Multiple Disturbances of Free Fatty Acid Metabolism in Noninsulin - dependent Diabetes

To assess the mechanisms for the elevation of free fatty acids in noninsulin-dependent diabetes, free fatty acid metabolism and lipid and carbohydrate oxidation were compared in 14 obese diabetic Pima Indians and in 13 age-, sex-, and weightmatched nondiabetics. The studies were repeated in 10 of the diabetics after 1 mo of oral hypoglycemic therapy. Fasting plasma glucose concentrations were elevated in diabetics (242±14 vs. 97±3 mg/dl, P < 0.01) and decreased to 142±12 (P < 0.01) after therapy. Fasting free fatty acid concentrations were elevated in diabetics (477±26 vs. 390±39 ;tmol/liter, P < 0.01) and declined to normal values after therapy (336±32, P < 0.01). Although free fatty acid transport rate was correlated with obesity (r = 0.75, P < 0.001), the transport of free fatty acid was not higher in diabetics than in nondiabetics and did not change after therapy. On the other hand, the fractional catabolic rate for free fatty acid was significantly lower in untreated diabetics (0.55±0.04 vs. 0.71±0.06 min', P < 0.05); it increased after therapy to 0.80±0.09 min-', P < 0.05, and was inversely correlated with fasting glucose (r = -0.52, P < 0.01). In diabetics after therapy, lipid oxidation rates fell significantly (from 1.35±0.06 to 1.05±0.01 mg/min per kg fatfree mass, P < 0.01), whereas carbohydrate oxidation increased (from 1.21±0.10 to 1.73±0.13 mg/min per kg fat-free mass, P < 0.01); changes in lipid and carbohydrate oxidation were correlated (r = 0.72, P < 0.02), and in all subjects lipid oxidation accounted for only -40% of free fatty acid transport. The data suggest that in noninsulin-dependent diabetics, although free fatty acid production may be elevated because of obesity, the elevations in plasma free fatty acid concentrations are also a result of reduced removal, and fractional clearance of free fatty acid appears to be closely related to diabetic control. Furthermore, the increase in fractional clearance rate, despite a marked decrease in lipid oxidation, suggests that the clearance defect in the diabetics is due to an impairment in reesterification, which is restored after therapy.