Insulin resistance and dysregulation of
free fatty acid (FFA) metabolism are core defects in type 2 diabetic (T2DM) and obese normal
glucose tolerant (NGT) individuals. Impaired muscle mitochondrial function (reduced
ATP synthesis) also has been described in
insulin-resistant T2DM and obese subjects. We examined whether reduction in plasma FFA concentration with
acipimox improved
ATP synthesis rate and altered
reactive oxygen species (ROS) production. Eleven NGT obese and 11 T2DM subjects received 1) OGTT, 2) euglycemic
insulin clamp with muscle biopsy, and 3) (1)H-magnetic resonance spectroscopy of tibialis anterior muscle before and after
acipimox (250 mg every 6 h for 12 days).
ATP synthesis rate and ROS generation were measured in mitochondria isolated from muscle tissue ex vivo with chemoluminescence and fluorescence techniques, respectively.
Acipimox 1) markedly reduced the fasting plasma FFA concentration and enhanced suppression of plasma FFA during oral
glucose tolerance tests and
insulin clamp in obese NGT and T2DM subjects and 2) enhanced
insulin-mediated muscle
glucose disposal and suppression of hepatic
glucose production. The improvement in
insulin sensitivity was closely correlated with the decrease in plasma FFA in obese NGT (r = 0.81) and T2DM (r = 0.76) subjects (both P < 0.001). Mitochondrial
ATP synthesis rate increased by >50% in both obese NGT and T2DM subjects and was strongly correlated with the decrease in plasma FFA and increase in
insulin-mediated
glucose disposal (both r > 0.70, P < 0.001). Production of ROS did not change after
acipimox. Reduction in plasma FFA in obese NGT and T2DM individuals improves mitochondrial
ATP synthesis rate, indicating that the
mitochondrial defect in
insulin-resistant individuals is, at least in part, reversible.