SUN-651 - Glutamine-Dependent Renal Gluconeogenesis Maintains Glucose Homeostasis during Glycosuria Induced by Genetic Renal-Glut2 Deficiency or SGLT2 Inhibition

Sodium–glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose by inducing glycosuria, but their efficacy is limited by a compensatory rise in endogenous glucose production (EGP). Although the liver is a primary source of EGP, our prior work shows that afferent renal denervation reduces glycosuria-induced glucose compensation by ~50% without abolishing it, implicating kidney-intrinsic mechanisms in glucose homeostasis. However, renal glucose compensation remains poorly understood. To address this gap, we studied renal glucose transporter 2 knockout (rGlut2 KO) mice, which exhibit massive renal glycosuria while maintaining euglycemia. We measured renal expression of glutamine transporters (Slc1a5 & Slc38a3), glutaminase 1 (Gls1) and glutamine synthetase (Glul) using quantitative PCR (qPCR). We tested the functional relevance of glutamine metabolism in renal gluconeogenesis by pharmacologically inhibiting glutamine transport using V-9302 in both rGlut2 KO mice and C57BL/6 mice treated with dapagliflozin (DAPA). Paired abdominal aortic and renal venous blood glucose measurements were used to assess kidney-derived glucose production. rGlut2 KO mice showed increased renal expression of Slc1a5 (100 ±4.9 vs 134.4 ±15.8, p< 0.05), Slc38a3 (100 ±7.3 vs 125.4 ±17.2, p< 0.05), Gls1 (100 ±6.3 vs 124.1±10.4, p< 0.05) and a decreased expression of Glul (100 ±4.1 vs 51.2±8.9, p< 0.05), suggesting increased renal glutamine transport and utilization, likely for renal gluconeogenesis. Furthermore, inhibition of glutamine transport caused a rapid decline in blood glucose in KO mice (137.3 ±13.2 vs 95.3 ±10.9 mg/dL at 7 h post V-9302 administration), leading to hypoglycemia. Consistent with this observation, male C57BL/6 mice treated with DAPA and V-9302 exhibited significantly lower blood glucose levels compared with mice treated with DAPA alone (117.0 ±12.6 vs 175.9 ±9.6 mg/dL). These findings indicate that glutamine-dependent renal gluconeogenesis is required to sustain normal blood glucose during chronic and DAPA-induced glycosuria. Treatment with sotagliflozin, a dual SGLT1/2 inhibitor, reduced blood glucose to a similar extent in both control and KO mice, indicating that SGLT1 compensation is insufficient to maintain euglycemia. Additionally, there was no change in the renal venous–aortic blood glucose difference between control and rGlut2 KO (12.3 ±21.1 vs 21.2 ±13.5 mg/dL) mice despite massive glycosuria, suggesting the significant role of renal gluconeogenesis in response to glucose loss in urine. Our findings demonstrate that glutamine-dependent renal gluconeogenesis is required to maintain glucose homeostasis during glycosuria. These results establish glutamine metabolism and renal gluconeogenesis as key compensatory responses to SGLT2 inhibitor–induced glycosuria, with important implications for improving the efficacy of type 2 diabetes therapy.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*