EARLY CHANGES IN POSTPRANDIAL INSULIN-SECRETION, NOT IN INSULIN SENSITIVITY, CHARACTERIZE JUVENILE OBESITY

The development of hyperinsulinemia and insulin resistance, both commo n in adults with established obesity, was studied in 16 children, weig hing 169 +/- 8% ideal body weight who were 12.7 +/- 0.4 years of age w ith obesity duration of 0.5-8.5 years and continuous weight gain in ex cess of normal, and compared with 11 age-matched normal children. Earl y in the evolution of obesity, insulin and C-peptide responses to a no rmal meal were increased by 76 and 80%. The first insulin peak was hig her (613 +/- 53 pmol/ml)than normal (413 +/- 59 pmol/ml, P < 0.02) and occurred only 50 +/- 7 min after onset of lunch versus 33 +/- 11 min in normal children (P < 0.0005). Obese patients had a total of 3.0 +/- 0.2 large insulin peaks within the 6-h period after the lunch versus only 1.5 +/- 0.2 peaks in normal children (P < 0.0005), In contrast, f asting plasma insulin and C-peptide levels remained normal during the initial years of obesity, then increased progressively with duration ( r = 0.73, P < 0.001) and degree (r = 0.59, P < 0.02) of obesity. Insul in sensitivity evaluated as the rate of glucose uptake during a three- step hyperinsulinemic euglycemic clamp was comparable in the obese (20 +/- 1.5 mmol.m(-2).min(-1)) and the norma1(21.7 +/- 1.5 mmol.m(-2) mi n(-1)) children. Initially higher than normal in obese children, the m aximal rate of glucose uptake decreased with both obesity duration (r = -0.67, P < 0.005) and children's age (r = -0.66, P < 0.005), indicat ing the progressive development of insulin resistance. No correlation was found with overweight (r = -0.17, NS). Fasting plasma insulin leve l and maximal glucose uptake were inversely related (r = -0.67, P < 0. 005). During the first years of obesity, insulin concentrations corres ponding to half-maximal glucose uptake remained comparable in obese (6 77 +/- 51 pM) and normal children (654 +/- 59 pM) and showed no change s with duration of obesity. In conclusion, an abnormal pattern of insu lin response to meals is one of the earliest metabolic alterations cha racterizing the obesity syndrome, followed by the parallel, time-depen dent development of fasting hyperinsulinemia and insulin resistance. T hese results support the primacy of a dysfunction or dysregulation of beta-cell function in obesity of juvenile onset.