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New Research into the Mechanism of Action of Metformin

Fatty liver disease patients may react differently to metformin than those without the disease…. 

Research from McMaster University has shown that metformin works with fat in the liver in order to exert its blood glucose-lowering effects. This is a result of lowering hepatic fat molecules, allowing insulin to work more efficiently to take up glucose from the bloodstream. This is especially important in patients with fatty liver, the result of both alcohol consumption and obesity. Since many patients have comorbid obesity and type 2 diabetes, it is important to recognize why metformin is so effective in this population.

When the body accumulates fat and we become obese, our insulin doesn’t work as well to constantly remove sugar from the blood and can’t stop sugar release from the liver. It was found that a single-point mutation in acetyl-CoA carboxylase (ACC) was shown to cause fatty liver in murine models. ACC, along with AMP-activated protein kinase which controls ACC, regulate fat cell proliferation and catabolism. Even in the absence of obesity, murine models demonstrated fatty liver development in the absence of other risk factors.

When obese mutant mice (ACC-mutated) were given metformin, they consistently failed to lower their blood glucose levels. This shows that metformin doesn’t work directly on the glucose metabolism itself, but rather the fat cells. This allows insulin to work better in the liver. The result of this research is that better personalization of mono- and combination therapies can be used in patients for whom first-line metformin isn’t very effective.

Practice Pearls:

  • Obesity is a common comorbid condition with diabetes and often leads to fatty liver.
  • Metformin doesn’t work to reduce glucose metabolism but rather reduces fat in the liver to allow insulin to work better.
  • Personalized combination therapies can be used for patients with diabetes and fatty liver that may have reduced effect from metformin.

Nature Medicine, November 2013