Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP.
Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP.
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在禁食期间，肝脏产生的葡萄糖是为大脑提供底物所必需的。胰岛素不能抑制肝脏葡萄糖输出是2型糖尿病和其他胰岛素抵抗疾病高血糖的主要病因。50年来，在为数不多的几类有效减少葡萄糖产生的疗法中，双胍类药物一直是其中之一，其中包括苯福明和二甲双胍，后者是治疗2型糖尿病最常用的处方药。尽管如此，双胍类化合物的作用机制仍不完全清楚。十年前关于二甲双胍通过激活AMP激活蛋白激酶(AMPK)来减少葡萄糖合成的说法，最近受到了遗传功能丧失实验的挑战。在这里，我们提供了一种新的机制，通过二甲双胍拮抗胰升糖素的作用，从而降低空腹血糖水平。在小鼠肝细胞中，二甲双胍导致AMP和相关核苷酸的积聚，从而抑制腺苷环化酶，降低环磷酸腺苷和蛋白激酶A(PKA)的活性，阻止PKA关键蛋白靶标的磷酸化，并阻断肝细胞对胰高血糖素依赖的葡萄糖输出。这些数据支持二甲双胍与胰高血糖素拮抗有关的作用机制，并为抗糖尿病药物的开发提供了一种途径。
Glucose production by the liver is essential for providing a substrate for the brain during fasting. The inability of insulin to suppress hepatic glucose output is a major aetiological factor in the hyperglycaemia of type-2 diabetes mellitus and other diseases of insulin resistance,. For fifty years, one of the few classes of therapeutics effective in reducing glucose production has been the biguanides, which include phenformin and metformin, the latter the most frequently prescribed drug for type-2 diabetes. Nonetheless, the mechanism of action of biguanides remains imperfectly understood. The suggestion a decade ago that metformin reduces glucose synthesis through activation of the enzyme AMP-activated protein kinase (AMPK) has recently been challenged by genetic loss-of-function experiments. Here we provide a novel mechanism by which metformin antagonizes the action of glucagon, thus reducing fasting glucose levels. In mouse hepatocytes, metformin leads to the accumulation of AMP and related nucleotides, which inhibit adenylate cyclase, reduce levels of cyclic AMP and protein kinase A (PKA) activity, abrogate phosphorylation of critical protein targets of PKA, and block glucagon-dependent glucose output from hepatocytes. These data support a mechanism of action for metformin involving antagonism of glucagon, and suggest an approach for the development of antidiabetic drugs.
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