Adrb2 controls glucose homeostasis by developmental regulation of pancreatic islet vasculature.

Abstract

A better understanding of processes controlling the development and function of pancreatic islets is critical for diabetes prevention and treatment. Here, we reveal a previously unappreciated function for pancreatic β2-adrenergic receptors (Adrb2) in controlling glucose homeostasis by restricting islet vascular growth during development. Pancreas-specific deletion of <i>Adrb2</i> results in glucose intolerance and impaired insulin secretion in mice, and unexpectedly, specifically in females. The metabolic phenotypes were recapitulated by <i>Adrb2</i> deletion from neonatal, but not adult, β-cells. Mechanistically, <i>Adrb2</i> loss increases production of Vascular Endothelial Growth Factor-A (VEGF-A) in female neonatal β-cells and results in hyper-vascularized islets during development, which in turn, disrupts insulin production and exocytosis. Neonatal correction of islet hyper-vascularization, via VEGF-A receptor blockade, fully rescues functional deficits in glucose homeostasis in adult mutant mice. These findings uncover a regulatory pathway that functions in a sex-specific manner to control glucose metabolism by restraining excessive vascular growth during islet development.