Lactate activation of α-cell K(ATP) channels inhibits glucagon secretion by hyperpolarizing the membrane potential and reducing Ca(2+) entry

OBJECTIVE: Elevations in pancreatic α-cell intracellular Ca(2+) ([Ca(2+)](i)) lead to glucagon (GCG) secretion. Although glucose inhibits GCG secretion, how lactate and pyruvate control α-cell Ca(2+) handling is unknown. Lactate enters cells through monocarboxylate transporters (MCTs) and is also produced during glycolysis by lactate dehydrogenase A (LDHA), an enzyme expressed in α-cells. As lactate activates ATP-sensitive K(+) (K(ATP)) channels in cardiomyocytes, lactate may also modulate α-cell K(ATP). Therefore, this study investigated how lactate signaling controls α-cell Ca(2+) handling and GCG secretion. METHODS: Mouse and human islets were used in combination with confocal microscopy, electrophysiology, GCG immunoassays, and fluorescent thallium flux assays to assess α-cell Ca(2+) handling, V(m), K(ATP) currents, and GCG secretion. RESULTS: Lactate-inhibited mouse (75 ± 25%) and human (47 ± 9%) α-cell [Ca(2+)](i) fluctuations only under low-glucose conditions (1 mM) but had no effect on β- or δ-cells [Ca(2+)](i). Glyburide inhibition of K(ATP) channels restored α-cell [Ca(2+)](i) fluctuations in the presence of lactate. Lactate transport into α-cells via MCTs hyperpolarized mouse (14 ± 1 mV) and human (12 ± 1 mV) α-cell V(m) and activated K(ATP) channels. Interestingly, pyruvate showed a similar K(ATP) activation profile and α-cell [Ca(2+)](i) inhibition as lactate. Lactate-induced inhibition of α-cell [Ca(2+)](i) influx resulted in reduced GCG secretion in mouse (62 ± 6%) and human (43 ± 13%) islets. CONCLUSIONS: These data demonstrate for the first time that lactate entry into α-cells through MCTs results in K(ATP) activation, V(m) hyperpolarization, reduced [Ca(2+)](i), and inhibition of GCG secretion. Thus, taken together, these data indicate that lactate either within α-cells and/or elevated in serum could serve as important modulators of α-cell function.