Glucose and Pharmacological Modulators of ATP-Sensitive K+ Channels Control [Ca2+]c by Different Mechanisms in Isolated Mouse α-Cells

OBJECTIVE-We studied how glucose and ATP-sensitive K+ (K-ATP) channel modulators affect alpha-cell [Ca2+](c). RESEARCH DESIGN AND METHODS-GYY mice (expressing enhanced yellow fluorescent protein in alpha-cells) and NMRI mice were used. [Ca2+](c), the K-ATP current (I-KATP, perforated mode) and cell metabolism [NAD(P)H fluorescence] were monitored in single alpha-cells and, for comparison, in single beta-cells. RESULTS-In 0.5 mmol/l glucose, [Ca2+](c), oscillated in some alpha-cells and was basal in the others. Increasing glucose to 15 mmol/l decreased [Ca2+](c) by similar to 30% in oscillating cells and was ineffective in the others. alpha-Cell I-KATP was inhibited by tolbutamide and activated by diazoxide or the mitochondrial poison azide, as in beta-cells. Tolbutamide increased alpha-cell [Ca2+](c), whereas diazoxide and azide abolished [Ca2+](c), oscillations. Increasing glucose from 0.5 to 15 mmol/l did not change I-KATP and NAD(P)H fluorescence in alpha-cells in contrast to beta-cells. The use of nimodipine showed that L-type Ca2+ channels are the main conduits for Ca2+ influx in alpha-cells. gamma-Aminobutyric acid and zinc did not decrease alpha-cell [Ca2+](c), and insulin, although lowering [Ca2+](c) very modestly, did not affect glucagon secretion. CONCLUSIONS-alpha-Cells display similarities with beta-cells: K-ATP channels control Ca2+ influx mainly through L-type Ca2+ channels. However, alpha-cells have distinct features from beta-cells: Most K-ATP channels are already closed at low glucose, glucose does not affect cell metabolism and I-KATP, and it slightly decreases [Ca2+](c). Hence, glucose and K-ATP channel modulators exert distinct effects on alpha-cell [Ca2+](c). The direct small glucose-induced drop in alpha-cell [Ca2+](c) contributes likely only partly to the strong glucose-induced inhibition of glucagon secretion in islets. Diabetes 58:412-421, 2009