226-OR: ADA Presidents’ Select Abstract: Exercise Training Promotes Mitochondrial Remodeling in Skeletal Muscle of Type 2 Diabetes Humans

Abstract

Altered mitochondrial dynamics may contribute to impaired mitochondrial function and insulin sensitivity in type 2 diabetes (T2D). High intensity interval training (HIIT) can induce mitochondrial biogenesis in healthy humans, but its impact on mitochondrial remodeling in insulin resistant states is still unclear. To this end, this study examined the effect of HIIT on mitochondrial function and dynamics in T2D as well as in insulin resistant (IR) and sensitive (IS) glucose tolerant humans to elucidate the interplay between mitochondrial turnover and muscle insulin sensitivity. Twenty T2D, 11 IR and 12 IS humans age- and BMI-matched (HbA1c in %: 7.2 ± 0.2, 5.4 ± 0.1, 5.5 ± 0.1; M-value in mg*kg-1*min-1: 3.0 ± 0.4, 4.1 ± 0.3, 7.4 ± 0.4) performed a 12-week HIIT cycling protocol for 3 days/week. Before the intervention (baseline) and 72 h after the last exercise bout, whole-body insulin sensitivity was measured by hyperinsulinemic-euglycemic clamps, whereas mitochondrial respiration and dynamics were assessed by high resolution respirometry and immunoblotting of skeletal muscle biopsies. After HIIT, all participants showed improved cardiorespiratory fitness and increased muscle maximal oxygen uptake (p<0.001 vs. baseline), whereas insulin sensitivity increased only in T2D and IR (M-value; 4.3 ± 0.5 and 5.7 ± 0.6; p<0.01 vs. baseline). Moreover, HIIT doubled muscle citrate synthase activity in all groups, while biomarkers of mitochondrial fission (p<0.01), fusion (p<0.001) and mitophagy (p<0.001 for phospho-Parkin(Ser65) and p<0.05 for phospho-Pink(Thr257)) increased only in T2D. In conclusion, this study suggests that mitochondrial fusion and fission synergically respond to chronic exercise training and likely contribute to the exercise training response of insulin sensitivity at least in overt T2D. Targeting these mechanisms might help to better understand muscle insulin resistance and to identify novel therapeutic strategies for tailored prevention and treatment of T2D. Disclosure L. Mastrototaro: None. M. Apostolopoulou: None. D. Pesta: None. K. Strassburger: None. Y. Karusheva: None. S. Gancheva: None. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Allergan plc, Bristol-Myers Squibb Company, Novo Nordisk A/S, Research Support; Self; Boehringer Ingelheim International GmbH, Danone Nutricia, Sanofi-Aventis Deutschland GmbH.