When I was diagnosed in 1996 and my doctor suggested metformin, no one knew how it worked. I told him I was hesitant to take a drug when no one knew what it did. He agreed about the lack of knowledge but then said, "However, we do know what high blood glucose (BG) does, and it’s not a pretty picture."
So I reluctantly decided to give the drug a try. And metformin, plus a drastic change in diet, did bring my BG levels down to close to normal ranges.
Not long after that, they discovered that metformin keeps the liver from dumping a lot of glucose into the bloodstream. And after that they decided it did so by increasing levels of a molecule called AMPK.
AMPK is known as the "energy sensor" of the cell. When your cellular energy levels are low, meaning you’re not producing a lot of ATP (known as the "energy currency" of the cell), you produce more AMPK. This hypothesis continued to be accepted as true.
But now, new evidence suggests that the main effect of metformin is not by way of AMPK after all, and the livers of mice that don’t produce AMPK still respond to metformin. The new theory is that metformin inhibits glucagon. If you want more details about glucagon, I’ve written about it here, and even more technical articles can be found here, here, here, and here.
Insulin and glucagon are like the brake and gas pedal on your car. They do opposite things. Insulin lowers BG levels in your blood, and glucagon makes them go up. If you have type 1 diabetes, you’re probably familiar with glucagon, as many carry glucagon kits to bring the BG up if they go too low. If you have type 2, you might not be as aware of glucagon.
People with type 2 diabetes not only don’t produce enough insulin, or their insulin isn’t working well because of insulin resistance, but they also produce too much glucagon. This is as if your gas pedal (the glucagon that makes BG go up) was stuck on high and your brakes (the insulin that makes your BG go down) didn’t work. You’d be in much more trouble much more quickly.
The diabetes drug exenatide (Byetta) works in part by inhibiting glucagon. And some diabetes researchers are concentrating on glucagon instead of focusing on insulin alone. One group concluded, "The metabolic manifestations of diabetes cannot occur without glucagon action and, once present, disappear promptly when glucagon action is abolished. Glucagon suppression should be a major therapeutic goal in diabetes."
Now it seems that metformin, if not abolishing glucagon action, is at least suppressing it. Higher levels of the drug might do more, but many people get side effects from metformin and couldn’t tolerate high doses. Perhaps this new work will stimulate more research on drugs that have metformin’s glucagon-reducing properties without the side effects.
Morris J. Birnbaum, the lead author of the new article on metformin and glucagon, suggests that the enzyme adenylate cyclase, which increases glucagon output, could be one target for such a new drug. Even if that doesn’t pan out, the new theory of how metformin works should stimulate research that will eventually help scientists solve the problem of high BG levels.
Progress always seems slow when you’re a patient, but today’s research is complex and time-consuming, and I’m actually amazed at how much we’ve learned about metformin since I was diagnosed. We’ve cured mice zillions of times. Now if we could just do the same for humans.