Intramyocellular lipid is associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle

To examine whether and how intramyocellular lipid (IMCL) content contributes to interindividual variation in insulin action, we studied 20 healthy men with no family history of type 2 diabetes. IMCL was measured as the resonance of intramyocellular CH2 protons in lipids/resonance of CH3 protons of total creatine (IMCL/Cr-T), using proton magnetic resonance spectroscopy in vastus lateralis muscle. Whole-body insulin sensitivity was measured using a 120-min euglycemic-hyperinsulinemic (insulin infusion rate 40 mU/m(2) . min) clamp. Muscle biopsies of the vastus lateralis muscle were taken before and 30 min after initiation of the insulin infusion to assess insulin signaling. The subjects were divided into groups with high IMCL (HiIMCL; 9.5 +/- 0.9 IMCL/Cr-T, n = 10) and low IMCL (LoIMCL; 3.0 +/- 0.5 IMCL/Cr-T, n = 10), the cut point being median IMCL (6.1 IMCL/Cr-T). The groups were comparable with respect to age (43 +/- 3 vs. 40 +/- 3 years, NS, HiIMCL versus LoIMCL), BMI (26 +/- I vs. 26 +/- 1 kg/m(2), NS), and maximal oxygen consumption (33 +/- 2 vs. 36 +/- 3 ml . kg(-1) . min(-1), NS). Whole-body insulin-stimulated glucose uptake was lower in the HiIMCL group (3.0 +/- 0.4 mg . kg(-1) . min(-1)) than the LoIMCL group (5.1 +/- 0.5 mg . kg(-1) . min(-1), P < 0.05). Serum free fatty acid concentrations were comparable basally, but during hyperinsulinemia, they were 35% higher in the HiIMCL group than the LoIMCL group (P < 0.01). Study of insulin signaling indicated that insulin-induced tyrosine phosphorylation of the insulin receptor (IR) was blunted in HiIMCL compared with LoIMCL (57 vs. 142% above basal, P < 0.05), while protein expression of the IR was unaltered. IR substrate-1-associated phosphatidylinositol (PI) 3-kinase activation by insulin was also lower in the HiIMCL group than in the LoIMCL group (49 +/- 23 vs. 84 +/- 27% above basal, P < 0.05 between HiIMCL and LoIMCL). In conclusion, IMCL accumulation is associated with whole-body insulin resistance and with defective insulin signaling in skeletal muscle independent of body weight and physical fitness.