Paige Bauer
Paige Bauer, Ph. D. student in the lab of Dr. Tony Lam and in the Department of Physiology at the University of Toronto, designed a series of experiments with the Lam lab team to determine how metformin lowers blood sugar through changes in gut bacteria. (Photo: UHN)

Researchers at the Toronto General Hospital Research Institute and Princess Margaret Cancer Centre have discovered that metformin (the most widely prescribed type 2 diabetic medication) alters gut bacteria to impact a major signaling pathway in the small intestine to lower blood sugar.

The team, led by Dr. Tony Lam, his Ph.D. student, Paige Bauer, and former Banting fellow Dr. Frank Duca, used high-fat diet rodents to discover how metformin alters a specific family of bacteria commonly found in the upper small intestine. The bacteria, in turn, impact a glucose-SGLT1 regulating pathway in the intestine to lower glucose or sugar production.

The findings are published online today in the international science journal Cell Metabolism entitled, "Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1 sensing glucoregulatory pathway."

Working with rodents, Paige, Dr. Duca and Dr. Lam designed a series of experiments to determine how metformin lower blood sugar through changes in gut microbiota.

"Metformin is the most widely-prescribed type 2 diabetic medication but its mechanism of action is not understood," says Paige, a Ph. D. student in the Department of Physiology at the University of Toronto.

One-quarter of patients suffer from metformin-associated side effects

She adds that dissecting the mechanism of metformin action can help identify and develop alternative but effective treatments for diabetes, an important goal given that about 25 per cent of patients suffer from metformin-associated side effects such as weakness, stomach pain and nausea.   

In their experiments, the researchers found that high-fat diet reduces the amount of Lactobacillus bacteria in the small intestine, and disrupts a major signalling pathway important in regulating and stabilizing blood sugar. However, metformin treatment restores the amount of Lactobacillus bacteria in the upper small intestine, along with the vital SGLT1 signalling pathway which promotes the lowering of blood sugar levels.

Additional experiments involving transplanting upper small intestinal bacteria from metformin-treated rodents fed a high-fat diet to the upper small intestine of rodents who were untreated with metformin, but also ate a high-fat diet, showed an increase in Lactobacillus bacteria in the small intestine and a restored function of the SGLT1 pathway.

The research team is now experimenting with the Lactobacillus bacteria to see which specific species from that group of bacteria can exert similar beneficial changes in the important signalling pathways involved in blood sugar stabilization.

"Previous laboratories have correlated metformin action to changes in the gut microbiota in both rodents and humans," notes Dr. Lam, who holds The John Kitson McIvor (1915 – 1942) Endowed Chair in Diabetes Research and the Canada Research Chair in Obesity, and is also a Senior Scientist at the Toronto General Hospital Research Institute and a Full Professor of Physiology and Medicine at the University of Toronto.

More than two million Canadians have diabetes

"The current study reports for the first time a mechanism in the upper small intestine that links changes of the gut microbiota incurred by metformin to the lowering of blood glucose in rodents."

Dr. Lam emphasized that the clinical relevance of this linking mechanism remains to be investigated in humans.

More than two million Canadians have diabetes. Currently, those with diabetes lower their glucose through diet, exercise, anti-diabetic tablets or insulin injections (usually several times a day) and must regularly monitor blood glucose levels.

High glucose levels result in damage to eyes, nerves and kidneys and increase the risk of heart attack, stroke, blindness, erectile dysfunction, foot problems and amputations. Many laboratories around the world are in a race to find alternative and effective ways in which to lower glucose because of the severe complications which can result from high sugar levels.

Other researchers involved in the studies include Drs. T.M. Zaved Waise, Brittany A. Rasmussen, Mona A. Abraham, Helen J. Dranse, from the Toronto General Hospital Research Institute, and Ms. Akshita Puri and Dr. Catherine A. O'Brien from the Princess Margaret Cancer Centre.

​The work was funded by the Canadian Institutes of Health Research.​

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