Altered skeletal muscle fatty acid handling is associated with the degree of insulin resistance in overweight and obese humans

Disturbances in skeletal muscle fatty acid (FA) handling may contribute to the development and progression of whole-body insulin resistance (IR). In this study, we compared fasting and postprandial skeletal muscle FA handling in individuals with varying degrees of IR. Seventy-four overweight/obese participants (62 men) were divided into two groups based on the HOMA-IR median (3.35). Fasting and postprandial skeletal muscle FA handling were determined by combining the forearm muscle balance technique with stable isotopes. [H-2(2)]palmitate was infused i.v. to label VLDL-triacylglycerol (VLDL-TAG) and NEFA in the circulation, whereas [U-C-13]palmitate was incorporated in a high-saturated FA mixed-meal labelling chylomicron-TAG. Skeletal muscle biopsies were taken to assess intramuscular lipid content, fractional synthetic rate (FSR) and the transcriptional regulation of FA metabolism. Postprandial forearm muscle VLDL-TAG extraction was elevated in the high-IR vs the mild-IR group (AUC(0-4h): 0.57 +/- 0.32 vs -0.43 +/- 0.38 nmol [100 ml tissue](-1) min(-1), respectively, p = 0.045). Although no differences in skeletal muscle TAG, diacylglycerol, NEFA content and FSR were present between groups, the high-IR group showed increased saturation of the intramuscular NEFA pool (p = 0.039). This was accompanied by lower muscle GPAT1 (also known as GPAM) expression (p = 0.050). Participants with high-IR demonstrated increased postprandial skeletal muscle VLDL-TAG extraction and higher saturation of the intramuscular NEFA pool vs individuals with mild-IR. These data support the involvement of disturbances in skeletal muscle FA handling in the progression of whole-body IR.