Metformin Lowers Glucose Levels by Blocking the Action of Liver Cell Glucagon

The diabetes drug metformin works by inhibiting formation of adenylate cyclase, which blocks liver cell glucagon-dependent glucose output, and not by reducing glucose synthesis by activating the enzyme AMPK (5' adenosine monophosphate-activated protein kinase) as had been postulated previously.

Metformin is used alone or with other medications, including insulin, to treat type II diabetes. The drug helps to control the amount of glucose in the blood by decreasing the amount of glucose absorbed from food and the amount of glucose made by the liver. Metformin also increases the body's response to insulin. Metformin is not used to treat type I diabetes where the body does not produce insulin due to autoantibodies that attack pancreatic beta cells.

Despite more than 50 years of use, how metformin actually works was not known. The more accepted view, activation of AMPK, was disproved in 2010 when it was found that mice genetically engineered to lack AMPk in their liver cells still responded to metformin, indicating that blood glucose levels were being controlled outside of the AMPK pathway.

In the current study, investigators at the University of Pennsylvania (Philadelphia, USA) described a new mechanism to explain how metformin functions. They wrote in the January 6, 2013, online edition of the journal Nature that metformin antagonized the action of glucagon, thus reducing fasting glucose levels.

Glucagon is a hormone, secreted by the pancreas that raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood glucose levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is released into the bloodstream. It also stimulates the release of insulin, so that glucose can be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels at the right level.

In mouse liver cells, treatment with metformin led to the accumulation of AMP and related nucleotides, which inhibited adenylate cyclase, reduced levels of cyclic AMP and protein kinase A (PKA) activity, abrogated phosphorylation of critical protein targets of PKA, and blocked glucagon-dependent glucose output from hepatocytes.

"Overall, metformin lowers blood glucose by decreasing liver production of glucose," said senior author Dr. Morris J. Birnbaum, professor of medicine at the University of Pennsylvania. "But we did not really know how the drug accomplished that."

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