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Metformin in the treatment of adults with type 2 diabetes mellitus

INTRODUCTION

Two classes of oral hypoglycemic drugs directly improve insulin action: biguanides (only metformin is currently available) and thiazolidinediones. In the absence of contraindications, metformin is considered the first choice for oral treatment of type 2 diabetes (table 1). A 2006 consensus statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), updated in 2009 and 2012, proposed that metformin therapy (in the absence of contraindications) be initiated, concurrent with lifestyle intervention, at the time of diabetes diagnosis [1,2].

The pharmacology, efficacy, and side effects of metformin for the treatment of diabetes will be reviewed here. A general discussion of initial pharmacologic treatment of type 2 diabetes and the role of metformin in the prevention of diabetes, in the treatment of polycystic ovary syndrome, and in gestational diabetes are reviewed separately. (See "Initial management of blood glucose in adults with type 2 diabetes mellitus" and "Prevention of type 2 diabetes mellitus", section on 'Metformin' and "Metformin for treatment of the polycystic ovary syndrome" and "Gestational diabetes mellitus: Glycemic control and maternal prognosis", section on 'Metformin'.)

MECHANISM OF ACTION

Metformin is effective only in the presence of insulin, and its major effect is to decrease hepatic glucose output [3,4]. In addition, metformin increases insulin-mediated glucose utilization in peripheral tissues (such as muscle and liver), particularly after meals, and has an antilipolytic effect that lowers serum free fatty acid concentrations, thereby reducing substrate availability for gluconeogenesis [3-5]. As a result of the improvement in glycemic control, serum insulin concentrations decline slightly [6,7].

Metformin also increases intestinal glucose utilization via nonoxidative metabolism, at least in experimental animals [4]. The lactate produced by this process is largely metabolized in the liver as a substrate for gluconeogenesis [3]. The latter effect could protect against hypoglycemia.

The molecular mechanisms of metformin action are not fully known. Activation of the enzyme AMP-activated protein kinase (AMPK) appears to be the mechanism by which metformin lowers serum lipid and blood glucose concentrations [8-10]. AMPK-dependent inhibitory phosphorylation of acetyl-coA carboxylases Acc1 and Acc2 then suppresses lipogenesis and lowers cellular fatty acid synthesis in liver and muscle, which in turn improves insulin sensitivity and reduces blood glucose levels [11,12]. Metformin works through the Peutz-Jeghers protein, LKB1, to regulate AMPK [13]. LKB1 is a tumor suppressor and activation of AMPK through LKB1 may play a role in inhibiting cell growth [14]. (See 'Cancer incidence' below.)

               

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Literature review current through: Jun 2014. | This topic last updated: Dec 20, 2013.
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