Mitochondrial DNA DAMPs, Inflammation, and Insulin Sensitivity After Dietary Interventions in Adults with Type 2 Diabetes

<b>Background/Objectives</b>: Mitochondrial damage is implicated in metabolic dysfunction and may contribute to inflammation and insulin resistance, key features of type 2 diabetes. This study examined the relationship among inflammatory markers, mtDNA DAMPs, and insulin sensitivity/resistance, and evaluated their response to three dietary interventions in type 2 diabetes. <b>Methods</b>: Data was pooled from two clinical trials involving adults aged 35 to 75 with type 2 diabetes (<i>n</i> = 39). Participants followed one of three 12-week diet interventions aimed at enhancing glucose metabolism without causing weight loss. The sample was 74% female and 64% African American with a mean age of 55.6 ± 7.7 years, and 92.3% (<i>n</i> = 36) had overweight/obesity. Participants were assigned to either a carbohydrate-restricted, low-fat, or fruit-rich Mediterranean diet. Primary outcomes included insulin resistance (HOMA-IR), insulin sensitivity (Matsuda index), mtDNA DAMPs (ND1, ND6), pro/anti-inflammatory cytokines (IFN-γ, IL-10, IL-6, IL-8, TNF-α), CRP, and cortisol. Associations among mtDNA DAMPs, inflammation, and insulin sensitivity/resistance were examined using regression analysis <b>Results</b>: The carbohydrate-restricted diet led to the greatest improvements in insulin sensitivity (72.7%) and reductions in HOMA-IR (41.3%) (<i>p</i> = 0.03). All diets increased mtDNA DAMPs, with most observed in the fruit-rich Mediterranean diet and low-fat diet groups and the smallest in the carbohydrate-restricted group. Total mtDNA DAMPs were associated with lower insulin sensitivity (Matsuda index: β = -0.77; SE = 0.31; <i>p</i> = <i>0</i>.02), and ND6 mtDNA DAMP levels were associated with greater insulin resistance (HOMA-IR: β = 0.90; SE = 0.40; <i>p</i> = 0.03) and lower insulin sensitivity (Matsuda index: β = -0.86; SE = 0.33; <i>p</i> = 0.01), independent of BMI and race. Proinflammatory cytokines were associated with increased HOMA-IR (β = 0.45; <i>p</i> = 0.007) and reduced Matsuda index (β = -0.43; <i>p</i> = 0.009) and moderated effects of mtDNA DAMPs on insulin sensitivity/resistance. <b>Conclusions</b>: These findings highlight mtDNA DAMPs in metabolic dysfunction in the context of inflammation.