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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 …