Introduction and Objective: Vascular inflexibility, impairments in vascular perfusion in the setting of metabolic demand, associated with T2D may contribute to the muscle mitochondrial dysfunction and metabolic inflexibility. Oxidative flux in response to ATP demand is dependent on the intrinsic properties of the skeletal muscle mitochondria, insulin action, and perfusion for the delivery of oxygen and substrate necessary for oxidative flux. We hypothesize that skeletal muscle respiration kinetics are impaired in T2D and may respond to supraphysiological insulin.Methods: We examined substrate oxidation of carbohydrate and lipid at sub-saturating ADP concentrations before and after hyperinsulemic-euglycemic clamp. The vastus lateralis was sampled in adults with (n=10, 6M/4F) and without (n=9, 3M/6F) T2D of similar age and BMI before and at the end of a clamp. Mitochondrial respiration was measured by high-resolution respirometry in permeabilized muscle using an ADP titration protocol with pyruvate+malate (carbohydrate) or octanoylcarnitine+malate (lipid) as substrates.Results: In response to insulin, carbohydrate Vmax decreased in people without T2D but not in people with T2D (p=0.022). Km was not different. Lipid Vmax was lower in T2D before (P=0.05) and after insulin (P=0.025). Lipid Km increased in people with T2D in response to insulin (P=0.039) suggesting lower ADP sensitivity. No results differed by sex.Conclusion: The impact of acute hyperinsulinemia on mitochondrial ADP sensitivity with T2D supports metabolic inflexibility to lipid substates. Changes in mitochondrial function before and after insulin exposure support a model of dynamic in vivo mitochondrial regulation which is impaired in T2D. Implication: Mitochondrial dysfunction in T2D is not corrected by acute hyperinsulinemia consistent with intrinsic mitochondrial defects.
L.Knaub: None. R.L.Scalzo: None. J.H.Chun: None. I.E.Schauer: None. B.R.Juckett: None. J.G.Regensteiner: None. J.E.Reusch: n/a.
NIH (R01 DK124344)
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