Hyperexcitability reduces TRPM5 in pancreatic β-cells: Insights into disruption of insulin secretion in chronically stimulated islets.

Abstract

Acute inhibition of ATP-sensitive K+ (KATP) channels in pancreatic β-cells results in depolarization, Ca2+ influx, and insulin secretion. Accordingly, loss of KATP is associated with congenital hyperinsulinism in humans. However, many patients with congenital hyperinsulinism caused by KATP LOF mutations gradually remit or even progress to a diabetic state, and adult mice that chronically lack KATP exhibit reduced insulin secretion and are glucose-intolerant. The mechanism for this counterintuitive progression remains unknown. Ca2+ imaging revealed elevated [Ca2+]i at low glucose in islets from KATP KO animals, but mean [Ca2+]i is similar to WT in high glucose. To look for potential contributors to reduced insulin secretion in KATP KO, we examined gene expression using whole islet and single cell RNAseq and qPCR in several different mouse models of loss of β-cell KATP­ activity. One of the most consistent and marked changes is a profound decrease in expression of the [Ca2+]i-activated non-selective cation channel TRPM5 in all models. TRPM5 is normally expressed in β cells and acts to promote insulin secretion. Steviol, a pharmacological activator of TRPM5, increased [Ca2+]i in WT islets at all glucose levels, but there was no response to steviol in KATP KO islets. Furthermore, steviol failed to stimulate insulin secretion in KATP KO animals. The data suggest that loss of TRPM5 may contribute to reduced levels of stimulatory [Ca2+]i and to reduced insulin secretion following KATP loss. These findings represent new insights to a phenomenon that has long remained unexplained, yet is critical to understand, given the potentially profound clinical consequences.