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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 LAPP 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 LAPP oligomers contribute to increased β-cell apoptosis and β-cell failure in humans with type 2 diabetes. Diabetes 58: 906-916, 2009
Insulin resistance, most often attributed to high- caloric food intake and consequent obesity (1), is a well-characterized risk factor for type 2 diabetes (2,3). However, most obese individuals (>80%) do not develop diabetes (4) because they are able to compen- sate for insulin resistance by an adaptive increase in insulin secretion (5,6). Type 2 diabetes develops as a result of a failure to adequately increase insulin secretion to meet demands of insulin resistance (5,7,8). Consistent with this, genomewide studies imply that the genetic variance that underlies predisposition to type 2 diabetes is manifest in pancreatic β-cells (9-11). By implication, there is a subset of individuals in the general population at risk of developing type 2 diabetes if subject to insulin resistance. These observations raise the question, what underlies the failure of β-cell adaptation to insulin resistance in those predisposed to...