Circulating Mitochondrial DNA Provides a Novel Biomarker for Hyperinsulinemia and Disease Severity in Type 2 Diabetes

Introduction and Objective: Circulating cell-free mitochondrial DNA (cf-mtDNA) activates innate immunity and has been implicated in animal models of diabetes. This study aimed to assess how mitochondrial DNA levels correlate with diabetes disease state and hospitalization in humans. Methods: Using droplet digital PCR (ddPCR), we quantified plasma cf-mtDNA concentrations in 52 adults classified into 4 groups: non-diabetes (Non-DM), obesity without diabetes (ObND), outpatient Type 2 Diabetes (T2D) and hospitalized T2D (T2D-Hosp). ObND group participants had BMI >30 and hyperinsulinemia without hyperglycemia (~2-fold fasting insulin vs. Non-DM, p = 0.028). Results: Compared to Non-DM controls, logarithmic analysis revealed a progressive increase in plasma cf-mtDNA concentrations in ObND (p = 0.042), T2D (p = 0.006), and T2D-Hosp groups (p <0.001) (Figure). Conclusion: Here we show that cf-mtDNA is elevated in people with ObND or T2D compared to Non-DM controls. This effect is exacerbated by physiologic stress, with an additional ~3-fold increase in cf-mtDNA during hospitalization. Early cf-mtDNA elevation is detectable in obese patients with hyperinsulinemia before significant hyperglycemia develops. Plasma cf-mtDNA may thus provide a biomarker for early diagnosis and clinical severity in T2D. Disclosure: R.L. Thomas: Research Support; REMD Therapeutics, Carmot Therapeutics. J.D. Garcia: None. A.J. Kumar: None. L. Carter: None. J.A. Masso-Silva: None. V. Hamidi: None. S.C. Boeder: Consultant; Cecelia Health. Advisory Panel; Novo Nordisk. Consultant; Lexicon Pharmaceuticals, Inc, Persperion Diagnostics. Research Support; Eli Lilly and Company, Carmot Therapeutics, Inc, REMD Therapeutics, Dexcom, Inc., Lexicon Pharmaceuticals, Inc. T.P. Ciaraldi: None. J.H. Pettus: None. M.L. Hepokoski: None. Funding: R.L. Thomas: Altman Clinical and Translational Research Institute Pilot Project National Institutes of Health, CTSA Grant (UL1TR0014422); National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK063491); Foundation for the National Institutes of Health T32 (2T32DK007044-41); National NIH K12 DiabDocs Program (K12DK133995)