| First Author | Zaborska KE | Year | 2020 |
| Journal | Mol Metab | Volume | 42 |
| Pages | 101056 | PubMed ID | 32736089 |
| Mgi Jnum | J:359410 | Mgi Id | MGI:6714917 |
| Doi | 10.1016/j.molmet.2020.101056 | Citation | Zaborska KE, et al. (2020) Lactate activation of alpha-cell KATP channels inhibits glucagon secretion by hyperpolarizing the membrane potential and reducing Ca(2+) entry. Mol Metab 42:101056 |
| abstractText | OBJECTIVE: Elevations in pancreatic alpha-cell intracellular Ca(2+) ([Ca(2+)]i) lead to glucagon (GCG) secretion. Although glucose inhibits GCG secretion, how lactate and pyruvate control alpha-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 alpha-cells. As lactate activates ATP-sensitive K(+) (KATP) channels in cardiomyocytes, lactate may also modulate alpha-cell KATP. Therefore, this study investigated how lactate signaling controls alpha-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 alpha-cell Ca(2+) handling, Vm, KATP currents, and GCG secretion. RESULTS: Lactate-inhibited mouse (75 +/- 25%) and human (47 +/- 9%) alpha-cell [Ca(2+)]i fluctuations only under low-glucose conditions (1 mM) but had no effect on beta- or delta-cells [Ca(2+)]i. Glyburide inhibition of KATP channels restored alpha-cell [Ca(2+)]i fluctuations in the presence of lactate. Lactate transport into alpha-cells via MCTs hyperpolarized mouse (14 +/- 1 mV) and human (12 +/- 1 mV) alpha-cell Vm and activated KATP channels. Interestingly, pyruvate showed a similar KATP activation profile and alpha-cell [Ca(2+)]i inhibition as lactate. Lactate-induced inhibition of alpha-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 alpha-cells through MCTs results in KATP activation, Vm hyperpolarization, reduced [Ca(2+)]i, and inhibition of GCG secretion. Thus, taken together, these data indicate that lactate either within alpha-cells and/or elevated in serum could serve as important modulators of alpha-cell function. |
