The effect of acute dual SGLT1/SGLT2 inhibition on incretin release and glucose metabolism after gastric bypass surgery

Abstract

Enhanced meal-related enteroendocrine secretion, particularly of glucagon-like peptide-1 (GLP-1), contributes to weight-loss and improved glycemia after Roux-en-Y gastric bypass (RYGB). Dietary glucose drives GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion postoperatively. Understanding how glucose triggers incretin secretion following RYGB could lead to new treatments of diabetes and obesity. In vitro, incretin release depends on glucose absorption via sodium-glucose cotransporter 1 (SGLT1). We investigated the importance of SGLT1/SGLT2 for enteropancreatic hormone concentrations and glucose metabolism after RYGB in a randomized, controlled, crossover study. Ten RYGB-operated patients ingested 50 g of oral glucose with and without acute pretreatment with 600 mg of the SGLT1/SGLT2-inhibitor canagliflozin. Paracetamol and 3- O-methyl-d-glucopyranose (3-OMG) were added to the glucose drink to evaluate rates of intestinal entry and absorption of glucose, respectively. Blood samples were collected for 4 h. The primary outcome was 4-h plasma GLP-1 (incremental area-under the curve, iAUC). Secondary outcomes included glucose, GIP, insulin, and glucagon. Canagliflozin delayed glucose absorption (time-to-peak 3-OMG: 50 vs. 132 min, P < 0.01) but did not reduce iAUC GLP-1 (6,067 vs. 7,273·min·pmol−1·L−1, P = 0.23), although peak GLP-1 concentrations were lowered (−28%, P = 0.03). Canagliflozin reduced GIP (iAUC −28%, P = 0.01; peak concentrations −57%, P < 0.01), insulin, and glucose excursions, whereas plasma glucagon (AUC 3,216 vs. 4,160 min·pmol·L−1, P = 0.02) and amino acids were increased. In conclusion, acute SGLT1/SGLT2-inhibition during glucose ingestion did not reduce 4-h plasma GLP-1 responses in RYGB-patients but attenuated the early rise in GLP-1, GIP, and insulin, whereas late glucagon concentrations were increased. The results suggest that SGLT1-mediated glucose absorption contributes to incretin hormone secretion after RYGB.

Do Gut Hormones Contribute to Weight Loss and Glycaemic Outcomes after Bariatric Surgery?

“…The nutrient absorption from the gut appears to be more important for the gut hormone secretion compared to the exposure of the gut to nutrients [59,60]. Further evidence on the importance of glucose absorption on GLP-1 secretion after RYGB comes from a study where sodium glucose co-transporters-1 (SGLT-1), a major mechanism of dietary glucose absorption from the gastrointestinal tract, were blocked in people who have undergone RYGB through canagliflozin, a dual SGLT-1/SGLT-2 inhibitor [61]. The study found that indeed dual SGLT-1/SGLT-2 inhibition could reduce glucose absorption and subsequently reduce peak GLP-1 levels and insulin secretion after RYGB [61].…”

Canagliflozin: A New Therapeutic Option in Patients That Present Postprandial Hyperinsulinemic Hypoglycemia after Roux-en-Y Gastric Bypass: A Pilot Study

“…These authors found that canagliflozin treatment reduced postprandial plasma glucose and insulin excursions during OGTT. More recently, Martinussen et al [13] suggested that SGLT-1-mediated glucose absorption contributed to incretin hormone secretion after RYGB. In this study, the authors showed a significant reduction in postprandial levels of glucose and insulin during OGTT using 600 mg of canagliflozin.…”

“…It should be noted that in RYGB, the passage of nutrients from the gastric reservoir to the jejunum is accelerated up to 100 times, while the hypertrophy of the intestinal mucosa favors a faster absorption of glucose [5]. Recent trials have suggested the role of intestinal SGLT-1 in the pathophysiology of reactive hypoglycemia [13,14], and several studies have shown a dysregulation of these transporters in obesity, diabetes, or in patients having a high sugar diet [15,16]. Additionally, Nguyen et al [17] found an upregulation of intestinal glucose transporters, SGLT-1, after RYGB.…”

Do sodium‐glucose co‐transporter‐2 inhibitors increase plasma glucagon by direct actions on the alpha cell? And does the increase matter for the associated increase in endogenous glucose production?

“…As mentioned, alpha‐cell electrical activity decreases with increasing ambient glucose concentrations, meaning that SGLT1 activity presumably, as is the case for SGLT2 activity, plays a minor role in overall electrical regulation at higher glucose concentrations 58–60 . Interestingly, a recent human study showed that canagliflozin intake at a concentration that inhibits both SGLT1 and SGLT2 (600 mg) increased plasma glucagon concentrations 3‐4 hours after intake 63 . However, whether this effect resulted from a direct action on the alpha cell was unclear because it occurred much later than the maximum effects on urinary glucose excretion.…”

“…[58][59][60] Interestingly, a recent human study showed that canagliflozin intake at a concentration that inhibits both SGLT1 and SGLT2 (600 mg) increased plasma glucagon concentrations 3-4 hours after intake. 63 However, whether this effect resulted from a direct action on the alpha cell was unclear because it occurred much later than the maximum effects on urinary glucose excretion. Furthermore, as already mentioned, a recent study on perifused human islets using the dual SGLT1/2 inhibitor, sotagliflozin, did not indicate effects of islet SGLT1 inhibition on glucagon output.…”