Glucose-fatty acid substrate competition in isolated soleus muscle

Obesity and NIDDM are associated with increased plasma free fatty acids (FFA), hyperinsulinemia and elevated muscle triacylglycerol (TAG). We investigated: 1) the role of elevated FFA as a direct inhibitor of muscle glucose metabolism, and 2) the effects of insulin and glucose on muscle lipid utilization Soleus muscle isolated from obese (ob/ob) mice and lean littermates were incubated for 90 minutes in Kreb's Ringer buffer (5.0 mM glucose) with 14C-glucose (1.0 μCi/ml) with and without 1.0 mM oleate; or with 0.5-1.5 mM 14C-oleate (1.0 μCi/ml). One muscle from each animal served as a basal control and the contralateral muscle was treated with insulin (10-7 M). Incorporation of label into CO2. and into either glycogen or TAG was determined. Obesity-associated insulin resistance was demonstrated by an 8 fold, compared to a 2-fold, insulin-stimulated increase in glycogen synthesis in muscle from lean and obese mice. respectively. Addition of oleate to the media did not affect either basal or insulin-stimulated glycogen synthesis, but oleate inhibited both basal and insulin-stimulated glucose oxidation by 40-50%. In the presence of both glucose and 14C-oleate. insulin increased TAG synthesis by 77% and 45% in muscle from lean compared to obese animals Basal oleate oxidation was similar in muscle from lean and obese mice, but insulin suppressed oleate oxidation by 44% and 20%, respectively. These data indicate: 1) that FFA selectively inhibits glucose oxidation but not glycogen synthesis. 2) that the degree of insulin resistance in muscle from obese animals differs for specific insulin-regulated glucose and lipid metabolic pathways, and 3) that insulin and glucose regulate muscle lipid partitioning by favoring lipid storage over oxidation. This suggests that hyperinsulinemic states suppress muscle FFA utilization and contribute to accumulation of muscle TAG.

Duke Scholars

Author Deborah Marie Muoio Medicine, Endocrinology, Metabolism, and Nutrition