Effect of Vertical Sleeve Gastrectomy (VSG) on the Kidney Transcriptome of Youth with Type 2 Diabetes (T2D)

Introduction: VSG attenuates early diabetic kidney disease (DKD) in youth with T2D, yet the molecular mechanisms of VSG on kidney health are unknown. We analyzed single-cell RNA sequencing data from paired kidney biopsies obtained from youth with T2D before and 1-year after VSG. Methods: Data from 5 youths with T2D who underwent kidney biopsies before and after VSG were included in this analysis (pre-VSG:17±2 years, HbA1c 7.5±2.6%, BMI 41±3 kg/m2, 40% with albuminuria (UACR≥30mg/g). A total of 23598 cells were profiled from the five paired kidney biopsies, with 19735 cells from 12 HC. Cell selective differentially expressed genes in disease (T2D vs. HC) were computed. Disease genes that reversed directionality post-VSG were termed "suppressed by VSG" or "upregulated by VSG," depending on the direction of the reversal. Results: VSG resulted in the normalization of HbA1c and UACR in all cases at 12 months. Post VSG, 73% of proximal tubule (PT) genes that were upregulated in T2D vs. HC were suppressed in VSG vs. T2D. These suppressed genes were enriched for glycolysis, gluconeogenesis, and TCA cycle pathways (Figure). Gene and pathway changes in the PT were similar to what was recently demonstrated with SGLT2i in T2D youth. Conclusion: VSG, like SGLT2i, is associated with reduced central carbon metabolism in the PT and other nephron segments. Disclosure A.Naik: Advisory Panel; CareDx. K.N.Z.Fuller: None. P.E.Ladd: None. D.A.Sandoval: Consultant; Metis Therapeutics. S.Gross: None. P.Zeitler: Consultant; Eli Lilly and Company, Boehringer Ingelheim Inc., Johnson & Johnson. K.J.Nadeau: None. J.R.Ryder: None. T.Inge: None. J.B.Hodgin: None. F.C.Brosius: Advisory Panel; Gilead Sciences, Inc. F.Alakwaa: None. R.G.Nelson: None. M.Kretzler: Research Support; Lilly, Boehringer Ingelheim Inc., Traveere Pharmaceuticals, Novo Nordisk, certa, Chinook Therapeutics Inc., Janssen Research & Development, LLC, AstraZeneca, Moderna, Inc., Gilead Sciences, Inc., Regeneron, Ionis Pharmaceuticals, Angioin, Renalytix. P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. J.A.Schaub: None. P.J.Mccown: None. V.Nair: None. S.Eddy: None. L.Pyle: None. T.B.Vigers: None. M.M.Kelsey: Other Relationship; Boehringer Ingelheim Inc., Janssen Pharmaceuticals, Inc., Rhythm Pharmaceuticals, Inc., Lilly. Funding Boettcher Foundation; National Institute of Diabetes and Digestive and Kidney Diseases (K23116720, R01DK129211); JDRF (2-SRA-2019-845-S-B)