NOV 16, 2020 5:08 AM PST

How Gut Microbes Deactivate a Common Diabetes Drug

WRITTEN BY: Carmen Leitch

Metformin is a frequently prescribed type 2 diabetes treatment but its effects can vary significantly. In some patients, it lowers blood sugar and can slow the progression of type 2 diabetes, but in others, it has little impact. Scientists have now found that some bacteria in our guts generate a molecule, called imidazole propionate that can disrupt insulin as well as inactivate the effect of metformin. This can explain why the drug is ineffective in some type 2 diabetes patients. The findings have been reported in Cell Metabolism.

Image credit: Pxabay/stevepb

"Our study demonstrates clearly that imidazole propionate not only inhibits the effects of insulin but may also reduce the therapeutic action of the metformin," said the study leader, Fredrik Backhed, Professor of Molecular Medicine at Sahlgrenska Academy, University of Gothenburg.

"Since imidazole propionate has also been linked to inflammation in the gut, and metformin has several side effects in the form of intestinal problems, it's conceivable that imidazole propionate both blocks the treatment effect and contributes to side effects of metformin. But new studies are needed to verify this hypothesis."

Previous work by Backhed has indicated that alterations in microbes in the gut, which are known to have a profound effect on human health and disease, can alter how an amino acid called histidine is metabolized. That metabolic alteration can raise imidazole propionate levels, which inhibit insulin's blood glucose-lowering effects.

In this work, Backhed and his team have suggested that imidazole propionate doesn't only raise blood sugar by disrupting the effects of insulin; it also reduces metformin's efficacy. High imidazole propionate levels have been connected to the impairment of metformin, and vice versa.

"We found out that imidazole propionate interacts with AMPK (AMP-activated protein kinase), the same molecule as metformin. But instead of activating AMPK, imidazole propionate inhibits metformin-induced AMPK activation," explained the first study author Ara Koh.

When the scientists halted the activity of a molecule called p38gamma, which is necessary for imidazole propionate to stop AMPK, the effects of imidazole propionate were inhibited.

"The work demonstrates the robustness of the translational research carried out at the Wallenberg [Laboratory for Cardiovascular and Metabolic Research at the University of Gothenburg]. There, observations of patients can be explained in molecular terms, which can give rise to new therapies," concluded Backhed.

Sources: AAAS/Eurekalert! via University of Gothenburg, Cell Metabolism

About the Author
Bachelor's (BA/BS/Other)
Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
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