IMPAIRED ACTIVITY AND GENE-EXPRESSION OF HEXOKINASE-II IN MUSCLE FROMNON-INSULIN-DEPENDENT DIABETES-MELLITUS PATIENTS

After entering the muscle cell, glucose is immediately and irreversibl y phosphorylated to glucose-6-phosphate by hexokinases (HK) I and II, Previous studies in rodents have shown that HKII may be the dominant H K in skeletal muscle, Reduced insulin-stimulated glucose uptake and re duced glucose-6-phosphate concentrations in muscle have been found in non-insulin-dependent diabetes mellitus (NIDDM) patients when examined during a hyperglycemic hyperinsulinemic clamp, These finding are cons istent with a defect in glucose transport and/or phosphorylation, In t he present study comprising 29 NIDDM patients and 25 matched controls, we tested the hypothesis that HKII activity and gene expression are i mpaired in vastus lateralis muscle of NIDDM patients when examined in the fasting state, HKII activity in a supernatant of muscle extract ac counted for 28 +/- 5% in NIDDM patients and 40 +/- 5% in controls (P = 0.08) of total muscle HK activity when measured at a glucose media of 0.11 mmol/liter and 31 +/- 4 and 47 +/- 7% (P = 0.02) when measured a t 11.0 mmol/liter of glucose, HKII mRNA, HKII immunoreactive protein l evel, and HKII activity were significantly decreased in NIDDM patients (P < 0.0001, P = 0.03, and P = 0.02, respectively) together with sign ificantly decreased glycogen synthase mRNA level and total glycogen sy nthase activity (P = 0.02 and P = 0.02, respectively), In the entire s tudy population HKII activity estimated at 0.11 and 11.0 mM glucose wa s inversely correlated with fasting plasma glucose concentrations (r = -0.45, P = 0.004; r = -0.54, P < 0.0001, respectively) and fasting pl asma nonesterified fatty acid concentrations (r = -0.46, P = 0.003; r = -0.37, P = 0.02, respectively),In conclusion, NIDDM patients are cha racterized by a reduced activity and a reduced gene expression of HKII in muscle which may be secondary to the metabolic perturbations, HKII contributes with about one-third of total HK activity in a supernatan t of human vastus lateralis muscle.