MECHANISMS OF THE KINETIC DEFECT IN INSULIN ACTION IN OBESITY AND NIDDM

To evaluate kinetic defects in insulin action, we performed time-cours e studies during hyperinsulinemic (120 mU . m(-2) . min(-1)) isoglycem ic clamps in seven subjects with NIDDM (194 +/- 29 mg/dl) and in seven lean and seven obese nondiabetic subjects. The time course of whole-b ody glucose disposal rate (GDR), leg glucose uptake (LGU), hepatic glu cose output (HGO), and muscle insulin receptor tyrosine kinase (IRTK) activation were measured. The obese and NIDDM subjects had marked dela ys in activation of GDR (T-50 74 +/- 14 and 95 +/- 15 min, respectivel y, compared with 33 +/- 2 min in lean control subjects), arteriovenous glucose difference (T-50 80 +/- 12 and 109 +/- 31 min compared with 3 0 +/- 3 min) and LGU (T-50 89 +/- 25 and 98 +/- 27 min compared with 2 9 +/- 4 min). All three measurements reached normal levels in the NIDD M group after 4-5 h of insulin infusion. Although only a limited numbe r of data points could be obtained from serial muscle biopsies, no del ay in the rate of activation of IRTK was apparent in the obese and NID DM groups. In conclusion, 1) in obese and NIDDM subjects, insulin-medi ated GDR and LGU are delayed to a similar degree; 2) mass action norma lizes GDR and LGU in NIDDM, but only after several hours of insulin in fusion; and 3) The kinetic defect in NIDDM and obesity most likely inv olves intracellular loci distal to activation of the insulin receptor kinase.