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Metformin, routinely used as first-line drug in the treatment of type 2 diabetes, has been shown to have cardioprotective effects beyond its glycemic control. These have been attributed to increases in Akt concentrations and activation of protein kinases in the RISK pathways, which prevent the mPTP from opening and rupturing it and therefore, protects myocyte viability. In myocardial infarction and subsequent reperfusion, metformin activation of AMPK promotes glycolysis and keeps the mPTP closed. Given as a preconditioning and/or postconditioning agent, metformin has been shown to decrease infarct size and improve survival rates after myocardial infarction. Metformin has further been reported to restore depleted PGC-1α levels and improve mitochondrial biogenesis by increasing phosphorylation of eNOSser1177, which produces NO and leads to reduced vascular inflammation and myocardial injury after ischemia. There is strong evidence suggesting that metformin improves cardiovascular outcomes by influencing metabolic signal transduction pathways. There are growing calls for metformin use to be expanded off-label beyond the traditional glycemic control. We review experimental evidence for metformin's impact on cardiovascular disease and its underlying molecular mechanisms of action and also discuss why significant gains made in experimental conditions have not translated into significant therapeutic applications.

Background: Oxidative stress and impaired antioxidant capacity in diabetes are associated with diabetic nephropathy. Metformin, as an adjunct to insulin could decrease oxidative stress and may therefore improve renal function in type 1 diabetes (T1D). Objectives: To investigate the effects of metformin as adds-on therapy to insulin on renal dysfunction in T1D. Materials and Methods: Male Sprague-Dawley rats (230-250 g) were divided into 5 groups (n =7). Rats in groups A and B were orally treated with 3.0 mL/kg body weight (BW) of distilled water, while those in groups C and D were treated with insulin (4.0 U/kg BW bid) or oral metformin (250 mg/kg BW), respectively. Group E rats were similarly treated with both metformin and insulin. Groups B-E were rendered diabetic by intraperitoneal injections of 65 mg/kg BW of streptozotocin. Fasting blood glucose concentrations and glucose tolerance tests were done. The animals were sacrificed by halothane overdose after 56 days, blood taken by cardiac puncture and kidneys excised and stored at -80°C for further analysis. Results: Untreated diabetic rats exhibited significant weight loss, increased polydipsia and polyuria, impaired glucose tolerance, electrolyte retention, reduced creatinine clearance and urea excretion and increased oxidative stress compared to controls, respectively. However, these were reversed by treatment with metformin and insulin. Conclusions: Metformin does not improve glycemic control in TID but exerts renoprotective effects by reducing oxidative stress in the presence of insulin. Metformin should therefore be considered for adjunct therapy with insulin in TID.

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