Abstract P049: Mitochondrial DNA Copy Number and Diabetes in the ARIC Study

Abstract

Introduction: In the United States, the rising number of adults with type 2 diabetes (T2D) is thought to be associated with the rise in obesity. Obesity may be associated with T2D through biologic pathways where excess weight strains the body’s metabolic machinery, such as mitochondria. Mitochondria are dynamic organelles whose regulation and function respond to cell stress, such as insulin resistance. Previous research reveals that insulin resistance is associated with obesity prior to hyperglycemia. Mitochondrial DNA copy number is a measure of mitochondrial DNA content, and correlates with both the number and size of mitochondria. We assessed the hypothesis that mitochondrial DNA copy number is associated with T2D in a community-based, prospective cohort study. A lower mitochondrial DNA copy number in these analyses represents worse mitochondrial function. Methods: We included 6,633 white ARIC participants without coronary heart disease who had mitochondrial DNA copy number measured from visit 2 (1990-1992). Our sample had a mean age of 57 ± 5.6 years, was 43% male, average BMI of 27 ± 4.9 kg/m2, and 27% with hypertension. Those with diabetes had an average hemoglobin A 1c of 7.2 ± 1.8 (n=681). The mitochondrial DNA copy number value used in analyses represents a sample’s standard deviation (SD) from a mean of zero for age- and sex-adjusted distributions. The mitochondrial DNA copy number data was then divided into quintiles, with the most negative mitochondrial DNA copy number in quintile 1 (Q1), the mean of zero in Q3, and the most positive in Q5. We defined T2D as self-report of doctor diagnosis, current use of glucose-lowering medication, or fasting blood glucose ≥ 126 mg/dL or non-fasting blood glucose ≥ 200 mg/dL measured at study visits. We used logistic regression to estimate the odds of prevalent T2D for each quintile group compared to Q3. Confounders considered in the base model included age at sample collection, sex, education level, and medication use (thyroid and estrogen). All analyses were done in Stata 14.1. Results: The prevalence of T2D was higher in the lower mitochondrial DNA copy number quintiles: 15% in Q1 (mean copy number: -1.40 SD) 11% in Q2 (-0.46 SD), and 9% in Q3-Q5 (0.04 SD, 0.52 SD, 1.33 SD). There was increased odds of T2D in lower mitochondrial DNA copy number quintiles, but with no additional benefit of copy number above the mean. The odds of T2D in each quintile compared to Q3 was 1.9 in Q1 (95% CI 1.49, 2.46), 1.36 in Q2 (95% CI 1.05, 1.77), 0.99 in Q4 (95% CI 0.76, 1.30) and 0.96 in Q5 (95% CI 0.74, 1.26). Conclusion: Examining the association of mitochondrial dysfunction and diabetes in a large community-based cohort connects results from experimental studies to epidemiologic studies and provides the opportunity to characterize the complex pathogenesis of diabetes using cohort data.