Understanding insulin resistance's impact on renal vasculature, especially arterioles, in T1D is vital, given its significant role in onset of diabetic kidney disease. We have previously demonstrated strong associations between circulating adiponectin and whole-body insulin sensitivity in T1D. This study interrogates the transcriptome of renal arteriolar cells to characterize transcript patterns of adiponectin receptors (ADIPOR1 and ADIPOR2) and co-receptor (CDH13) in young adults with T1D compared to healthy controls (HC), as well as their associations with whole-body insulin sensitivity (IS). This cross-sectional study included 30 participants with T1D (age: 23±3 years, diabetes duration: 13±5 years, 53% female, HbA1c: 7.9±1.1%, BMI: 25±3 kg/m2) and 20 HC (age: 25±3, 50% female, HbA1c: 5.2±0.3%, BMI: 23±2 kg/m2). Twenty eight participants with T1D and 12 HC underwent research kidney biopsies, followed by single-cell RNA sequencing of the tissue. IS was quantified using hyperinsulinemic-euglycemic clamps. Compared to HC, participants with T1D exhibited lower IS (7.8±2.6 vs. 14.3±4.0 mg/kg/min, p<0.0001). Renal arteriolar ADIPOR2 expression was lower in T1D vs. HC (logFC: -0.41, p<0.0001), whereas CDH13 was higher (logFC: 0.29, p<0.0001). No group difference observed for ADIPOR1. ADIPOR1 correlated positively with insulin sensitivity (r: 0.43, p=0.03) and CDH13 correlated negatively with insulin sensitivity (r:-0.40, p=0.04). ADIPOR2 did not correlate with insulin sensitivity. The study reveals distinct renal arteriolar expression patterns of adiponectin receptors and co-receptors in T1D and their association with insulin sensitivity. The upregulation of ADIPOR1 and downregulation of CDH13 with greater IS highlight the complex interplay in adiponectin signaling within the kidney endothelium. These findings open avenues for targeted interventions in the adiponectin pathway to promote renal vascular health in T1D.
K.L. Tommerdahl: None. Y. Choi: None. L. Pyle: None. J.A. Schaub: None. D. van Raalte: Consultant; Eli Lilly and Company. Research Support; Eli Lilly and Company, Boehringer-Ingelheim. Consultant; Boehringer-Ingelheim. Research Support; Merck & Co., Inc. Advisory Panel; Merck & Co., Inc. Consultant; Bayer Inc. K. Bornfeldt: Advisory Panel; ESPERION Therapeutics, Inc. I. de Boer: Consultant; Boehringer-Ingelheim, Lilly Diabetes, AstraZeneca, Novo Nordisk, Alnylam Pharmaceuticals, Inc., George Clinical. Research Support; Dexcom, Inc., Novo Nordisk. P. Narongkiatikhun: None. C. Birznieks: None. M. Kretzler: Research Support; Boehringer-Ingelheim, Certa, Traveere Pharmaceuticals, Maze Therapeutics, Roche Pharmaceuticals, AstraZeneca, Novo Nordisk, Moderna, Inc., Chinook Therapeutics Inc., angion, Lilly Diabetes, Renalytix, Gilead Sciences, Inc., Regeneron Pharmaceuticals Inc., Janssen Pharmaceuticals, Inc. P.J. McCown: None. P. Bjornstad: Consultant; AstraZeneca, Boehringer-Ingelheim. Advisory Panel; Lilly Diabetes, Novo Nordisk, Bayer Inc., Horizon Therapeutics plc.
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