Institute of Pharmacy, Department of Pharmacology, University of Tübingen, Tübingen, Germany.
Islets. 2010 May-Jun;2(3):156-63. doi: 10.4161/isl.2.3.11412.
The AMP-activated protein kinase (AMPK) is one of the key players in cellular energy regulation adapting cellular demands to nutritional and metabolic variations. Oral antidiabetic drugs like metformin and glitazones (thiazolidinediones) are known to stimulate this enzyme. Besides their established action on peripheral organs including liver and muscles, it has been claimed that these drugs may affect β-cell function. However, it is still a matter of debate whether pharmacological AMPK stimulation increases or decreases insulin secretion. To study this point and to reveal mechanisms underlying changes in insulin secretion we used the specific AMPK activator AICAR and investigated its effects on stimulus-secretion coupling. Membrane potential and currents were measured by the patch-clamp technique, [Ca (2+)]c, mitochondrial membrane potential, and NAD(P)H by fluorescence techniques and insulin secretion by a radioimmunoassay. AICAR enhanced glucose-stimulated insulin release, an effect that can be attributed to the augmentation of electrical activity and [Ca (2+)]c resulting from an AICAR-evoked inhibition of the KATP current. This latter effect was not due to a direct interaction of AICAR with the K[ATP] channels but was dependent on cell metabolism. AICAR did not affect mitochondrial membrane potential or NAD(P)H autofluorescence. Metformin mimicked the action of AICAR on electrical activity, [Ca (2+) ]c, and K[ATP] current. However, compared to AICAR the effects were less pronounced and not sufficient to stimulate insulin secretion. In conclusion, activation of AMPK augments nutrient-induced insulin secretion. Thus, targeting AMPK of β-cells may be an appropriate strategy for the treatment of disturbed glucose homeostasis..
腺苷酸活化蛋白激酶（AMPK）是细胞能量调节的关键因子之一，可根据营养和代谢变化来调节细胞需求。二甲双胍和噻唑烷二酮类（格列酮类）等口服抗糖尿病药物已知可刺激这种酶。除了它们在包括肝脏和肌肉在内的外周器官中的既定作用外，据称这些药物可能会影响β细胞功能。但是，关于药理 AMPK 刺激是否会增加或减少胰岛素分泌，仍存在争议。为了研究这一点并揭示胰岛素分泌变化的机制，我们使用了特定的 AMPK 激活剂 AICAR，并研究了其对刺激-分泌偶联的影响。通过膜片钳技术测量膜电位和电流，通过荧光技术测量 [Ca（2+）]c、线粒体膜电位和 NAD（P）H，通过放射免疫测定法测量胰岛素分泌。AICAR 增强了葡萄糖刺激的胰岛素释放，这种作用可归因于 AICAR 抑制 KATP 电流引起的电活动和 [Ca（2+）]c 的增加。后一种作用不是由于 AICAR 与 K[ATP]通道的直接相互作用，而是依赖于细胞代谢。AICAR 不影响线粒体膜电位或 NAD（P）H 自发荧光。二甲双胍模拟了 AICAR 对电活动、[Ca（2+）]c 和 K[ATP]电流的作用。然而，与 AICAR 相比，其作用不太明显，不足以刺激胰岛素分泌。总之，AMPK 的激活增强了营养诱导的胰岛素分泌。因此，针对β细胞的 AMPK 可能是治疗葡萄糖稳态紊乱的合适策略。
