Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects

Insulin resistance plays an important role in the pathogenesis of type 2 di abetes; however, the multiple mechanisms causing insulin resistance are not yet fully understood. The aim of this study was to explore the possible co ntribution of intramyocellular lipid content in the pathogenesis of skeleta l muscle insulin resistance. We compared insulin-resistant and insulin-sens itive subjects. To meet stringent matching criteria for other known confoun ders of insulin resistance, these individuals were selected from an extensi vely metabolically characterized group of 280 first-degree relatives of typ e 2 diabetic subjects. Some 13 lean insulin-resistant and 13 lean insulin-s ensitive subjects were matched for sex, age, BMI, percent body fat, physica l fitness, and waist-to-hip ratio. Insulin sensitivity was determined by th e hyperinsulinemic-euglycemic clamp method (for insulin-resistant subjects, glucose metabolic clearance rate [MCR] was 5.77 +/- 0.28 ml . kg(-1) . min [mean +/- SE]; for insulin-sensitive subjects, MCR was 10.15 +/- 0.7 ml . kg(-1) . min(-1); P < 0.002). Proton magnetic resonance spectroscopy (MRS) was used to measure intramyocellular lipid content (IMCL) in both groups. M RS studies demonstrated that in soleus muscle, IMCL was increased by 84% (1 1.8 +/- 1.6 vs. 6.4 +/- 0.59 arbitrary units; P = 0.008), and in tibialis a nterior muscle, IMCL was increased by 57% (3.26 +/- 0.36 vs. 2.08 +/- 0.3 a rbitrary units; P = 0.017) in the insulin-resistant offspring, whereas the extramyocellular lipid content and total muscle lipid content were not stat istically different between the two groups. These data demonstrate that in these well-matched groups of lean subjects, IMCL is increased in insulin-re sistant offspring of type 2 diabetic subjects when compared with an insulin -sensitive group matched for age, BMI, body fat distribution, percent body fat, and degree of physical fitness. These results indicate that increased IMCL represents an early abnormality in the pathogenesis of insulin resista nce and suggest that increased IMCL may contribute to the defective glucose uptake in skeletal muscle in insulin-resistant subjects.