Increased β-Cell Apoptosis Prevents Adaptive Increase in β-Cell Mass in Mouse Model of Type 2 Diabetes

Evidence for Role of Islet Amyloid Formation Rather Than Direct Action of Amyloid

  1. Alexandra E. Butler1,
  2. Juliette Janson2,
  3. Walter C. Soeller3 and
  4. Peter C. Butler1
  1. 1Division of Endocrinology and Diabetes, Keck School of Medicine, University of Southern California, Los Angeles, California
  2. 2Karolinska Institutet, Stockholm, Sweden
  3. 3Pfizer Global Research and Development, Pfizer, Groton, Connecticut
  1. Address correspondence and reprint requests to Dr. Peter C. Butler, Division of Endocrinology and Diabetes, Keck School of Medicine, University of Southern California, 1333 San Pablo St., BMT-B11, Los Angeles, CA 90033. E-mail: pbutler{at}usc.edu

Abstract

Nondiabetic obese humans adapt to insulin resistance by increasing β-cell mass. In contrast, obese humans with type 2 diabetes have an ∼60% deficit in β-cell mass. Recent studies in rodents reveal that β-cell mass is regulated, increasing in response to insulin resistance through increased β-cell supply (islet neogenesis and β-cell replication) and/or decreased β-cell loss (β-cell apoptosis). Prospective studies of islet turnover are not possible in humans. In an attempt to establish the mechanism for the deficit in β-cell mass in type 2 diabetes, we used an obese versus lean murine transgenic model for human islet amyloid polypeptide (IAPP) that develops islet pathology comparable to that in humans with type 2 diabetes. By 40 weeks of age, obese nontransgenic mice did not develop diabetes and adapted to insulin resistance by a 9-fold increase (P < 0.001) in β-cell mass accomplished by a 1.7-fold increase in islet neogenesis (P < 0.05) and a 5-fold increase in β-cell replication per islet (P < 0.001). Obese transgenic mice developed midlife diabetes with islet amyloid and an 80% (P < 0.001) deficit in β-cell mass that was due to failure to adaptively increase β-cell mass. The mechanism subserving this failed expansion was a 10-fold increase in β-cell apoptosis (P < 0.001). There was no relationship between the extent of islet amyloid or the blood glucose concentration and the frequency of β-cell apoptosis. However, the frequency of β-cell apoptosis was related to the rate of increase of islet amyloid. These prospective studies suggest that the formation of islet amyloid rather than the islet amyloid per se is related to increased β-cell apoptosis in this murine model of type 2 diabetes. This finding is consistent with the hypothesis that soluble IAPP oligomers but not islet amyloid are responsible for increased β-cell apoptosis. The current studies also support the concept that replicating β-cells are more vulnerable to apoptosis, possibly accounting for the failure of β-cell mass to expand appropriately in response to obesity in type 2 diabetes.

Footnotes

    • Accepted May 21, 2003.
    • Received February 18, 2003.
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