Background: Both metabolic surgery and sodium glucose co-transporter (SGLT2) inhibitors have been demonstrated to improve insulin sensitivity and glucose clearance, but also increase glucagon secretion and cardiovascular health.
Aim: To examine the effect of metabolic surgery (Vertical Sleeve Gastrectomy; VSG) on SGLT2 expression in kidney cortex of lean mice.
Methods: In order to assess whether exogenous SGLT2 inhibition has the same euglycemic effects as bariatric surgery, 14 lean mice underwent VSG (n=8) or sham (n=6) surgery. Glucose (3 g/kg) tolerance tests with or without treatment with the SGLT2 inhibitor dapagliflozin were performed four weeks post operatively. Kidneys were harvested from fed mice and analysed using Quantitative real-time PCR (qRT-PCR) and immunofluorescence.
Results: Quantitative RT PCR 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, P<0.0001) levels four weeks after VSG. VSG did not cause any weight loss when compared to sham operated mice (P=0.37, Mann-Whitney test). Nevertheless, VSG mice displayed significantly improved glucose tolerance (P<0.001) and insulin secretion (P<0.01), 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. Glucagon levels were elevated post VSG and post treatment with dapagliflozin in both VSG and sham groups (P<0.01). Glycosuria was observed in 2/5 VSG mice, yet not in controls.
Conclusions: Our previous results on the effects of Duodenal Jejunal Bypass in lean rats showed a significant lowering of SGLT2 expression, confirming that both gastric and intestinal surgery in lean animals causes a significant inhibition of SGLT2 in the kidney cortex. These findings 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.