Mechanisms of the kinetic defect in insulin action in obesity and NIDDM.
To evaluate kinetic defects in insulin action, we performed time-course studies during hyperinsulinemic (120 mU x m(-2) x min(-1)) isoglycemic clamps in seven subjects with NIDDM (194 +/- 29 mg/dl) and in seven lean and seven obese nondiabetic subjects. The time course of whole-body glucose disposal rate (GDR), leg glucose uptake (LGU), hepatic glucose output (HGO), and muscle insulin receptor tyrosine kinase (IRTK) activation were measured. The obese and NIDDM subjects had marked delays in activation of GDR (T50 74 +/- 14 and 95 +/- 15 min, respectively, compared with 33 +/- 2 min in lean control subjects), arteriovenous glucose difference (T50 80 +/- 12 and 109 +/- 31 min compared with 30 +/- 3 min) and LGU (T50 89 +/- 25 and 98 +/- 27 min compared with 29 +/- 4 min). All three measurements reached normal levels in the NIDDM group after 4-5 h of insulin infusion. Although only a limited number of data points could be obtained from serial muscle biopsies, no delay in the rate of activation of IRTK was apparent in the obese and NIDDM groups. In conclusion, 1) in obese and NIDDM subjects, insulin-mediated GDR and LGU are delayed to a similar degree; 2) mass action normalizes GDR and LGU in NIDDM, but only after several hours of insulin infusion; and 3) The kinetic defect in NIDDM and obesity most likely involves intracellular loci distal to activation of the insulin receptor kinase.
Nolan
J J
JJ
Department of Medicine, University of California, San Diego, La Jolla, USA.
Ludvik
B
B
Baloga
J
J
Reichart
D
D
Olefsky
J M
JM
D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000178:diet therapy / Q000503:physiopathology*; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism*; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D007700:Kinetics; D009765:Obesity / Q000178:diet therapy / Q000503:physiopathology*; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism*; D013997:Time Factors
D007328:Insulin; D011972:Receptor, Insulin; D005947:Glucose