Abstract
Metformin is considered the first-choice drug for type 2 diabetes treatment. Actually, pleiotropic effects of metformin have been recognized, and there is evidence that this drug may have a favorable impact on health beyond its glucose-lowering activity. In summary, despite its long history, metformin is still an attractive research opportunity in the field of endocrine and metabolic diseases, age-related diseases, and cancer. To this end, its mode of action in distinct cell types is still in dispute. The aim of this work was to review the current knowledge and recent findings on the molecular mechanisms underlying the pharmacological effects of metformin in the field of metabolic and endocrine pathologies, including some endocrine tumors. Metformin is believed to act through multiple pathways that can be interconnected or work independently. Moreover, metformin effects on target tissues may be either direct or indirect, which means secondary to the actions on other tissues and consequent alterations at systemic level. Finally, as to the direct actions of metformin at cellular level, the intracellular milieu cooperates to cause differential responses to the drug between distinct cell types, despite the primary molecular targets may be the same within cells. Cellular bioenergetics can be regarded as the primary target of metformin action. Metformin can perturb the cytosolic and mitochondrial NAD/NADH ratio and the ATP/AMP ratio within cells, thus affecting enzymatic activities and metabolic and signaling pathways which depend on redox- and energy balance. In this context, the possible link between pyruvate metabolism and metformin actions is extensively discussed.
Highlights
Metformin (N,N-dimethylbiguanide) is considered the first-choice drug for type 2 diabetes treatment in conjunction with life style modifications, due to its efficacy, safety profile, low risk of hypoglycemia, and reduction of the risk for macrovascular complications [1,2]
Ohara and coworkers showed that metformin treatment resulted in decreased androgen receptor (AR) expression and increased expression of Homeobox A10 (HOXA10), a transcription factor required for the implantation of embryos, in the endometrium of women with polycystic ovary syndrome (PCOS)
Some metabolic rearrangements associated with the response to high metformin concentrations within cells may resemble a deficiency of the pyruvate dehydrogenase (PDH) complex activity, with a decrease in tricarboxylic acid (TCA) cycle flux and mitochondrial NADH oxidation, the enhancement of glycolysis and lactate production, and the switch to glutamine utilization to provide ATP or biosynthetic intermediates [12,147]
Summary
Metformin (N,N-dimethylbiguanide) is considered the first-choice drug for type 2 diabetes treatment in conjunction with life style modifications, due to its efficacy, safety profile, low risk of hypoglycemia, and reduction of the risk for macrovascular complications [1,2]. In vitro studies using cell lines and few studies in animal models have suggested to extend the efficacy of metformin to other endocrine tumors and contributed to characterize the differential effects of metformin in distinct cell types [18–20] These laboratory-based data have not been confirmed by clinical evidence yet. As to the direct actions of metformin at cellular level, the intracellular milieu cooperates to cause differential responses to the drug between distinct cell types, both normal and tumor cells, despite the primary molecular target may be the same within cells. The preliminary review work throughout the events triggered by metformin at cellular level in distinct cell types helps to discuss the biological traits which may drive the tumor cell response to metformin In this context, metformin is a potential therapeutic tool, but it has a role as a valid tool in the basic research area aimed at identifying new targets for drug development. Phenformin has been banned from clinical use due to increased risk of lactic acidosis [7,35]
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