Editors' ChoiceDiabetes

Sugar, drugs, and gut bugs

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Science Translational Medicine  01 Nov 2017:
Vol. 9, Issue 414, eaaq1228
DOI: 10.1126/scitranslmed.aaq1228


A high-fat diet in rodents causes changes in gut microbiota and glucose sensing that may be mitigated by treatment with metformin.

Metformin, the first line therapy for treatment of type 2 diabetes, acts in part by suppressing glucose production. Metformin’s underlying mechanism of action is still under debate. A gut-restricted form of metformin successfully lowers blood glucose levels in humans, highlighting the potential role of pre-absorptive metformin’s interaction with upper small intestinal receptors, such as sodium glucose cotransporter-1 (SGLT1). The gut microbiome is increasingly recognized as a regulator of glucose and energy homeostasis, but the role of metformin in altering small intestinal microbiota is unknown.

Bauer et al. hypothesized that changes in the microbiota may mediate the glucose lowering actions of metformin by altering expression of glucose sensing proteins. First, investigators used the pancreatic-euglycemic clamp technique to determine if preabsorptive glucose sensing could regulate whole-body glucose metabolism. In both mice and rats, infusion of glucose into the upper small intestine led to an inhibition of glucose production without an increase in glucose uptake. Suppression of glucose production was also seen with infusion of galactose, a glucose epimer, but not fructose or sucralose. These data pointed to SGLT1 as the responsible glucose transporter. Next, investigators showed that activation of SGLT1 was necessary for upper small intestinal glucose sensing using a chemical inhibitor, phlorizin, and a knockdown model using SGLT1 shRNA-expressing lentivirus.

In rats fed a high-fat diet, upper small intestinal glucose infusion no longer suppressed glucose production. Pretreatment with metformin rescued upper intestinal glucose sensing in rats but did not rescue glucose sensing in the SGLT1 knockdown model. High-fat diet also altered the rat small intestinal microbiota, resulting in a decreased abundance of Lactobacillus, typically the dominant genus. Pretreatment with metformin increased the abundance of Lactobacillus in high-fat diet–fed rats. Investigators next performed upper small intestinal microbiota transplants, in which high-fat diet–fed rats received gut infusions with the intestinal luminal contents of high-fat diet–fed rats that were pretreated either with metformin or saline. One day later, pancreatic-euglycemic clamps showed that upper small intestine glucose infusion reduced glucose production in the rats that received metformin-pretreated microbiota compared with saline infusion.

In conclusion, high-fat diet alters small intestine microbiota, whereas treatment with metformin may normalize microbiota and restore glucose sensing in the small intestine. This novel mechanism has expanded our understanding of how metformin improves blood glucose levels in patients with type 2 diabetes.

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