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After entering the muscle cell, glucose is immediately and irreversibly phosphorylated to glucose-6-phosphate by hexokinases (HK) I and II. Previous studies in rodents have shown that HKII may be the dominant HK in skeletal muscle. Reduced insulin-stimulated glucose uptake and reduced 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 consistent with a defect in glucose transport and/or phosphorylation. In the present study comprising 29 NIDDM patients and 25 matched controls, we tested the hypothesis that HKII activity and gene expression are impaired in vastus lateralis muscle of NIDDM patients when examined in the fasting state. HKII activity in a supernatant of muscle extract accounted for 28 plus minus 5% in NIDDM patients and 40 plus minus 5% in controls (P equals 0.08) of total muscle HK activity when measured at a glucose media of 0.11 mmol/liter and 31 plus minus 4 and 47 plus minus 7% (P equals 0.02) when measured at 11.0 mmol/liter of glucose. HKII mRNA, HKII immunoreactive protein level, and HKII activity were significantly decreased in NIDDM patients (P less than 0.0001, P equals 0.03, and P equals 0.02, respectively) together with significantly decreased glycogen synthase mRNA level and total glycogen synthase activity (P equals 0.02 and P equals 0.02, respectively). In the entire study population HKII activity estimated at 0.11 and 11.0 mM glucose was inversely correlated with fasting plasma glucose concentrations (r equals minus 0.45, P equals 0.004; r equals minus 0.54, P less than 0.0001, respectively) and fasting plasma nonesterified fatty acid concentrations (r equals minus 0.46, P equals 0.003; r equals minus 0.37, P equals 0.02, respectively). In conclusion, NIDDM patients are characterized 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 supernatant of human vastus lateralis muscle. (J. Clin. Invest. 1995. 96:2639-2645.) Key words: muscle hexokinase II gene expression centered dot non-insulin-dependent diabetes mellitus centered dot insulin resistance

Copyright (C) 1995 The American Society for Clinical Investigation, Inc.