Abstract
Metformin is a biguanide drug that has been used to treat type 2 diabetes mellitus for more than 60 years. The United Kingdom Prospective Diabetic Study (UKPDS) has shown metformin to improve mortality rates in diabetes patients, and recent studies suggest metformin has additional effects in treating cancer, obesity, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome. Metformin has also been shown to alleviate weight gain associated with antipsychotic medication. Metformin has recently been extensively studied and emerging evidence suggests metformin decreases hepatocyte triglyceride accumulation in NAFLD and prevents liver tumorigenesis. Interestingly, studies have also shown metformin reduces visceral fat, suppresses white-adipose-tissue (WAT) extracellular matrix remodeling, and inhibits obesity-induced inflammation. However, clinical evidence for using metformin to treat NAFLD, cancer, metabolic syndrome, or to prevent hepatocellular carcinoma in NAFLD patients is lacking. This review therefore addresses the potential beneficial effects of metformin on NAFLD, its role in protecting against cardiac ischemia–reperfusion (I/R) injury, atherosclerosis, glucotoxicity, and lipotoxicity induced oxidative and ER stress in pancreatic β-cell dysfunction, as well as its underlying molecular mechanisms of action.
Highlights
Metformin, a guanidine derivative that was initially extracted from the plant Galega officinalis (French lilac) has been used as a glucose-lowering medication in humans for more than 60 years [1]
BAT is an important regulator of energy metabolism and one study has shown that the expression of uncoupling protein-1 (UCP-1) in BAT and uncoupling protein-3 (UCP-3) in skeletal muscle were upregulated after metformin treatment (1500 mg/day) [31]
A recent cohort study of older U.S veterans with type 2 diabetes (T2D) showed that metformin reduced cardiovascular disease (CVD) events among individuals with T2D [50]. These findings indicate the potential role of metformin for decreasing CVD risk, and evidence suggests that a combination therapy of metformin with statins has an even more favorable effect on CVD comorbidity in T2D patients [10]
Summary
A guanidine derivative that was initially extracted from the plant Galega officinalis (French lilac) has been used as a glucose-lowering medication in humans for more than 60 years [1]. The United Kingdom Prospective Diabetic Study (UKPDS) observed reduced mortality rates in patients using metformin [5]. Metformin is one of the few drugs that significantly reduce macrovascular events in diabetes patients when compared to other antidiabetic medications [2,5]. It may be effective in a number of other applications, such as treating cancer, obesity, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome [4]. Emerging evidence suggests metformin may have many other benefits, including reducing endoplasmic reticulum (ER).
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