Successful Versus Failed Adaptation to High-Fat Diet–Induced Insulin Resistance: The Role of IAPP-Induced β-Cell Endoplasmic Reticulum Stress

OBJECTIVE: Obesity is a known risk factor for type 2 diabetes. However, most obese individuals do not develop diabetes because they adapt to insulin resistance by increasing β-cell mass and insulin secretion. Islet pathology in type 2 diabetes is characterized by β-cell loss, islet amyloid derived from islet amyloid polypeptide (IAPP), and increased β-cell apoptosis characterized by endoplasmic reticulum (ER) stress. We hypothesized that IAPP-induced ER stress distinguishes successful versus unsuccessful islet adaptation to insulin resistance. RESEARCH DESIGN AND METHODS: To address this, we fed wild-type (WT) and human IAPP transgenic (HIP) rats either 10 weeks of regular chow or a high-fat diet and prospectively examined the relations among β-cell mass and turnover, β-cell ER stress, insulin secretion, and insulin sensitivity. RESULTS: A high-fat diet led to comparable insulin resistance in WT and HIP rats. WT rats compensated with increased insulin secretion and β-cell mass. In HIP rats, in contrast, neither β-cell function nor mass compensated for the increased insulin demand, leading to diabetes. The failure to increase β-cell mass in HIP rats was the result of ER stress–induced β-cell apoptosis that increased in proportion to diet-induced insulin resistance. CONCLUSIONS: IAPP-induced ER stress distinguishes the successful versus unsuccessful islet adaptation to a high-fat diet in rats. These studies are consistent with the hypothesis that IAPP oligomers contribute to increased β-cell apoptosis and β-cell failure in humans with type 2 diabetes.