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

ABSTRACT:

Objective

Elevations in pancreatic α-cell intracellular Ca²⁺ ([Ca²⁺]_i) lead to glucagon (GCG) secretion. Although glucose inhibits GCG secretion, how lactate and pyruvate control α-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 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 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 α-cell Ca²⁺ handling, V_m, K_ATP currents, and GCG secretion.

Results

Lactate-inhibited mouse (75 ± 25%) and human (47 ± 9%) α-cell [Ca²⁺]_i fluctuations only under low-glucose conditions (1 mM) but had no effect on β- or δ-cells [Ca²⁺]_i. Glyburide inhibition of K_ATP channels restored α-cell [Ca²⁺]_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 [Ca²⁺]_i inhibition as lactate. Lactate-induced inhibition of α-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 α-cells through MCTs results in K_ATP activation, V_m hyperpolarization, reduced [Ca²⁺]_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.

SUBMITTER: Zaborska KE 

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

REPOSITORIES: biostudies-literature