Plasma free fatty acids decrease insulin-stimulated skeletal muscle glucose uptake by suppressing glycolysis in...

Area of Science:

• Metabolic regulation
• Skeletal muscle physiology
• Insulin signaling

Background:

• Elevated plasma free fatty acid (FFA) levels are linked to insulin resistance.
• Understanding the precise mechanisms by which FFAs impact glucose metabolism is crucial.

Purpose of the Study:

• To investigate the effects of elevated plasma FFA on insulin-stimulated glucose metabolism in conscious rats.
• To determine the impact on whole-body and skeletal muscle glucose transport, uptake, glycolysis, and glycogen synthesis.

Main Methods:

• Hyperinsulinemic-euglycemic clamps were performed in rats with and without Intralipid/heparin infusion to elevate plasma FFAs.
• Glucose metabolism was assessed using isotopic tracers (D-[3-3H]glucose, 2-[14C]deoxyglucose, L-[14C]glucose, 3-O-[3H]-methylglucose).
• Analysis included glucose uptake, glycolysis, glycogen synthesis, and glucose transport activity.

Main Results:

• Elevated FFAs significantly decreased insulin-stimulated whole-body and skeletal muscle glucose uptake (15-20%).
• A profound 30-50% suppression of insulin-stimulated glycolysis was observed in both whole body and skeletal muscle.
• Physiological insulin-stimulated glycogen synthesis increased, and glucose-6-phosphate levels rose in skeletal muscles.

Conclusions:

• Elevated plasma FFAs inhibit insulin-stimulated glucose uptake in skeletal muscle primarily by suppressing glycolysis.
• Increased glucose-6-phosphate levels suggest a potential bottleneck in glucose metabolism.
• Findings support the glucose-fatty acid cycle as the main mechanism for FFA-induced inhibition of skeletal muscle glucose uptake.