Growth hormone receptor regulates β cell hyperplasia and glucose-stimulated insulin secretion in obese mice

Insulin, growth hormone (GH), and insulin-like growth factor-1 (IGF-1) play key roles in the regulation of beta cell growth and function. Although beta cells express the GH receptor, the direct effects of GH on beta cells remain largely unknown. Here we have employed a rat insulin II promoter-driven (RIP-driven) Cre recombinase to disrupt the GH receptor in beta cells (beta GHRKO). beta GHRKO mice fed a standard chow diet exhibited impaired glucose-stimulated insulin secretion but had no changes in beta cell mass. When challenged with a high-fat diet, beta GHRKO mice showed evidence of a beta cell secretory defect, with further deterioration of glucose homeostasis indicated by their altered glucose tolerance and blunted glucose-stimulated insulin secretion. Interestingly, beta GHRKO mice were impaired in beta cell hyperplasia in response to a high-fat diet, with decreased P cell proliferation and overall reduced beta cell mass. Therefore, GH receptor plays critical roles in glucose-stimulated insulin secretion and beta cell compensation in response to a high-fat diet.