Glucose turnover and adipose tissue lipolysis are insulin-resistant in healthy relatives of type 2 diabetes patients - Is cellular insulin resistancea secondary phenomenon?

To elucidate potential mechanisms for insulin resistance occurring early in the development of type 2 diabetes, we studied 10 young healthy individual s, each with two first-degree relatives with type 2 diabetes, and 10 contro l subjects without known type 2 diabetic relatives. They were pairwise matc hed for age (35 +/- 1 vs. 35 a 1 years), BMI (23.6 +/- 0.6 vs, 23.1 +/- 0.4 kg/m(2)), and sex (four men, six women). Glucose turnover was assessed dur ing a euglycemic clamp at two insulin levels (low similar to 20 mU/l; high similar to 90 mU/l), and abdominal subcutaneous adipose tissue (SAT) lipoly sis and blood flow were concomitantly studied with microdialysis and Xe-133 clearance. HbA(1c) was higher in patients with type 2 diabetic relatives t han in control subjects (4.8 +/- 0.1 vs. 4.5 +/- 0.1%, P < 0.02), but fasti ng glucose, insulin,and C-peptide levels were similar. During the clamp, th e insulin sensitivity index for glucose disposal was lower (P < 0.03) in re latives than in control subjects (low 12.0 +/- 1.6 vs. 18.1 +/- 1.4; high 9 .4 +/- 0.8 vs. 12.9 +/- 0.6 [100.mg.l.kg(-1).mU(-1).min(-1)]). This differe nce was partially attributed to slightly higher clamp insulin levels in the relatives (P < 0.03), suggesting an impaired rate for insulin clearance. S AT lipolysis measured as in situ glycerol release did not differ under basa l conditions (2.0 +/- 0.2 vs. 2.1 +/- 0.2 mu mol.kg(-1).min(-1)), but the s uppression during the insulin infusion was less marked in relatives than in control subjects (glycerol release: low 0.92 +/- 0.09 vs. 0.68 +/- 0.16; h igh 0.71 +/- 0.10 vs. 0.34 +/- 0.10 mu mol.kg(-1).min(-1); P < 0.03). Plasm a nonesterified fatty acids also tended to be higher in relatives than in c ontrol subjects during the insulin infusion (NS). In contrast, in vitro exp eriments with isolated subcutaneous adipocytes displayed similar effects of insulin in relatives and control subjects with respect to both glucose upt ake and antilipolysis, In conclusion, insulin action in vivo on both lipoly sis and glucose uptake is impaired early in the development of type 2 diabe tes. Since this impairment was not found in isolated adipocytes, it may be suggested that neural or hormonal perturbations precede cellular insulin re sistance in type 2 diabetes.