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Metformin mechanisms

Submitted by cdkelly on Wed, 10/03/2018 - 18:59

In terms of antidiabetic properties, metformin is typically used to combat type 2 diabetes mellitus. It is thought to decrease the hepatic (relating to the liver) production of glucose and increase the sensitivity to insulin as well as use of glucose by peripheral tissue. In addition metformin has been shown to successfully combat polycystic ovarian syndrome, which results in metabolic disorders due to the development of insulin resistance(Ikhlas, et al.). The anticancer properties of metformin were first discovered when researchers realized that cancer patients who were on metformin showed less mortality than other diabetic cancer patients on different drugs to deal with their diabetes (Ikhlas et al.). Mechanistically, metformin targets a number of important players in cancer pathway, but specifically the inhibition of mTORC1 via AMPK independent and AMPK dependant pathways.

    Activated AMPK causes the p53 to become active. This then induces cell cycle arrest at G1/S phase, simultaneously upregulating pro-apoptotic genes including p21 and Bax. In addition Foxo3a, a tumor suppressor that affects genes including Bim, bNIP3, and Bcl-xLon are activated by AMPK as well. Furthermore, lipogenesis (acetyl CoA is converted to fatty acids) is inhibited (Ikhlas, et al.). AMPK finally leads to the inhibition of mTORC1, which is a huge player in proliferation and cell growth via its control of autophagy, translation of mRNA and metabolic effects (Ikhlas, et al.).