The diabetes drug metformin has been prescribed to hundreds of millions of people worldwide as the frontline treatment for type 2 diabetes.
Yet scientists don’t fully understand how the drug is so effective at controlling blood glucose.
In a new study, researchers have found the importance of specific enzymes in the body for metformin’s function.
In addition, they found that the same proteins, regulated by metformin, controlled aspects of inflammation, something the drug has not typically been prescribed for.
Apart from clarifying how metformin works, the study has relevance for many other inflammatory diseases.
The research was conducted by a team at the Salk Institute.
Researchers have known for 20 years that metformin activates a metabolic master switch, a protein called AMPK, which conserves a cell’s energy under low nutrient conditions, and which is activated naturally in the body following exercise.
Twelve years ago, the team discovered that in healthy cells, AMPK starts a cascade effect, regulating two proteins called Raptor and TSC2, which results in a block of the central pro-growth protein complex called mTORC1.
These findings helped explain the ability of metformin to inhibit the growth of tumor cells.
But in recent years, many additional proteins and pathways that metformin regulates have been discovered.
Indeed, metformin is currently entering clinical trials in the United States as a general anti-aging treatment because it is effects are so well established from millions of patients and its side effects are minimal.
In the study, in mice, the team genetically disconnected the master protein, AMPK, from the other proteins, so they could not receive signals from AMPK, but were able to otherwise function normally and receive input from other proteins.
When these mice were put on a high-fat diet triggering diabetes and then treated with metformin, the drug no longer had the same effects on liver cells as it did in normally diabetic animals.
This suggests that communication between AMPK and mTORC1 is crucial for metformin to work.
By looking at genes regulated in the liver, the researchers found that when AMPK couldn’t communicate with Raptor or TSC2, metformin’s effect on hundreds of genes was blocked.
Some of these genes were related to lipid (fat) metabolism, helping explain some of the metformin’s beneficial effects.
But surprisingly, many others were linked to inflammation.
Metformin, the genetic data showed, normally turned on anti-inflammatory pathways and these effects required AMPK, TSC2 and Raptor.
People suffering from obesity and diabetes often exhibit chronic inflammation, which further leads to additional weight gain and other maladies including heart disease and stroke.
Therefore, identifying an important role for metformin and the interrelationship between AMPK and mTORC1 in control of both blood glucose and inflammation reveals how metformin can treat metabolic diseases by multiple means.
Metformin and exercise elicit similar beneficial outcomes, and research has previously shown that AMPK helps mediate some of the positive effects of exercise on the body, so among other questions, the team are interested in exploring whether Raptor and TSC2 are involved in the many beneficial effects of exercise, as well.
One author of the study is Jeanine L. Van Nostrand.
The study is published in Genes & Development.
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