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Vertical Sleeve Gastrectomy Lowers SGLT2/Slc5a2 Expression in the Mouse Kidney

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posted on 20.05.2022, 18:01 authored by Elina Akalestou, Livia Lopez-Noriega, Iain R. Tough, Ming Hu, Isabelle Leclerc, Helen M. Cox, Guy A. Rutter

  

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 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. 

Funding

E.A. was supported by a grant from the Rosetrees Trust (M825) and from the British Society for Neuroendocrinology. G.A.R. was supported by a Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1), and Experimental Challenge Grant (DIVA, MR/L02036X/1), MRC (MR/N00275X/1), and Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA 16/0005485) grants. This project has received funding from the European Union’s Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 115881 (RHAPSODY) to G.R. I.L. was supported by a project grant from Diabetes UK (16/0005485). I.R.T was funded by a BBSRC project grant (BB/N006763/1).

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