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Cyclic amp glucose8/9/2023 ![]() This has been challenged recently in experiments utilizing livers and primary hepatocytes lacking either AMPK or its upstream activating enzyme LKB1 4. Metformin inhibits mitochondrial respiratory Complex 1, thus reducing hepatic energy charge ten years ago it was suggested that metformin functioned through activation of the kinase AMPK 7– 10. Despite the wide acceptance of metformin as a first line therapeutic for diabetes, its mechanism of action remains unclear. These data support a mechanism of action for metformin involving antagonism of glucagon and suggest an approach to the development of antidiabetic drugs.īiguanides exert their major effect through inhibition of liver glucose production, though enhanced glucose disposal has been noted in some studies 5, 6. Metformin leads to the accumulation of AMP and related nucleotides, which inhibit adenylate cyclase, reduce levels of cyclic AMP and protein kinases A (PKA) activity, abrogate phosphorylation of critical protein targets of PKA, and block glucagon-dependent glucose output from hepatocytes. Here we provide a novel mechanism by which metformin antagonizes the action of glucagon, thus reducing fasting glucose levels. The suggestion a decade ago that metformin reduces glucose synthesis via activation of the enzyme AMP-activated protein kinase (AMPK) has recently been seriously challenged in genetic loss of function experiments 4. Nonetheless, the mechanism of action of biguanides remains imperfectly understood. 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 T2DM 3. The inability of insulin to suppress hepatic glucose output is a major etiological factor in the hyperglycemia of type 2 diabetes mellitus (T2DM) and other diseases of insulin resistance 1, 2. ![]() Glucose production by the liver is essential to providing substrate to the brain during fasting. ![]()
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