Metformin reversed liver inflammation

The diabetes drug metformin – derived from a lilac plant that has been used medicinally for more than a thousand years – has been prescribed to hundreds of millions of people worldwide for the treatment of type 2 diabetes. Yet scientists do not fully understand how effective the drug is for controlling blood sugar.

Now, researchers at the Salk Institute say they have shown the importance of specific enzymes in the body for the function of metformin. In addition, new work has shown that the same protein, regulated by metformin, controlled aspects of inflammation in mice, something the drug has not usually been prescribed.

In addition to elucidating how metformin works, research focuses on “AMPK regulation of raptor and TSC2 on the metaborphine effect of anabolic and transcriptional control of inflammation”, which appears Genes and development It is reportedly of relevance to many other inflammatory diseases.

“Despite having frontline therapy for type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still to be discovered. In particular, the detailed molecular differences between the AMPK and mTORC1 pathway in the liver benefits of metformin are still incurable. Metformin-dependent activation of AMPK inhibits mTORC1 via TST / RHEB. But several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1, “write to investigators.”

“Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA Mouse model, in which the AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were transformed into alanine. Metformin treatment of primary hepatocytes and intact Fife liver requires AMPK regulation of both RAPTOR and TSC2 and completely inhibits mTORC1, and this regulation is important for metformin both translational and transcriptional.

“Transcriptively, both AMPK and mTORC1 were important for the regulation of anabolic metabolism and inflammatory programs triggered by metabolic treatment. The liver transcriptional response in mice on a high-fat diet treated with metformin was largely abolished under conditions investigated by AMPK-depletion, an essential role of this kinase and its targets in metformin action. it shows. In vivo. ”

“These findings give us a precise dig at what metformin is doing at a molecular level,” says Reben Shaw, PhD, a professor in Salk’s molecular and cell biology laboratory and senior author of the new paper. “This more nuanced understanding of medicine is important because there is increasing interest in targeting these pathways not only for diabetes but also for immune diseases and cancer.”

Researchers have known for 20 years that metformin activates a protein called AMPK, a metabolic master switch, which conserves the energy of a cell in a state of low nutrient levels, and which naturally occurs in the body after exercise is activated. Twelve years ago, Shaw found that in healthy cells, AMPK initiates a cascade effect, regulating two proteins called raptors and TSC2, resulting in a block of the central pro-growth protein complex mTORC1 (rapamycin complex 1 Of mammals).

These findings helped to explain the ability of metformin to inhibit the growth of tumor cells, an area of ​​research that began to produce excitement after Shaw and others reported AMPK as a ban fide in the early 2000s. Cancer gene linked.

But in the intervening years, several additional proteins and pathways that control metformin have been discovered, questioning which of metformin’s targets are most important for metformin’s various beneficial outcomes. Indeed, metformin is currently entering clinical trials in the United States as a common anti-aging treatment because this effect is well established from millions of patients and its side effects are minimal.

But whether AMPK or its targets are important for the various effects of raptor or TSC2 metformin remains poorly understood.

In the new work, in mice, Shaw and his colleagues genetically isolated the master protein, AMPK, from other proteins, so they did not receive signals from AMPK, but otherwise function normally and receive input from other proteins Were able

When these mice were placed on a high-fat diet triggering diabetes and were then treated with metformin, the drug would not have the same effect on liver cells as it usually does in diabetic animals, Suggesting that communication between AMPK and mTOR1 is important for metformin work.

By looking at regulated genes in the liver, researchers found that when AMPK could not communicate with raptor or TSC2, the effect of metformin on hundreds of genes was blocked. Some of these genes were related to lipid metabolism, helping to explain some of the beneficial effects of metformin. But surprisingly, many others were associated with inflammation.

Metformin, genetic data showed, generally triggered anti-inflammatory pathways and these effects required AMPK, TSC2, and raptor.

“We didn’t go looking for a role in inflammation, so it had to be so strongly surprised,” says Salk Postdoctoral Fellow and first author Jeanine Van Nostrand, PhD.

People with obesity and diabetes often exhibit chronic inflammation, which subsequently leads to excess weight gain and other pathologies including heart disease and stroke. Therefore, the identification of an important role for metformin and the interrelationship between AMPK and mTORC1 in the control of both blood glucose and inflammation suggests how metformin can treat metabolic diseases.

Metformin and exercise achieve similar beneficial results, and research has previously shown that AMPK helps to take into account some of the positive effects of exercise on the body, so Shaw and Van Nostrand learn, among other questions Interested in whether Raptor and TSC2 are involved in many beneficial effects of exercise, as well.

“If turning on AMPK and turning off mTORC1 is responsible for some of the systemic benefits of exercise, it means we’re better able to mimic some of those effects with new medical science designed to Can, ”says Shaw, who holds William R. . Brody Chair.

Meanwhile, new data suggest researchers should study the potential use of metformin in inflammatory diseases, particularly those that involve liver inflammation. The findings also point toward potential targets toward AMPK, raptor and TSC2 in more widely inflammatory conditions, suggesting the need for an in-depth investigation of metformin, as well as new AMPK agonists and mTOR inhibitors, the researchers say.