Mechanism of Metformin: A Tale of Two Sites.

Metformin (dimethylbiguanide) features as a current first-line pharmacological treatment for type 2 diabetes (T2D) in almost all guidelines and recommendations worldwide. It has been known that the antihyperglycemic effect of metformin is mainly due to the inhibition of hepatic glucose output, and therefore, the liver is presumably the primary site of metformin function.However, in this issue of Diabetes Care, Fineman and colleagues (1) demonstrate surprising results from their clinical trials that suggest the primary effect of metformin resides in the human gut. Metformin is an orally administered drug used for lowering blood glucose concentrations in patients with T2D, particularly in those overweight and obese as well as those with normal renal function. Pharmacologically, metformin belongs to the biguanide class of antidiabetes drugs. The history of biguanides can be traced from the use of Galega officinalis (commonly known as galega) for treating diabetes in medieval Europe (2). Guanidine, the active component of galega, is the parent compound used to synthesize the biguanides. Among three main biguanides introduced for diabetes therapy in late 1950s, metformin (Fig. 1A) has a superior safety profile and is well tolerated. The other two biguanides, phenformin and buformin, were withdrawn in the early 1970s due to the risk of lactic acidosis and increased cardiac mortality. The incidence of lactic acidosis with metformin at therapeutic doses is rare (less than three cases per 100,000 patient-years) and is not greater than with nonmetformin therapies (3). Major clinical advantages of metformin include specific reduction of hepatic glucose output, with subsequent improvement of peripheral insulin sensitivity, and remarkable cardiovascular safety, but without increasing islet insulin secretion, inducingweight gain, or posing a risk of hypoglycemia. Moreover, metformin has also shown benefits in reducing cancer risk and improving cancer prognosis (4,5), as well as counteracting the cardiovascular complications associated with diabetes (6). Although metformin has been widely prescribed to patients with T2D for over 50 years and has been found to be safe and efficacious both as monotherapy and in combination with other oral antidiabetes agents and insulin, the mechanism of metformin action is only partially explored and remains controversial. In mammals, oral bioavailability of metformin is;50% and is absorbed through the upper small intestine (duodenum and jejunum) (7) and then is delivered to the liver, circulates unbound essentially, and finally is eliminated by the kidneys. Note that metformin is not metabolized and so is unchanged throughout the journey in the body. The concentration of metformin in the liver is threeto fivefold higher than that in the portal vein (40–70 mmol/L) after single therapeutic dose (20 mg/kg/day in humans or 250 mg/kg/day in mice) (3,8), and metformin in general circulation is 10–40 mmol/L (8). As the antihyperglycemic effect of metformin is mainly due to the inhibition of hepatic glucose output and the concentration ofmetformin in the hepatocytes is much higher than in the blood, the liver is therefore presumed to be the primary site of metformin function. Indeed, the liver has been the focus of themajority of metformin research by far, and hepatic mechanisms of metformin that have been suggested include the activation of AMPK through liver kinase B1 and decreased energy charge (9,10), the inhibition of glucagon-induced cAMP production by blocking adenylyl cyclase (11), the increase of the AMP/ATP ratio by restricting NADHcoenzymeQ oxidoreductase (complex I) in themitochondrial electron transport chain (12) (albeit at high metformin concentrations,;5mmol/L), and,more recently, the reduction of lactate and glycerol metabolism to glucose through a redox change by inhibitingmitochondrial glycerophosphate dehydrogenase (13). It is noteworthy that the remaining ;50%ofmetformin,which is unabsorbed, accumulates in the gut mucosa of the distal small intestine at concentrations 30to