THE EFFECT OF ACUTE (60 MINUTE) INSULIN STIMULATION UPON HUMAN SKELETAL-MUSCLE GLYCOGEN-SYNTHASE AND PROTEIN PHOSPHATASE-1 IN NON-INSULIN-DEPENDENT DIABETIC-PATIENTS AND CONTROL SUBJECTS

Previous studies have established that activation of muscle glycogen s ynthase (GS) is abnormal in non-insulin-dependent diabetes mellitus (N IDDM). Insulin-mediated activation of GS depends upon protein phosphat ase-l (PP1), which dephosphorylates the relevant sites of GS. In order to determine whether defects in PP1 activation cause subnormal activa tion of CS or whether PP1 activation itself is normal, we administered a short insulin infusion to 8 NIDDM subjects and 8 healthy controls m atched for gender, age, and body mass index (BMI). GS fractional activ ity and PP1 activity were determined in biopsies taken from the gastro cnemius muscle before and after 60 min insulin infusion (0.1 U kg h(-1 )). In the NIDDM group, muscle GS fractional activity was 6.8 +/- 1.6 and 10.0 +/- 1.5% (mean +/- SEM) (p = 0.11) before and after insulin i nfusion. in the control group, muscle GS fractional activity increased from 7.3 +/- 2.0 to 13.3 +/- 2.7% (p < 0.02). PPI activity had return ed towards basal levels after insulin infusion; NIDDM group 156 +/- 24 .7 to 184.1 +/- 28.1 U mg(-1); control group 220.8 +/- 30.1 to 233.8 /- 29.8 U m(-1). In the NIDDM group there was a positive correlation b etween the increases in GS fractional activity and PP1 activity follow ing insulin stimulation r = 0.77; p < 0.025). These data indicate that in vivo insulin-dependent activation of muscle PP1 is transient in no rmal subjects but is delayed in NIDDM. The defect in GS activation in NIDDM is likely to be proximal to PP1 in the pathway of transmission o f the insulin signal.