(OR22-05-26) Association Between mtDNA DAMPs, Adipokines, and Insulin Resistance and Sensitivity

Objectives: mtDNA DAMPs are linked to insulin resistance and metabolic inflammation in type 2 diabetes, but underlying mechanisms remain unclear. Adipokines regulate mitochondrial function and inflammation responses. Therefore, we examined whether adipokines influence the relationship between mtDNA DAMPs, insulin resistance, and insulin sensitivity.

Methods: This cross-sectional study included adults aged 19-45 years in Alabama, who self-reported as African American (AA, n=52) or European American (EA, n=57). Multiple regression models evaluated the associations between mtDNA DAMPs, adipokines, and their interactions with insulin resistance and insulin sensitivity. The dependent variables were HOMA-IR and SIClamp. Independent variables included total mtDNA DAMPs (ND1 + ND6) and adipokines (leptin, adiponectin, and leptin-adiponectin ratio; LAR). Models were adjusted for total fat mass, age, sex, and race.

Results: Participants had a mean age of 29.3 ± 7.9 years, evenly distributed by sex and race. Inflammation measures and mtDNA DAMPs were similar by race. EA participants showed higher adiponectin levels, whereas AA participants exhibited a higher leptin-adiponectin ratio (p < 0.05). Total mtDNA DAMPs were positively associated with HOMA-IR (β=0.2457, p=0.0348). Leptin significantly modified the association between mtDNA DAMPs and insulin resistance (p=0.0004), with stronger relationships observed at higher levels. LAR was also associated with HOMA-IR (β=0.1886, p < 0.001) and significantly modified the association between mtDNA DAMPs and insulin resistance (p=0.0053). For SIClamp, mtDNA DAMPs were not independently associated; however, leptin modified this relationship (p=0.0325), with a stronger reduction in insulin sensitivity observed at higher leptin levels. Total fat mass, male sex, and AA race were also significantly associated with HOMA-IR.

Conclusions: Adipokine balance appears to modify the association of mtDNA DAMPs with both insulin resistance and insulin sensitivity. These findings suggest mtDNA DAMPs may contribute to metabolic dysfunction in a pro-inflammatory adipokine environment.

Funding Sources: This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases at the NIH, University of Alabama at Birmingham (UAB) Nutrition Obesity Research Center, and Diabetes Research Center.