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Insulin secretion by pancreatic islet β cells is critical for glucose homeostasis, and a blunted β cell secretory response is an early deficit in type 2 diabetes. Here, we uncover a regulatory mechanism by which glucose recruits vascular-derived neurotrophins to control insulin secretion. Nerve growth factor (NGF), a classical trophic factor for nerve cells, is expressed in pancreatic vasculature while its TrkA receptor is localized to islet β cells. High glucose rapidly enhances NGF secretion and increases TrkA phosphorylation in mouse and human islets. Tissue-specific deletion of NGF or TrkA, or acute disruption of TrkA signaling, impairs glucose tolerance and insulin secretion in mice. We show that internalized TrkA receptors promote insulin granule exocytosis via F-actin reorganization. Furthermore, NGF treatment augments glucose-induced insulin secretion in human islets. These findings reveal a non-neuronal role for neurotrophins and identify a new regulatory pathway in insulin secretion that can be targeted to ameliorate β cell dysfunction.

Original publication

DOI

10.1016/j.devcel.2016.10.003

Type

Journal article

Journal

Dev Cell

Publication Date

07/11/2016

Volume

39

Pages

329 - 345

Keywords

actin remodeling, endosomal signaling, glucose homeostasis, human islets, insulin secretion, neurotrophins, pancreatic vasculature, pericytes, Actins, Animals, Endocytosis, Exocytosis, Gene Deletion, Glucose, Glucose Intolerance, Glucose Tolerance Test, Homeostasis, Humans, Insulin, Integrases, Mice, Inbred C57BL, Models, Biological, Nerve Growth Factor, Organ Specificity, Pancreas, Phosphorylation, Receptor, trkA, Signal Transduction