Successful Versus Failed Adaptation to High-Fat Diet–Induced Insulin Resistance

The Role of IAPP-Induced β-Cell Endoplasmic Reticulum Stress

  1. Aleksey V. Matveyenko,
  2. Tatyana Gurlo,
  3. Marie Daval,
  4. Alexandra E. Butler and
  5. Peter C. Butler
  1. From the Larry Hillblom Islet Research Center, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California.
  1. Corresponding author: Aleksey V. Matveyenko, amatveyenko{at}


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.


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    • Received October 23, 2008.
    • Accepted January 6, 2009.
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