Successful versus failed adaptation to high-fat diet-induced insulin resistance: the role of IAPP-induced beta-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 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.


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.
Matveyenko
Aleksey V
AV
Larry Hillblom Islet Research Center, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA. amatveyenko@mednet.ucla.edu
Gurlo
Tatyana
T
Daval
Marie
M
Butler
Alexandra E
AE
Butler
Peter C
PC
D000222:Adaptation, Physiological; D000682:Amyloid / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000473:pathology; D004041:Dietary Fats / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000473:pathology / Q000502:physiology*; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000473:pathology / Q000502:physiology*; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000473:pathology; D009765:Obesity / Q000150:complications; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic
D000682:Amyloid; D004041:Dietary Fats; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D001120:Arginine