Adrb2 controls glucose homeostasis by developmental regulation of pancreatic islet vasculature

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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 Adrb2 results in glucose intolerance and impaired insulin secretion in mice, and unexpectedly, specifically in females. The metabolic phenotypes were recapitulated by Adrb2 deletion from neonatal, but not adult, b-cells. Mechanistically, Adrb2 loss increases production of Vascular Endothelial Growth Factor-A (VEGF-A) in female neonatal b-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.

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All data generated or analyzed are included in the manuscript and supporting files

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Alexis M Ceasrine

Department of Biology, Johns Hopkins University, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.
Eugene E Lin

Department of Biology, Johns Hopkins University, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.
David N Lumelsky

Department of Biology, Johns Hopkins University, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.
Radhika Iyer

Department of Biology, Johns Hopkins University, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.
Rejji Kuruvilla

Department of Biology, Johns Hopkins University, Baltimore, United States

For correspondence
rkuruvilla@jhu.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2851-675X

Funding

National Institutes of Health (R01DK108267)

Rejji Kuruvilla

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures relating to animal care and treatment conformed to The Johns Hopkins University Animal Care and Use Committee (ACUC) and NIH guidelines. All of the animals were handled according to approved institutional ACUC protocols (#MO17A14) of Johns Hopkins University

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.