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The molecular link between obesity and [beta] cell failure that causes diabetes is difficult to establish. Here we show that a conditional knockout of insulin receptor substrate 2 (Irs2) in mouse pancreas [beta] cells and parts of the brain - including the hypothalamus - increased appetite, lean and fat body mass, linear growth, and insulin resistance that progressed to diabetes. Diabetes resolved when the mice were between 6 and 10 months of age: functional [beta] cells expressing Irs2 repopulated the pancreas, restoring sufficient [beta] cell function to compensate for insulin resistance in the obese mice. Thus, Irs2 signaling promotes regeneration of adult [beta] cells and central control of nutrient homeostasis, which can prevent obesity and diabetes in mice.

Copyright (C) 2004 The American Society for Clinical Investigation, Inc.