Both diabetes and cancer are prevalent diseases whose incidence rates are

Both diabetes and cancer are prevalent diseases whose incidence rates are increasing worldwide especially in countries that are undergoing rapid industrialization changes. to pancreatic and breast cancer the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes. While diabetes (type 2) and cancer share many risk factors the biological links between the two diseases are poorly characterized. In this review we highlight the mechanistic pathways that link diabetes to colorectal and prostate cancer and the use of Metformin a diabetes drug to prevent and/or treat colorectal and prostate cancer. We review the role of AMPK activation in autophagy oxidative stress inflammation apoptosis and cell cycle progression. and clinical studies. 2 Biological actions pharmacokinetics and pharmacogenetics of metformin The history of metformin a biguanide derivative dates back to the Middle-Ages and its structural analogue galegine was isolated from (goat’s rue French lilac Italian fitch); a plant native to the Middle East that has been used for treatment of diabetes in Europe 13. Accumulating evidence shows beneficial survival effects of therapeutic intervention with metformin for cancer patients with T2DM (Fig. ?(Fig.1).1). Metformin a cationic (hydrophilic base) medication exerts its pleiotropic pharmacological results beyond those of metabolic control 14 and contains favorable anti-inflammatory results 15 16 Shape 1 Metformin-mediated amelioration in diabetic and cancerous GW3965 HCl deranged metabolic profile improvements in hemostasis and endothelial function with regression of proliferative condition. Metformin works for the liver organ and decreases blood sugar result and secondarily mainly … Information for the pharmacological response to metformin needs a knowledge of both its pharmacokinetics and genetic variation of the different transporters for the di-directional movement of metformin across plasma membranes 17 (Fig.?(Fig.2).2). Metformin is absorbed from the lumen of the gastrointestinal tract (GI) through plasma membrane monoamine transporter (PMAT or equilibrative nucleoside transporter-ENT-4) 18. By its passage through the organic cation transporter 1 (OCT1) located in the basolateral membrane of human hepatocytes metformin decreases hepatic glucose synthesis 19. Indeed this was confirmed by investigations on OCT1 gene-deficient mice GW3965 HCl where the uptake of metformin in hepatic and intestinal tissues was lower compared to control animals 19. These studies implied that OCT1 is pivotal for raising the intracellular concentration of metformin; and as a corollary there was a corresponding derangement in glucose metabolism 19. Interestingly metformin is excreted unmetabolized through mutli-drug and toxin extrusion 1 (MATE1) and MATE2 located GW3965 HCl in the apical membrane of kidney proximal tubular cells into urine 20. Recent CLTB studies suggest that substantial inter-individual heterogeneity in metformin pharmacokinetics exists and this is recognized to be due to genetic variants of different metformin transporter proteins 20-22. Reduced expression or altered functionality of transporter proteins will result in less than optimum pharmacotherapy or undesirable toxic effects of metformin. Figure 2 Metformin transporters: Isoforms and genes that demonstrate a role in metformin pharmacokinetics pharmacogenetics and thus have an impact on its pharmacological efficacy. GW3965 HCl Metformin is absorbed from the lumen of the gastrointestinal tract through plasma … Due to the reduced uptake of glucose from the intestinal tract metformin improves insulin sensitivity by increasing peripheral glucose absorption and utilization by adipose tissue and skeletal muscle. It reduces hyperinsulinemia and improves GW3965 HCl insulin resistance by enhancing the affinity of insulin receptor for insulin 23. Moreover metformin-driven benefits GW3965 HCl negate dyslipidemia by creating a milieu to give rise to lower circulating levels of total cholesterol low-density lipoprotein (LDL) and triglycerides 24. In addition administration of metformin to patients promotes lower body weight or at least weight neutrality 25 26 Importantly metformin is a low cost drug with a well characterized safety profile in management of diabetes and cancer. 3.