development, and insulin resistance.

OBJECTIVEWe previously showed that peroxisome proliferator–activated receptor (PPAR)-γ in β-cells regulates pdx-1 transcription through a functional PPAR response element (PPRE). Gene Bank blast for a homologous nucleotide sequence revealed the same PPRE within the rat glucose-dependent insulinotropic polypeptide receptor (GIP-R) promoter sequence. We investigated the role of PPARγ in GIP-R transcription.RESEARCH DESIGN AND METHODSChromatin immunoprecipitation assay, siRNA, and luciferase gene transcription assay in INS-1 cells were performed. Islet GIP-R expression and immunohistochemistry studies were performed in pancreas-specific PPARγ knockout mice (PANC PPARγ−/−), normoglycemic 60% pancreatectomy rats (Px), normoglycemic and hyperglycemic Zucker fatty (ZF) rats, and mouse islets incubated with troglitazone.RESULTSIn vitro studies of INS-1 cells confirmed that PPAR-γ binds to the putative PPRE sequence and regulates GIP-R transcription. In vivo verification was shown by a 70% reduction in GIP-R protein expression in islets from PANC PPARγ−/− mice and a twofold increase in islets of 14-day post-60% Px Sprague-Dawley rats that hyperexpress β-cell PPARγ. Thiazolidinedione activation (72 h) of this pathway in normal mouse islets caused a threefold increase of GIP-R protein and a doubling of insulin secretion to 16.7 mmol/l glucose/10 nmol/l GIP. Islets from obese normoglycemic ZF rats had twofold increased PPARγ and GIP-R protein levels versus lean rats, with both lowered by two-thirds in ZF rats made hyperglycemic by 60% Px.CONCLUSIONSOur studies have shown physiologic and pharmacologic regulation of GIP-R expression in β-cells by PPARγ signaling. Also disruption of this signaling pathway may account for the lowered β-cell GIP-R expression and resulting GIP resistance in type 2 diabetes.

Background:The molecular mechanisms for islet ␤-cell compensation and failure are not fully known. Results: FoxO1/PPAR␥ signaling regulates key ␤-cell genes, with this network being up-regulated in nondiabetic insulinresistant rats and impaired in rodents with diabetes. Conclusion: We examine the potential for the FoxO1/PPAR␥ network as a feature of ␤-cell compensation and failure. Significance: We identify targets for prevention of type 2 diabetes.