METABOLIC DEFECTS IN LEAN NONDIABETIC OFFSPRING OF NIDDM PARENTS - A CROSS-SECTIONAL STUDY

First-degree relatives of NIDDM patients have an similar to 40% lifeti me risk of developing diabetes, and insulin resistance is the best pre dictor. However, insulin resistance is altered by many other factors, including age, diet, exercise, and medications. To investigate the met abolic and endocrine alterations associated with insulin resistance wh en all the above confounding factors are excluded, we examined the fir st phase of insulin secretion and insulin sensitivity in 49 white norm oglycemic (4.99 +/- 0.51 vs. 4.95 +/- 0.41 mmol/l) nonexercising lean (BMI, 24 +/- 3 vs. 23 +/- 2 kg/m(2); 105 +/- 3 vs. 104 +/- 3% of ideal body weight) offspring of NIDDM patients. These subjects were compare d with 29 matched healthy control subjects by means of an intravenous glucose bolus (0.3 g/kg body wt), immediately followed by a euglycemic -hyperinsulinemic (similar to 420 pmol/l) clamp, along with lipid and amino acid profiles. The offspring showed fasting hyperinsulinemia (40 .6 +/- 15.8 vs. 30.9 +/- 13.6 pmol/l; P = 0.005) and higher free fatty acid (FFA) levels (582 +/- 189 vs. 470 +/- 140 pmol/l; P = 0.007), wh ereas triglycerides, total cholesterol, and HDL and LDL cholesterol le vels were comparable with those of control subjects. Alanine (320 +/- 70 vs. 361 +/- 73 pmol/l; P = 0.017), serine (P = 0.05), and glutamine and glycine (P = 0.02) were lower in the offspring than in the contro l subjects, whereas branched-chain amino acids (343 +/- 54 vs. 357 +/- 54 mu mol/l; P = 0.28) were not different. Insulin sensitivity was lo wer (4.86 +/- 1.65 vs. 6.17 +/- 1.56 mg . kg(-1) . min(-1); P = 0.001) , and an inverse correlation with fasting FFAs in the offspring (adjus ted R-2 = 0.21, P = 0.0005), but not in control subjects (adjusted R-2 = 0.03, P = 0.368), was found. Because insulin sensitivity in the off spring appeared to be a mixture of three distributions, they were subd ivided into three subgroups: very low, low, and normal insulin sensiti vity (20, 47, and 33%, respectively). The same alterations in amino ac id and FFA metabolism were observed in the very low and low subgroups but not in the normal subgroup. The first phase of insulin secretion a ppeared to compensate significantly for insulin resistance in the low subgroup versus the normal subgroup and controls, but was inappropriat ely low in the subgroup with very low insulin sensitivity considering its degree of insulin resistance. In conclusion, lean insulin-resistan t offspring of NIDDM parents showed 1) trimodal distribution of insuli n sensitivity, 2) high fasting plasma FFA concentrations, 3) an invers e correlation between insulin sensitivity and FFA concentration, 4) lo w plasma gluconeogenic amino acid concentrations, and 5) defective ins ulin secretion when related to insulin sensitivity in the subgroup of very resistant offspring. These results suggest that, in this white po pulation, insulin sensitivity may be determined by a single major gene and that alterations in FFA metabolism may play a role in the pathoge nesis of NIDDM.