Lactate activation of ?-cell KATP channels inhibits glucagon secretion by hyperpolarizing the membrane potential and reducing Ca2+ entry.

ABSTRACT: OBJECTIVE:Elevations in pancreatic ?-cell intracellular Ca2+ ([Ca2+]i) lead to glucagon (GCG) secretion. Although glucose inhibits GCG secretion, how lactate and pyruvate control ?-cell Ca2+ 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 ?-cells. As lactate activates ATP-sensitive K+ (KATP) channels in cardiomyocytes, lactate may also modulate ?-cell KATP. Therefore, this study investigated how lactate signaling controls ?-cell Ca2+ 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 ?-cell Ca2+ handling, Vm, KATP currents, and GCG secretion. RESULTS:Lactate-inhibited mouse (75 ± 25%) and human (47 ± 9%) ?-cell [Ca2+]i fluctuations only under low-glucose conditions (1 mM) but had no effect on ?- or ?-cells [Ca2+]i. Glyburide inhibition of KATP channels restored ?-cell [Ca2+]i fluctuations in the presence of lactate. Lactate transport into ?-cells via MCTs hyperpolarized mouse (14 ± 1 mV) and human (12 ± 1 mV) ?-cell Vm and activated KATP channels. Interestingly, pyruvate showed a similar KATP activation profile and ?-cell [Ca2+]i inhibition as lactate. Lactate-induced inhibition of ?-cell [Ca2+]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 ?-cells through MCTs results in KATP activation, Vm hyperpolarization, reduced [Ca2+]i, and inhibition of GCG secretion. Thus, taken together, these data indicate that lactate either within ?-cells and/or elevated in serum could serve as important modulators of ?-cell function.

SUBMITTER: Zaborska KE 

PROVIDER: S-EPMC7479281 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature