Glycogen synthase and phosphofructokinase protein and mRNA levels in skeletal muscle from insulin-resistant patients with non-insulindependent diabetes mellitus. J Clin Invest

In patients with non-insulin-dependent diabetes mellitus (NIDDM) and matched control subjects we examined the in-terrelationships between in vivo nonoxidative glucose metabo-lism and glucose oxidation and the muscle activities, as well as the immunoreactive protein and mRNA levels of the rate-limit-ing enzymes in glycogen synthesis and glycolysis, glycogen syn-thase (GS) and phosphofructokinase (PFK), respectively. Analysis of biopsies of quadriceps muscle from 19 NIDDM patients and 19 control subjects showed in the basal state a 30% decrease (P < 0.005) in total GS activity and a 38 % decrease (P < 0.001) in GS mRNA/tjg DNA in NIDDM patients, whereas the GS protein level was normal. The enzymatic activity and protein and mRNA levels of PFK were all normal in diabetic patients. In subgroups ofNIDDM patients and control subjects an insulin-glucose clamp in combination with indirect calorime-try was performed. The rate of insulin-stimulated nonoxidative glucose metabolism was decreased by 47 % (P < 0.005) in NIDDM patients, whereas the glucose oxidation rate was nor-mal. The PFK activity, protein level, and mRNA/jig DNA re-mained unchanged. The relative activation of GS by glucose-6-phosphate was 33 % lower (P < 0.02), whereas GS mRNA/,jg DNA was 37 % lower (P < 0.05) in the diabetic patients after 4 h of hyperinsulinemia. Total GS immunoreac-tive mass remained normal. In conclusion, qualitative but not quantitative posttranslational abnormalities of the GS protein in muscle determine the reduced insulin-stimulated nonoxida-tive glucose metabolism in NIDDM. (J. Clin. Invest. 1993. 91:2342-2350.) Key words: NIDDM * skeletal muscle * glyco-gen synthase protein- phosphofructokinase protein * mRN