A Doctor Deals: Metformin

Jul 14 2015 Published by under Diabetes, Uncategorized

Structure of Metformin

Structure of Metformin

The first-line treatment for type 2 diabetes (DM2) is Metformin. First synthesized in the early 1920s, the discovery of insulin a few years later eclipsed these agents, at least for a time. In the latter part of the 20th century medicine rediscovered these drugs, and they entered clinical use. Despite becoming the standard of care for DM2, it took 30 years to figure out how Metformin works!

Human studies show that its major action is reduction of glucose production in the liver. When we eat, nutrients of all types enter the bloodstream and make a first stop in the liver for metabolism. The liver can convert these other molecules to glucose, our circulating fuel for cells, via a process called gluconeogenesis (literally new glucose).  Patients with DM2 have twice the rate of gluconeogenesis in the liver as nondiabetic people. Metformin for 3 months can normalize this process.

Metformin also has beneficial effects on levels of fats in the bloodstream and uptake of glucose by muscles. Unlike many therapies for DM2, patients usually do not gain weight with Metformin; indeed, many experience weight loss.

AMPK-regulated enzymes circled

AMPK-regulated enzymes circled

One documented cellular mechanism involves AMP-activated protein kinase (AMPK), a protein that functions in a number of metabolic processes. These include lipid (fat) synthesis, muscle glucose uptake, and control of a number of enzymes in the gluconeogenesis process (diagram to the right).

Zhou et al showed that Metformin activated AMPK in liver cells, leading to decreased fatty acid and lipid production (which in turn increases the sensitivity of the liver cell to insulin). Inhibition of AMPK blocks Metformin's beneficial effects on gluconeogenesis, so activation of AMPK also provides an explanation for this beneficial effect.

So have we answered the mystery of Metformin? Of course not!

Metformin has one obvious, often troubling, side effect: diarrhea. For myself and a number of friends who take it, the first dose induced events not unlike the clean-out for a colonoscopy (ask your 50+ year-old friends about the joy of colonoscopy prep). Some folks have ongoing diarrhea that limits therapy with the drug; in most patients, like yours truly, the problem eventually resolves (or becomes less problematic).

Why does Metformin cause intestinal problems? We really do not know. Some have suggested that it reduces intestinal absorption of glucose which could contribute to changes in stool pattern. Its effects on the liver may also change stuff downstream in the gut. Some have suggested that these intestinal effects may be beneficial as well, through changes in the microbiome.

For a drug that's a century old, there is still a lot we do not know about Metformin. At least we know it works!

 

2 responses so far

  • Dave says:

    Metformin also has beneficial effects on levels of fats in the bloodstream and uptake of glucose by muscles

    Careful. Metformin has no effect on skeletal muscle glucose uptake in humans (this is a very common misconception). It's all liver, with a bit of GLP-1 on the side (through its activity in the gut).

    For a drug that's a century old, there is still a lot we do not know about Metformin

    Yeh, like its mechanism of action.

  • […] diagnosed patients with type 2 diabetes generally start the drug metformin. Through a number of metabolic effects, this medication improves hyperglycemia. Over time, most […]

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