NEUROTROPHIN SIGNALING IS REQUIRED FOR GLUCOSE INDUCED INSULIN SECRETION

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Date
2016-10-17
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Johns Hopkins University
Abstract
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. While considerable attention has focused on mechanisms controlling β-cell mass, less is known about factors governing β-cell secretory responses. 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 TrkA phosphorylation in islets. Vascular-specific deletion of NGF, pancreas-specific TrkA deletion, or acute disruption of TrkA activity impairs glucose tolerance and insulin secretion in mice. Furthermore, we show that high glucose activates TrkA and NGF potentiates insulin secretion in human islets, and these effects are blunted in islets from pre-diabetic individuals. We find that internalized TrkA receptors promote insulin granule exocytosis via F-actin reorganization. These results 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.
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Keywords
insulin secretion, glucose homeostasis, actin remodeling, endosomal signaling, pericytes, neurotrophins, pancreatic veasculature
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