The role of mitochondria in insulin resistance and type 2 diabetes (T2D) is the subject of much debate. Recent evidence has suggested the presence of altered skeletal muscle mitochondrial dynamics, both increased fission and reduced fusion, in the etiology of insulin resistance and T2D, however, it is unclear what role, if any, changes in mitochondrial dynamics play in the induction of insulin resistance. We have proposed that increased mitochondrial fission may represent an early mechanistic link between the mitochondria and the onset of skeletal muscle insulin resistance. To test this hypothesis we recruited healthy humans to receive, in a randomized crossover design, an overnight saline (control) or lipid infusion (20% Intralipid) at 0.55 ml/kg/h, followed by a 2h, 90 mg/dL, 40 mU/m2 hyperinsulinemic-euglycemic clamp to assess insulin sensitivity. Changes to mitochondrial dynamics protein expression were assessed by western blot, ex vivo mitochondrial membrane potential (TMRM staining) by confocal microscopy, oxidative capacity by respirometry (Oroboros O2k), and mitochondrial morphology by transmission electron microscopy, in skeletal muscle biopsy samples following the overnight infusions. Preliminary data (n=8; 5M, 3F; Age: 26±1 years; BMI: 22.6±0.7; VO2max: 44.0±2.5) indicate that lipid infusion results in a tendency for reduced insulin sensitivity (P=0.08) and mitochondrial membrane potential (P=0.09), and an increase in Complex I state 3 respiration (P<0.05). Dynamin related protein 1 (Drp1) activation (P<0.05) by phosphorylation at serine 616—a key step in mitochondrial fission, and the Drp1 adaptor protein MiD49 (P=0.10) were increased after lipid infusion. No changes to mitochondrial fusion (Mfn1, Mfn2, OPA1), or mitophagy (Pink1, Parkin) proteins were observed following the lipid infusion. These data support our hypothesis that increased mitochondrial fission is an early adaptation to lipid induced insulin resistance in healthy humans.

Disclosure

C.E. Fealy: None. C.L. Axelrod: None. M.L. Erickson: None. E. Huang: None. A. Hari: None. A. Mulya: None. H. Fujioka: None. C.L. Hoppel: None. J.P. Kirwan: None.

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