β-cell–specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter β-cell mass

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Abstract
Regulation of glucose homeostasis by insulin depends on the maintenance of normal β-cell mass and function. Insulin-like growth factor 1 (Igf1) has been implicated in islet development and differentiated function1,2, but the factors controlling this process are poorly understood. Pancreatic islets produce Igf1 and Igf2, which bind to specific receptors on β-cells3,4,5,6. Igf1 has been shown to influence β-cell apoptosis7, and both Igf1 and Igf2 increase islet growth8,9; Igf2 does so in a manner additive with fibroblast growth factor 2 (ref. 10). When mice deficient for the Igf1 receptor (Igf1r+/−) are bred with mice lacking insulin receptor substrate 2 (Irs2−/−), the resulting compound knockout mice show a reduction in mass of β-cells11 similar to that observed in pancreas of Igf1r−/− mice (ref. 11), suggesting a role for Igf1r in growth of β-cells. It is possible, however, that the effects in these mice occur secondary to changes in vascular endothelium12 or in the pancreatic ductal cells, or because of a decrease in the effects of other hormones implicated in islet growth. To directly define the role of Igf1, we have created a mouse with a β-cell–specific knockout of Igf1r (βIgf1r−/−). These mice show normal growth and development of β-cells, but have reduced expression of Slc2a2 (also known as Glut2) and Gck (encoding glucokinase) in β-cells, which results in defective glucose-stimulated insulin secretion and impaired glucose tolerance. Thus, Igf1r is not crucial for islet β-cell development, but participates in control of differentiated function.