Leclerc Isabelle, Rutter Guy A
Henry Wellcome Laboratories for Integrated Cell Signalling and Department of Biochemistry, School of Medical Sciences, University of Bristol, University Walk, BS8 1TD Bristol, UK.
Diabetes. 2004 Dec;53 Suppl 3:S67-74. doi: 10.2337/diabetes.53.suppl_3.s67.
Stimulation of AMP-activated protein kinase (AMPK) in skeletal muscle and liver is seen as an exciting prospect for the treatment of type 2 diabetes. However, we have recently demonstrated that changes in AMPK activity accompany the exposure of pancreatic islet beta-cells to elevated glucose concentrations and may be involved in the activation of insulin secretion. Here, we discuss this hypothesis and explore the potential role of changes in AMPK activity in the actions of other secretagogues. Amino acids decreased AMPK activity in MIN6 beta-cells with an order of potency for inhibition: arg=leu < gln= leu + glu < glucose, which was closely correlated with the stimulation of insulin release (r2=0.76). By contrast, increases in intracellular Ca2+ concentration provoked by cell depolarization with KCl activated AMPK in the face of increased free intracellular ATP concentrations. Elevation of intracellular cAMP levels with isobutylmethylxanthine or forskolin had no effect on AMPK activity. We conclude that metabolizable amino acids regulate AMPK in the beta-cell via increases in the cytosolic ATP/AMP ratio and via phosphorylation by the upstream kinase LKB1. Intracellular Ca2+ ions may activate AMPK by calmodulin kinase 1 kinase-mediated phosphorylation. The latter may act as a novel feedback mechanism to inhibit excessive insulin secretion under some circumstances.
在骨骼肌和肝脏中刺激AMP活化蛋白激酶（AMPK）被视为治疗2型糖尿病的一个令人兴奋的前景。然而，我们最近证明，胰岛β细胞暴露于升高的葡萄糖浓度时，AMPK活性会发生变化，并且可能参与胰岛素分泌的激活。在这里，我们讨论这一假设，并探讨AMPK活性变化在其他促分泌剂作用中的潜在作用。氨基酸降低了MIN6β细胞中的AMPK活性，其抑制效力顺序为：精氨酸=亮氨酸＜谷氨酰胺=亮氨酸+谷氨酸＜葡萄糖，这与胰岛素释放的刺激密切相关（r2=0.76）。相比之下，在细胞内游离ATP浓度增加的情况下，用氯化钾使细胞去极化引起的细胞内Ca2+浓度升高激活了AMPK。用异丁基甲基黄嘌呤或福斯可林提高细胞内cAMP水平对AMPK活性没有影响。我们得出结论，可代谢氨基酸通过增加胞质ATP/AMP比值和上游激酶LKB1的磷酸化来调节β细胞中的AMPK。细胞内Ca2+离子可能通过钙调蛋白激酶1激酶介导的磷酸化激活AMPK。后者可能作为一种新的反馈机制，在某些情况下抑制过度的胰岛素分泌。
