Bariatric surgery improves glucose homeostasis, but the underlying mechanisms are not fully elucidated. Here, we show that the expression of sodium–glucose cotransporter 2 (SGLT2/Slc5a2) is reduced in the kidney of lean and obese mice following vertical sleeve gastrectomy (VSG). Indicating an important contribution of altered cotransporter expression to the impact of surgery, inactivation of the SGLT2/Slc5a2 gene by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 attenuated the effects of VSG, with glucose excursions following intraperitoneal injection lowered by ∼30% in wild-type mice but by ∼20% in SGLT2-null animals. The effects of the SGLT2 inhibitor dapaglifozin were similarly blunted by surgery. Unexpectedly, effects of dapaglifozin were still observed in SGLT2-null mice, consistent with the existence of metabolically beneficial off-target effects of SGLT2 inhibitors. Thus, we describe a new mechanism involved in mediating the glucose-lowering effects of bariatric surgery.

This article contains supplementary material online at https://doi.org/10.2337/figshare.19723642.

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