A High-Salt Diet Enhances Sodium-Driven Glucose Uptake via Colonic SGLT1 in a Salt-Sensitive Model of Hypertension and Insulin Resistance

Elevated blood pressure and insulin resistance are frequently comorbid in the setting of metabolic syndrome and have been associated with elevated dietary sodium intake. Sodium-glucose cotransporter isoform 1 (SGLT1) is a major route of sodium-driven glucose absorption in the gastrointestinal tract, but its role in salt-sensitive metabolic syndrome is unknown. We hypothesized that increased dietary salt intake promotes intestinal glucose uptake in salt-sensitive (SS) rats via SGLT1-dependent mechanisms. To test this hypothesis, adult male SS rats (12-14wo) were administered a low sodium diet (LSD; 0.3% NaCl, Teklad) or a moderately high sodium diet (HSD; 2.0% NaCl, Teklad) ad libitum for two weeks. SGLT1-driven sodium current across colonic tissue was measured ex vivo under voltage clamp conditions in the Ussing chamber, in the presence of increasing concentrations of the SGLT1 inhibitor KGA-2727 (0.1-100µM). SGLT1-dependent glucose uptake was also investigated in vivo in anaesthetized rats fed LSD or HSD by measuring blood glucose levels every 10 minutes for 2 hours following oral coadministration of D-glucose and saline at concentrations equivalent to LSD and HSD (0.3% or 2.0% NaCl respectively). Ussing chamber studies demonstrated that HSD potentiated SGLT1-dependent sodium current across the distal (ANOVA, p<0.05, n=4-6) and proximal colon (ANOVA, P=0.056, n=4-6). Whole animal studies showed that HSD but not LSD administration in SS rats increased blood glucose in an SGLT1-dependent manner (ANOVA, p<0.01, n=3-4). Overall, these data demonstrate that elevated dietary sodium intake modulates sodium-driven glucose absorption via SGLT1 in the gastrointestinal tract. Thus, colonic SGLT1 may be a pathogenic mechanism of salt-sensitive metabolic syndrome and a potential target for therapeutic intervention. This work is supported by University of Toledo start-up funds, HL1430820 to B. Joe and HL152162 to J. Zubcevic. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.