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Gut Microbiota Molecule Linked to Reduced Metformin Response

DYSBIOSIS of the gut microbiota is now recognised to have significant effects on the health of an individual, with changes in metabolism linked to diabetes also associated with dysbiosis. Now, according to a study from the University of Gothenburg, Gothenburg, Sweden, gut dysbiosis could also lead to the therapeutic effects of metformin being blocked.

Metformin is a drug commonly prescribed for Type 2 diabetes mellitus (T2DM) to control and stabilise blood glucose. The efficacy of the drug varies significantly, with some patients achieving an optimal reduction in blood glucose, and in others the effects are less favourable. Previous research has shown that altered gut microbiota can lead to changes in the metabolism of the amino acid histidine and in turn increase the production of imidazole propionate, which inhibits the effects of insulin in lowering blood glucose. Using this knowledge, the researchers set out to determine if imidazole propionate also interferes with the action of metformin in lower blood glucose.

In the study, the researchers demonstrated that T2DM patients with high blood glucose, despite metformin treatment, had higher levels of imidazole propionate. They then investigated the impact of imidazole propionate on the action of metformin in mice. The mice were pretreated with imidazole propionate before being given metformin, and it was observed that the blood glucose lowering abilities of metformin did not occur, demonstrating a clear relationship between the two. To decipher the potential mechanisms behind this blocking of effects, they investigated AMP-activated protein kinase (AMPK), a major cellular regulator known to be activated by metformin. “We found out that imidazole propionate interacts with AMPK, the same molecule as metformin. But instead of activating AMPK, imidazole propionate inhibits metformin-induced AMPK activation,” first author of the study Dr Ara Koh summarised. The researchers were then able to inhibit the effects of imidazole propionate by blocking p38γ, a protein required for imidazole propionate to block AMPK.

Study lead Prof Fredrik Backhed concluded that: “Our study demonstrates clearly that imidazole propionate not only inhibits the effects of insulin but may also reduce the therapeutic action of the metformin.” Identifying this potential cause for the varying responses seen in patients with T2DM taking metformin opens a new door to improving blood glucose control; however, human trials are needed to confirm these results.