Insulin secretion and hepatic insulin clearance as determinants of hyperinsulinaemia in normotolerant grossly obese adolescents.
Obesity is characterized by variable degrees of hyperinsulinaemia, which has been attributed to either β-cell hypersecretion or reduced hepatic insulin extraction, or both. To investigate this controversial issue, a 4-h frequently sampled i.v. glucose tolerance test (glucose dose 12.8 g m -2 ) was performed in 13 normotolerant, grossly obese adolescents (10 F/3 M; 13 ± 1 y; body mass index 32 ± 0.9; pubertal stage 4-5; obesity duration 7.8 ± 3 y) and in a comparable group of 8 healthy, normal-weight subjects. Glucose, insulin and C-peptide time-course were analysed by the minimal model technique, which estimates β-cell secretion, insulin sensitivity (S i ), glucose effectiveness (S G ) and hepatic insulin extraction (HE). Despite similar fasting and after load glucose patterns (S G similar in the two groups), obese adolescents showed sustained peripheral hyperinsulinaemia (total insulin area under the concentration curve 67.2 ± 10.8 vs 19.1 ± 1.2 pmol I 1 in 240 min; p < 0.002) and a 71% reduction in S i (2.02±0.33 vs 6.95 ± 1.03 x 10 4 min -1 (μU ml -1 ); p < 0.001). Compared with control subjects, the total amounts of prehepatic insulin secretion and posthepatic insulin delivery were also increased significantly in obese adolescents by 30% and 46%, respectively; HE was reduced by 15% during the first 30 min of the test, but recovered within the normal range during the rest of the test. In conclusion, severely obese adolescents are insulin resistant and their hyperinsulinaemia is primarily caused by β-cell hypersecretion, whereas the reduction in insulin hepatic extraction is a transient metabolic phenomenon.