Effects of Sustained Hyperglycemia on Skeletal Muscle Lipids in Healthy Subjects

Abstract

Asbtract Context Sustained increases in plasma glucose promote skeletal muscle insulin resistance independent from obesity and dyslipidemia (ie, glucotoxicity). Skeletal muscle lipids are key molecular determinants of insulin action, yet their involvement in the development of glucotoxicity is unclear. Objective To explore the impact of mild physiologic hyperglycemia on skeletal muscle lipids. Design Single group pretest-posttest. Participants Healthy males and females with normal glucose tolerance. Interventions 72-hour glucose infusion raising plasma glucose by ~50 mg/dL. Main Outcome Measures Skeletal muscle lipids, insulin sensitivity, lipid oxidation. Results Despite impairing insulin-mediated glucose disposal and suppressing fasting lipid oxidation, hyperglycemia did not alter either the content or composition of skeletal muscle triglycerides, diacylglycerides, or phospholipids. Skeletal muscle ceramides decreased after glucose infusion, likely in response to a reduction in free fatty acid concentrations. Conclusions Our results demonstrate that the major lipid pools in skeletal muscle are unperturbed by sustained increases in glucose availability and suggest that glucotoxicity and lipotoxicity drive insulin resistance through distinct mechanistic pathways.