9-OR: Insulin Resistance (IR) and Kidney Oxidative Metabolism in People with Type 1 Diabetes (T1D)

Abstract

IR has been linked to kidney injury in T1D. Animal models show that IR associates with impaired TCA cycle turnover and oxidative phosphorylation, collectively termed oxidative metabolism, but little is known about this relationship in humans with T1D. Thirty young adults with T1D (age: 23±3 years, diabetes duration: 13±5 years, 53% female, HbA1c: 7.9±1.1%, BMI: 25±3 kg/m2, UACR: 5 [3, 8] mg/g) and 20 healthy controls (HC) (age: 25±3, 50% female, HbA1c: 5.2±0.3%, BMI: 23±2 kg/m2, UACR: 5 [3, 9] mg/g) underwent hyperinsulinemic-euglycemic clamps to assess whole-body insulin sensitivity (IS), and MRI to assess kidney perfusion. A subset underwent voxel-wise and region-of-interest (ROI) pharmacokinetic (PK) 11C-acetate PET analyses (n=16 T1D; n=10 HC) to quantify kidney cortical oxidative metabolism (k 2), and research kidney biopsies with single-cell RNA sequencing (n=28 T1D; n=13 HC). Compared to HC, participants with T1D exhibited lower IS (7.8±2.6 vs. 14.3±4.0 mg/kg/min, p<0.0001), cortical perfusion (196±68 vs. 243±46 ml/min/100g, p=0.01) and lower cortical k 2 (0.16±0.02 vs. HC 0.18±0.02 min-1, p=0.04) in voxel-wise models, although significance was not reached in the ROI PK analyses. IS associated with cortical k 2 (r:0.43, p=0.03) and the associations remained significant after adjusting for age, sex, and HbA1c (p=0.04). No significant interaction observed between T1D and HC for IS and cortical k2 (p=0.78). Proximal tubular transcripts of the enzymes catalyzing the proximal steps of the TCA cycle (e.g., ACO1, IDH1, SUCLG1) were lower in T1D vs. HC (all FDR-adjusted p<0.0001). Kidney oxidative metabolism is impaired in young people with T1D and is linked to lower whole-body IS. Statistical differences in k 2 from ROI and voxel-wise analyses suggest regional variations in kidney oxidative metabolism that may not be apparent in global analysis. Spatial metabolomic analyses of kidney tissue in a subset of these participants are shown in abstract #2023-A-3407-Diabetes. Disclosure G.Richard: None. S.Gross: None. V.N.Shah: Advisory Panel; LifeScan Diabetes Institute, Medscape, Consultant; DKSH, Research Support; Novo Nordisk, Tandem Diabetes Care, Inc., Dexcom, Inc., Insulet Corporation, JDRF, National Institutes of Health, Speaker's Bureau; Dexcom, Inc., Insulet Corporation. L.Pyle: None. T.B.Vigers: None. J.K.Snell-bergeon: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc. D.Van raalte: Consultant; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc., Research Support; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc. L.Li: None. P.V.Prasad: None. P.E.Ladd: None. C.Birznieks: None. B.B.Chin: None. D.Cherney: Other Relationship; Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon and Novo-Nordisk, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo-Nordisk. P.J.Mccown: None. F.Alakwaa: 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. K.Sharma: Advisory Panel; Reata Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc. F.C.Brosius: Advisory Panel; Gilead Sciences, Inc. R.G.Nelson: None. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. G.Zhang: None. L.Driscoll: None. K.L.Tommerdahl: None. J.A.Schaub: None. A.Naik: Advisory Panel; CareDx. V.Nair: None. A.A.Macdonald: None. Funding JDRF; National Institute of Diabetes and Digestive and Kidney Diseases