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OBJECTIVE-We studied how glucose and ATP-sensitive K+ (K^sub ATP^) channel modulators affect α-cell [Ca^sup 2+^]^sub c^.
RESEARCH DESIGN AND METHODS-GYY mice (expressing enhanced yellow fluorescent protein in a-cells) and NMRI mice were used. [Ca^sup 2+^]^sub c^, the K^sub ATP^ current (I^sub KATP^, perforated mode) and cell metabolism [NAD(P)H fluorescence] were monitored in single α-cells and, for comparison, in single β-cells.
RESULTS-In 0.5 mmol/l glucose, [Ca^sup 2+^]^sub c^ oscillated in some α-cells and was basal in the others. Increasing glucose to 15 mmol/l decreased [Ca^sup 2+^]^sub c^ by ~30% in oscillating cells and was ineffective in the others. α-Cell I^sub KATP^ was inhibited by tolbutamide and activated by diazoxide or the mitochondrial poison azide, as in β-cells. Tolbutamide increased α-cell [Ca^sup 2+^]^sub c^, whereas diazoxide and azide abolished [Ca^sup 2+^]^sub c^ oscillations. Increasing glucose from 0.5 to 15 mmol/l did not change I^sub KATP^ and NAD(P)H fluorescence in α-cells in contrast to β-cells. The use of nimodipine showed that L-type Ca^sup 2+^ channels are the main conduits for Ca^sup 2+^ influx in α-cells. γ-Aminobutyric acid and zinc did not decrease α-cell [Ca^sup 2+^]^sub c^, and insulin, although lowering [Ca^sup 2+^]^sub c^ very modestly, did not affect glucagon secretion.
CONCLUSIONS-α-Cells display similarities with β-cells: K^sub ATP^ channels control Ca^sup 2+^ influx mainly through L-type Ca^sup 2+^ channels. However, α-cells have distinct features from β-cells: Most K^sub ATP^ channels are already closed at low glucose, glucose does not affect cell metabolism and I^sub KATP^, and it slightly decreases [Ca^sup 2+^]^sub c^. Hence, glucose and K^sub ATP^ channel modulators exert distinct effects on a-cell [Ca^sup 2+^]^sub c^. The direct small glucose-induced drop in α-cell [Ca^sup 2+^]^sub c^ contributes likely only partly to the strong glucose-induced inhibition of glucagon secretion in islets. Diabetes 58:412-421, 2009
Glucagon secretion is normally inhibited by hy- perglycemia and stimulated by hypoglycemia, but alterations of its physiological regulation contribute to abnormal glucose homeostasis in diabetes (1,2). The cellular mechanisms controlling gluca- gon secretion are still unclear. In particular, whether glucose directly or indirectly influences α-cells remains disputed. An indirect inhibition of glucagon secretion by glucose has variably been ascribed to glucose-induced release of an inhibitory paracrine messenger from β- or d-cells, such as insulin (3-5), γ-aminobutyric acid (GABA) (4,6-9), Zn^sup 2+^ (10,11), or somatostatin...