Diabetes Drug Metformin Finally Understood – Leading To Potential New Diabetes Drugs
Posted Jan 20 2013 7:58am
By Philip Tucker
When it comes to reporting on diabetes the news has been almost unrelentingly grim. The number of people with type-2 diabetes has skyrocketed across the globe, and while a better understanding of how diabetes works has led to extended life spans, the mortality rate is also rising. Which is why an article rather cryptically entitled, Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP is such good news – at long last scientists have deciphered the way in which metformin controls the levels of blood sugar in diabetic patients – and opened new potential pathways to developing even better treatments.
One of the most serious challenges facing diabetics is controlling their levels of blood sugar. Overactive glucose production in the liver can lead to serious health problems, as diabetic patients are unable to produce enough insulin to keep this process in check. This is where metformin came in. It lowered the production of liver produced glucose, but nobody quite understood why.
For awhile it was theorized that metformin reduced glucose production by activating an enzyme called AMPK, but this theory was demolished when Nature published a study showing that genetic manipulated mice who had no AMPK still responded to metformin. Enter senior author Morris J. Birnbaum, MD, PhD and Willard and Rhoda Ware Professor of Medicine. Along with his team from the Perelman School of Medicine, they have found through research on mice that metformin works by actually suppressing the liver hormone glucagon’s ability to generate an essential signaling molecule.
Glucagon is a hormone secreted by the pancreas which raises blood sugar levels.
Glucagon is a hormone secreted by the pancreas which raises blood sugar levels. Think of it as the anti-insulin; it does exactly the opposite job. Glucagon causes the liver to release glucose, and it is exactly this process that Dr. Birnbaum and his team discovered that metformin interrupted. Metformin causes the accumulation of AMP in mice, which prevents the signaling peptide adenylate cyclase from acting, reducing cyclic AMP and protein kinase activity, which eventually blocks the production of glucose.
Why are these details important? Because metformin is like a sledgehammer, and causes a wide array of side effects in those who take it, like affecting the mitochondria in cells, impeding their ability to make energy. Our new understanding of how it acts on glucagon could now allow us to take a shortcut and target adenylate cyclase directly, making for a more specific drug that could cut out many if not all of metformin’s side effects—and perhaps even work for those patients on whom metformin has no effect at all.