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Metformin, one of the most effective antidiabetic drugs, remains on market for a long time. Yet, the mechanisms of action are still elusive. Past studies point to LKB1/AMPK axis as the mediator of gluoneogenesis regulation. A recent report challenges this notion and provides evidence suggesting metformin can function in the absence of LKB1/AMPK.
Foretz and colleagues found metformin suppresses glucose production in wildtype primary hepatocytes dose-dependently. To their surprise, this suppression remains effective in AMPK deficient hepatocytes. They went further to show there is no difference between wildtype and AMPK liver specific knockout mice for glucose regulation by metformin. Similarly, LKB1, the upstream kinase of AMPK, is not required for glucose lowering effects of metformin in hepatocytes and in animals. More importantly, Foretz et al found metformin treatment reduces energy state of primary hepatocytes and in livers of mice, which is probably the primary reason of decreased glucose production. The new mechanism proposed by Foretz et al raises number of interesting questions, such as the target of metformin, the mitochondria changes after treatment, beta oxidation, glycolysis. Answers for them will provide more insights about the action of metformin and clear understanding of type II diabetes. ... Read more highlights.