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lüll Successful versus failed adaptation to high-fat diet-induced insulin resistance: the role of IAPP-induced beta-cell endoplasmic reticulum stress Matveyenko AV; Gurlo T; Daval M; Butler AE; Butler PCDiabetes 2009[Apr]; 58 (4): 906-16OBJECTIVE: 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 beta-cell mass and insulin secretion. Islet pathology in type 2 diabetes is characterized by beta-cell loss, islet amyloid derived from islet amyloid polypeptide (IAPP), and increased beta-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 beta-cell mass and turnover, beta-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 beta-cell mass. In HIP rats, in contrast, neither beta-cell function nor mass compensated for the increased insulin demand, leading to diabetes. The failure to increase beta-cell mass in HIP rats was the result of ER stress-induced beta-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 beta-cell apoptosis and beta-cell failure in humans with type 2 diabetes.|Adaptation, Physiological[MESH]|Amyloid/genetics/*physiology[MESH]|Animals[MESH]|Arginine/pharmacology[MESH]|Diabetes Mellitus, Type 2/epidemiology/pathology[MESH]|Dietary Fats/*pharmacology[MESH]|Endoplasmic Reticulum/pathology/*physiology[MESH]|Humans[MESH]|Hyperglycemia/blood/pathology[MESH]|Insulin Resistance/*physiology[MESH]|Insulin Secretion[MESH]|Insulin-Secreting Cells/pathology/*physiology[MESH]|Insulin/metabolism[MESH]|Islet Amyloid Polypeptide[MESH]|Islets of Langerhans/pathology[MESH]|Obesity/complications[MESH]|Rats[MESH]|Rats, Sprague-Dawley[MESH]|Rats, Transgenic[MESH] |