Intramyocellular Lipid Is Associated With Resistance to In Vivo Insulin Actions on Glucose Uptake, Antilipolysis, and Early Insulin Signaling Pathways in Human Skeletal Muscle

Abstract

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 CH 2 protons in lipids/ resonance of CH 3 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 ⅐ 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 ؎ 1 vs. 26 ؎ 1 kg/m 2 , NS), and maximal oxygen consumption (33 ؎ 2 vs. 36 ؎ 3 ml ⅐ kg ؊1 ⅐ min ؊1 , NS). Whole-body insulin-stimulated glucose uptake was lower in the HiIMCL group (3.0 ؎ 0.4 mg ⅐ kg ؊1 ⅐ min ؊1 ) than the LoIMCL group (5.1 ؎ 0.5 mg ⅐ kg ؊1 ⅐ 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, A bnormal lipid metabolism is a feature of the insulin resistance syndrome (1). In addition to an increase in the total amount of fat, the lipid disturbances include elevated circulating concentrations of triglycerides and free fatty acids (FFAs) (2) and an increase in visceral fat (3). Recently, several studies have shown an association between lipid accumulation in skeletal muscle and insulin resistance (4 -10). In four of these studies, this relation was shown to be caused by intramyocellular rather than extramyocellular lipids, as measured by proton spectroscopy (5-7,11).The causes for intramyocellular lipid (IMCL) accumulation are poorly understood. The first possibility is that IMCL is an innocent bystander and simply reflects overall adiposity. This is not supported by recent experiments in mice lacking subcutaneous fat, the A-ZIP/F-1 mice (12,13). These mice deposit fat intramyocellularly and exhibit severe insulin resistance, which is reversible by fat transplantation and rechanneling of IMCL back to subcutaneous depots. In humans, however, it is less clear whether IMCL is associated with insulin resistance independent of obesity. In 20 Europeans, Forouhi et al. (6) found the rela...

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