GLYCOGEN-SYNTHASE AND PHOSPHOFRUCTOKINASE PROTEIN AND MESSENGER-RNA LEVELS IN SKELETAL-MUSCLE FROM INSULIN-RESISTANT PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS

In patients with non-insulin-dependent diabetes mellitus (NIDDM) and m atched control subjects we examined the interrelationships between in vivo nonoxidative glucose metabolism and glucose oxidation and the mus cle activities, as well as the immunoreactive protein and mRNA levels of the rate-limiting enzymes in glycogen synthesis and glycolysis, gly cogen synthase (GS) and phosphofructokinase (PFK), respectively. Analy sis of biopsies of quadriceps muscle from 19 NIDDM patients and 19 con trol subjects showed in the basal state a 30% decrease (P < 0.005) in total GS activity and a 38% decrease (P < 0.00 1) in GS mRNA/mug DNA i n NIDDM patients, whereas the GS protein level was normal. The enzymat ic activity and protein and mRNA levels of PFK were all normal in diab etic patients. In subgroups of NIDDM patients and control subjects an insulin-glucose clamp in combination with indirect calorimetry was per formed. The rate of insulin-stimulated nonoxidative glucose metabolism was decreased by 47% (P < 0.005) in NIDDM patients, whereas the gluco se oxidation rate was normal. The PFK activity, protein level, and mRN A/mug DNA remained unchanged. The relative activation of GS by glucose -6-phosphate was 33% lower (P < 0.02), whereas GS mRNA/mug DNA was 37% lower (P < 0.05) in the diabetic patients after 4 h of hyperinsulinem ia. Total GS immunoreactive mass remained normal. In conclusion, quali tative but not quantitative posttranslational abnormalities of the GS protein in muscle determine the reduced insulin-stimulated nonoxidativ e glucose metabolism in NIDDM.