161-LB: Inhibition of Kidney SGLT2 Expression following Bariatric Surgery in Mice

Abstract

Background: Bariatric surgery is known to improve glucose tolerance and weight loss, but can also cause a postprandial increase in renal glucose excretion following oral glucose tolerance test. Both effects have also been observed following treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors. Aim: To investigate whether there is an effect of bariatric surgery (Vertical Sleeve Gastrectomy; VSG) on renal SGLT2 expression in mice. Methods: Fourteen lean mice underwent VSG (n=8) or sham (n=6) surgery. Glucose Tolerance tests with or without treatment with the SGLT2 inhibitor dapagliflozin were performed four weeks post operatively, in order to assess if exogenous SGLT2 inhibition has the same euglycemic effects as bariatric surgery. Kidneys were harvested from fed mice and analysed using Quantitative real-time PCR (qRT-PCR) and immunofluorescence. Results: VSG did not cause any weight loss when compared to sham operated mice (p=0.37, Mann-Whitney test). However, VSG mice displayed significantly improved glucose tolerance (AUC=103 ±6.8; AUC =66.6 ±2.9 in control and VSG mice, respectively; p<0.001), which was not further affected by dapagliflozin (10 mg/kg; p>0.05). In contrast, treatment of sham mice with dapagliflozin increased glucose tolerance, though to a lesser extent than VSG. Nevertheless, qPCR and immunofluorescence analysis on mouse kidneys demonstrated a significant lowering of SGLT2 expression at both the protein (n=5, p=0.0007) and mRNA (n=7, 0<0.0001) levels four weeks after VSG. Correspondingly, glycosuria was observed in 2/5 VSG mice, but not in controls. Conclusions: Both gastric and intestinal surgery in lean animals causes a significant inhibition of SGLT2 in the kidney cortex. These findings are in line with our previous results on the effects of Duodenal Jejunal Bypass in lean rats, and point towards a physiologically-relevant gut-kidney axis. SGLT2 inhibition may thus be an important mechanism through which bariatric surgery improves glucose tolerance in man. Disclosure E. Akalestou: None. L. Lopez Noriega: None. P.L. Chabosseau: None. I. Leclerc: None. G.A. Rutter: Consultant; Self; Sun Pharma. Funding UK Wellcome Trust