Vertical sleeve gastrectomy lowers kidney SGLT2 expression in the mouse

Abstract

Background: Bariatric surgery has been established to improve insulin sensitivity and glucose clearance, but also increases insulin and glucagon secretion. Each of the above effects have also been observed following treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors. Aim: To determine whether there is an effect of bariatric surgery (Vertical Sleeve Gastrectomy; VSG) on renal SGLT2 expression in mice. Methods: Eighteen lean mice underwent VSG (n=8) or sham (n=9) surgery. Glucose tolerance tests with or without treatment with the SGLT2 inhibitor dapagliflozin were performed four weeks post operatively, in order to assess if pharmacological SGLT2 inhibition has the same euglycemic effects after bariatric surgery. Kidneys were harvested from fed mice and SGLT2 expression was analysed using Quantitative reverse-transcription PCR and immunofluorescence.Results: 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), despite an absence of significant weight loss when compared to sham operated mice (p=0.37, Mann-Whitney test). Treatment of sham-operated mice with dapagliflozin (10 mg/kg) improved glucose tolerance. In contrast, dapagliflozin did not further improve glucose tolerance in VSG-operated mice. Moreover, qRT-PCR and immunofluorescence analysis on mouse kidneys demonstrated a significant lowering of SGLT2 expression at both the mRNA (n=7, p<0.0001) and protein (n=5, p=0.0007) levels four weeks after VSG. Conclusions: Vertical sleeve gastrectomy in lean animals causes a significant inhibition of SGLT2 expression 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.

Intravital imaging of islet Ca2+ dynamics reveals enhanced β cell connectivity after bariatric surgery in mice

“…This allowed us to separate marked improvements in insulin secretion from significant weight loss without the need to pair-feed the sham group 44 . Moreover, it corresponds with our previous findings in lean VSG-treated mice that demonstrated no weight difference when compared to sham mice at 4 weeks post-operatively, yet displayed improved glucose tolerance and corresponding insulin secretion curves during an IPGTT 45 . Of note, insulin tolerance tests at week 8 demonstrated that VSG mice had improved insulin sensitivity, an effect previously attributed in humans to rapid and significant enhancement of postoperative hepatic insulin clearance 46 .…”

Bariatric surgery normalizes circulating glucocorticoid levels and lowers glucocorticoid action tissue-selectively in mice

“…This incretin hormone has also been shown to increase significantly following VSG, and to regulate glucocorticoid secretion (25,26). We chronically injected a low dose of the GLP-1RA Semaglutide, to avoid significant body weight loss while achieving significantly lower glycemia, in lean mice as previously reported (17). Interestingly, 11β-HSD1 expression was not affected in either the liver or in the adipose tissue (Fig 4C, D) of Semaglutide-treated mice, suggesting that the observed effects are not driven by the reduction in blood glucose or a direct action of GLP-1.…”

“…These effects go beyond reductions in adipose tissue mass and weight loss, and numerous studies (11)(12)(13) have attempted to determine the exact pathways involved in order to replicate the bariatric effect in a less invasive way. These changes include substantial improvements in insulin sensitivity and hepatic gluconeogenesis alongside improvements in liver, cardiovascular, pancreatic islet and kidney function (14)(15)(16)(17), pointing to a potential trans-organ communication axis. Importantly, the potential mechanisms investigated include possible changes in the secretion or action of multiple hormones (18,19).…”