NONESTERIFIED FATTY-ACIDS DO NOT CONTRIBUTE TO INSULIN RESISTANCE IN PERSONS AT INCREASED RISK OF DEVELOPING TYPE-2 (NON-INSULIN-DEPENDENT) DIABETES-MELLITUS

The mechanisms underlying insulin resistance in Type 2 (non-insulin-dependent) diabetes mellitus are not fully understood. An enhanced lipid/non-esterified fatty acid oxidation could provide an explanation. To test this hypothesis we examined the relationship between glucose and lipid metabolism in 44 first-degree relatives (28 glucose-tolerant and 16 glucose-intolerant) of Type 2 diabetic patients and in 18 healthy control subjects. Total body glucose disposal was impaired among both glucose-tolerant and glucose-intolerant relatives compared with control subjects (36.3 +/- 3.8 and 30.4 +/- 2.7 vs 47.7 +/- 3.4-mu-mol.kgLBM-1.min-1; p < 0.05). The impairment in glucose disposal among the relatives was primarily accounted for by impaired nonoxidative glucose metabolism (14.8 +/- 3.0 and 12.5 +/- 1.8 vs 25.3 +/- 3.1-mu-mol.kgLBM-1.min-1; p < 0.05). Plasma non-esterified fatty acid concentrations were similar in both glucose-tolerant and glucose-intolerant relatives and control subjects (646 +/- 36, 649 +/- 43 and 615 +/- 41-mu-mol/l) and showed the same degree of suppression by insulin (99 +/- 8, 86 +/- 7 and 84 +/- 9-mu-mol/l). Basal lipid oxidation was similar in all groups (1.29 +/- 0.09, 1.52 +/- 0.13 and 1.49 +/- 0.21-mu-mol.kgLBM-1.min-1). Furthermore, insulin suppressed lipid oxidation to the same degree in glucose-tolerant, glucose-intolerant relatives and control subjects (0.65 +/- 0.13, 0.88 +/- 0.15 and 0.59 +/- 0.09-mu-mol.kgLBM-1.min-1). An inverse correlation between plasma non-esterified fatty acid concentration and total body glucose disposal was observed in the group of control subjects (r = -0.540; p < 0.05), but not among the relatives (r = 0.002; p = N.S.). In conclusion the present data challenge the view that the "glucose-fatty acid cycle" contributes to the insulin resistance seen in first-degree relatives of patients with Type 2 diabetes.