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.

中文翻译：

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α 细胞 KATP 通道的乳酸激活通过超极化膜电位和减少 Ca2+ 进入来抑制胰高血糖素分泌。

客观的

胰腺 α 细胞胞内 Ca ²⁺ ([Ca ²⁺ ] _i ) 升高导致胰高血糖素 (GCG) 分泌。尽管葡萄糖抑制 GCG 分泌，但乳酸和丙酮酸盐如何控制 α 细胞 Ca ²⁺处理尚不清楚。乳酸通过单羧酸转运蛋白 (MCT) 进入细胞，并且也在乳酸脱氢酶 A (LDHA) 的糖酵解过程中产生，LDHA 是一种在 α 细胞中表达的酶。由于乳酸激活心肌细胞中的 ATP 敏感 K ⁺ (K _ATP ) 通道，因此乳酸还可以调节 α 细胞 K _ATP。因此，本研究调查了乳酸信号如何控制 α 细胞 Ca ²⁺处理和 GCG 分泌。

方法

小鼠和人类胰岛与共聚焦显微镜、电生理学、GCG 免疫测定和荧光铊通量测定结合使用，以评估 α 细胞 Ca ²⁺处理、V _m、K _ATP电流和 GCG 分泌。

结果

乳酸抑制小鼠 (75 ± 25%) 和人 (47 ± 9%) α 细胞 [Ca ²⁺ ] _i仅在低葡萄糖条件下 (1 mM) 波动，但对 β 或 δ 细胞没有影响 [ Ca ²⁺ ] _i。K _ATP通道的格列本脲抑制可恢复 α 细胞 [Ca ²⁺ ] _i在存在乳酸的情况下的波动。乳酸通过 MCT 超极化小鼠 (14 ± 1 mV) 和人 (12 ± 1 mV) α 细胞V _m和激活的 K _ATP通道转运到 α 细胞中。有趣的是，丙酮酸显示出相似的 K _ATP激活曲线和 α 细胞 [Ca ²⁺ ] _i抑制作用如乳酸。乳酸诱导的 α 细胞 [Ca ²⁺ ] _i流入抑制导致小鼠 (62 ± 6%) 和人类 (43 ± 13%) 胰岛的 GCG 分泌减少。

结论

这些数据首次表明，乳酸通过 MCT 进入 α 细胞会导致 K _ATP激活、V _m超极化、[Ca ²⁺ ] _i减少和 GCG 分泌抑制。因此，综合起来，这些数据表明 α 细胞内和/或血清中升高的乳酸可以作为 α 细胞功能的重要调节剂。