Towards Elucidating the Mechanism of Action of Biguanides

Diabetes type 2 patients are insensitive to insulin, a condition that leads to reduced glucose uptake by cells and, subsequently, to high concentration of glucose in the blood. For 60 years, biguanides have been one of the few effective therapeutics in reducing blood glucose levels. These include phenformin and metformin, the latter the most frequently prescribed drug for type 2 diabetes up to date. Although the mechanism of action of biguanides remains imperfectly understood the efficacy of metformin in the treatment of type 2 diabetes is unchallenged. Metformin was developed based on the natural product galegine. Initially, metformin was believed to interfere with complex 1 of the respiratory chain leading to a reduced ratio of [ATP]/[ADP.AMP] activating the enzyme AMP-activated protein kinase (AMPK). The assumption that the effects of metformin are exclusively mediated by AMPK has recently been challenged by genetic loss-of-function experiments. Since then it has been hypothesized that metformin inhibits hepatic gluconeogenesis by interfering with the cAMP/PKA pathway acting as a glucagon antagonist. Another study has suggested that biguanides lead to an altered hepatocellular redox state through inhibition of mitochondrial glycerophosphate dehydrogenase (mGPD) yielding a decreased liver glucose output. However, none of the studies show a direct binding of biguanides to the assumed protein effector. In this thesis, we provide for the first time ever evidence for biguanides binding directly a cytosolic protein, Coronin1C. This study provides evidence that biguanides may indeed antagonize the action of glucagon, thus reducing fasting glucose levels, through modulation of Coronin1C. Coronin1C is a key regulator of actin homeostasis but is also involved directly in relaying extracellular signals through the cAMP/PKA pathway. It has been shown that functional modulation of Coronin1C through biguanide binding i) alters actin homeostasis, ii) attenuates cAMP/PKA pathway signaling and iii) leads to a displacement of AMPK from Coronin1C. Modulation of Coronin’s function is a new and potentially crucial piece of the puzzle as to how biguanides exert their therapeutic efficacy. A Coronin1C centered mechanism of action of biguanides is intriguing as it coherently links previously described cellular effects that cannot be explained with the currently available theories. This study sheds also light on biguanides anti-cancer properties. A better understanding of biguanides mechanism of action could lead to improved outcomes for millions of diabetics worldwide as well as it could provide a new protein target for the treatment of cancer.