Effects of free fatty acids on glucose transport and IRS-1–associated phosphatidylinositol 3-kinase activity

TLDR

Insulin stimulates whole‑body glucose uptake. The study examined how free fatty acids induce insulin resistance in human skeletal muscle by measuring metabolic markers before and after a hyperinsulinemic‑euglycemic clamp with lipid or glycerol infusion. The authors used ^13C/^31P NMR spectroscopy and muscle biopsies to assess glycogen, glucose‑6‑phosphate, intracellular glucose, and IRS‑1–associated PI3K activity before and after lipid or glycerol infusion during a hyperinsulinemic‑euglycemic clamp. Free fatty acid infusion reduced glucose oxidation, glycogen synthesis, and intramuscular glucose‑6‑phosphate by 50–60 % and 90 %, respectively, and lowered intracellular glucose, indicating impaired glucose transport; insulin‑stimulated IRS‑1–associated PI3K activity rose fourfold with glycerol but was abolished with lipid, suggesting FFA‑induced insulin resistance occurs through decreased PI3K activity and glucose transport.

Abstract

To examine the mechanism by which free fatty acids (FFA) induce insulin resistance in human skeletal muscle, glycogen, glucose-6-phosphate, and intracellular glucose concentrations were measured using carbon-13 and phosphorous-31 nuclear magnetic resonance spectroscopy in seven healthy subjects before and after a hyperinsulinemic-euglycemic clamp following a five-hour infusion of either lipid/heparin or glycerol/heparin. IRS-1–associated phosphatidylinositol 3-kinase (PI 3-kinase) activity was also measured in muscle biopsy samples obtained from seven additional subjects before and after an identical protocol. Rates of insulin stimulated whole-body glucose uptake. Glucose oxidation and muscle glycogen synthesis were 50%–60% lower following the lipid infusion compared with the glycerol infusion and were associated with a ∼90% decrease in the increment in intramuscular glucose-6-phosphate concentration, implying diminished glucose transport or phosphorylation activity. To distinguish between these two possibilities, intracellular glucose concentration was measured and found to be significantly lower in the lipid infusion studies, implying that glucose transport is the rate-controlling step. Insulin stimulation, during the glycerol infusion, resulted in a fourfold increase in PI 3-kinase activity over basal that was abolished during the lipid infusion. Taken together, these data suggest that increased concentrations of plasma FFA induce insulin resistance in humans through inhibition of glucose transport activity; this may be a consequence of decreased IRS-1–associated PI 3-kinase activity.