Successful versus failed Adaptation to High Fat Diet induced Insulin Resistance; the role of IAPP induced Beta Cell Endoplasmic Reticulum Stress
Obesity is a known risk factor for Type 2 diabetes (T2DM). 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 T2DM 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.
To address this we fed wild type (WT) and human IAPP transgenic rats (HIP rats) either 10 weeks of regular chow or high fat diet and prospectively examined the relationships between: 1) beta cell mass and turnover, 2) beta cell ER stress 3) insulin secretion and 4) insulin sensitivity.
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 contrast, in HIP rats neither beta cell function or mass compensated for the increased insulin demand, leading to diabetes. The failure to increase beta cell mass in HIP rats was due to ER stress induced beta cell apoptosis that increased in proportion to diet induced insulin resistance.
IAPP-induced ER stress distinguishes the successful versus unsuccessful islet adaptation to a high fat diet in rats. These studies are consistant with the hypothesis that IAPP oligomers contribute to increased beta-cell apoptosis and beta cell failure in humans with Type 2 diabetes.