Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion

Abstract

Summary 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, 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.

α2-adrenergic signaling disrupts β cell BDNF-TrkB receptor tyrosine kinase signaling

“…In that study, blockade of NGF-TrkA signaling in mice using chemical genetics and pancreas-specific TrkA knockout impaired insulin secretion and glucose tolerance. Glucose also induced TrkA phosphorylation (21). In several studies of NGF action on islets including those discussed here and our previous work (49), pharmacological concentrations of NGF were used, up to 50 times higher than the concentration of BDNF needed to induce ERK1/2 activation.…”

“…NGF and its receptor TrkA have been linked to β cells for a number of years (18,20,21,49,55). A recent study concluded that NGF and TrkA have a critical role in β cell function in mice and in isolated islets from mice and humans (21). In that study, blockade of NGF-TrkA signaling in mice using chemical genetics and pancreas-specific TrkA knockout impaired insulin secretion and glucose tolerance.…”

“…Our results suggest that physiological concentrations of BDNF impact signal transduction through TrkB in β cells and likely other islet cell types. NGF and its receptor TrkA have been linked to β cells for a number of years (18,20,21,49,55). A recent study concluded that NGF and TrkA have a critical role in β cell function in mice and in isolated islets from mice and humans (21).…”

“…TrkB is expressed in multiple islet cell types including rodent and human β and α cells (13)(14)(15)(16)(17), and usually to a greater extent than the related receptor tyrosine kinase TrkA. TrkA and its ligand nerve growth factor (NGF) function in β cell survival, pancreatic innervation, and are regulated by glucose (18)(19)(20)(21)(22)(23)(24).…”

Metabolic‐vascular coupling in skeletal muscle: A potential role for capillary pericytes?

“…For example, pericytes produce components of the extracellular matrix that promote beta cell proliferation, a process that is hindered when pericytes are depleted. Furthermore, it is proposed that pericytes produce growth factors required for glucose‐stimulated insulin exocytosis . In the absence of these growth factors, beta cells dedifferentiate into an immature form and lose the ability to tailor insulin secretion to blood glucose concentration .…”