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


Zaborska KEKarolina E , Dadi PKPrasanna K , Dickerson MTMatthew T , Nakhe AYArya Y , Thorson ASAriel S , Schaub CMCharles M , Graff SMSarah M , Stanley JEJade E , Kondapavuluru RSRoy S , Denton JSJerod S , Jacobson DADavid A . Molecular metabolism. 2020 07 28; 42(). 101056


OBJECTIVE: Elevations in pancreatic α-cell intracellular Ca ([Ca]) lead to glucagon (GCG) secretion. Although glucose inhibits GCG secretion, how lactate and pyruvate control α-cell Ca 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) channels in cardiomyocytes, lactate may also modulate α-cell K. Therefore, this study investigated how lactate signaling controls α-cell Ca 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 handling, V, K currents, and GCG secretion.

RESULTS: Lactate-inhibited mouse (75 ± 25%) and human (47 ± 9%) α-cell [Ca] fluctuations only under low-glucose conditions (1 mM) but had no effect on β- or δ-cells [Ca]. Glyburide inhibition of K channels restored α-cell [Ca] 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 and activated K channels. Interestingly, pyruvate showed a similar K activation profile and α-cell [Ca] inhibition as lactate. Lactate-induced inhibition of α-cell [Ca] 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 activation, V hyperpolarization, reduced [Ca], 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.