Vestergaard H, Bjørbaek C, Hansen T, Larsen F S, Granner D K, Pedersen O
Steno Diabetes Center, Copenhagen, Denmark.
J Clin Invest. 1995 Dec;96(6):2639-45. doi: 10.1172/JCI118329.
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 findings [correction of 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 +/- 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 at 0.11 mmol/liter of glucose. HKII mRNA, HKII immunoreactive protein level, and HKII activity were significantly decreased in NIDDM patients (P < 0.0001, P = 0.03, and P = 0.02, respectively) together with significantly decreased glycogen synthase mRNA level and total glycogen synthase activity (P = 0.02 and P = 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 = -0.45, P = 0.004; r = -0.54, P < 0.0001, respectively) and fasting plasma nonesterified fatty acid concentrations (r = -0.46, P = 0.003; r = -0.37, P = 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 peturbations. HKII contributes with about one-third of total HK activity in a supernatant of human vastus lateralis muscle.
进入肌肉细胞后，葡萄糖立即被己糖激酶（HK）I和II不可逆地磷酸化为6-磷酸葡萄糖。先前对啮齿动物的研究表明，HKII可能是骨骼肌中的主要己糖激酶。在非胰岛素依赖型糖尿病（NIDDM）患者进行高血糖高胰岛素钳夹试验时，发现其胰岛素刺激的葡萄糖摄取减少，肌肉中6-磷酸葡萄糖浓度降低。这些发现与葡萄糖转运和/或磷酸化缺陷一致。在本研究中，纳入了29例NIDDM患者和25例匹配的对照，我们检验了这样一个假设：在空腹状态下检测时，NIDDM患者股外侧肌中的HKII活性和基因表达受损。当在0.11 mmol/升的葡萄糖培养基中测量时，肌肉提取物上清液中的HKII活性在NIDDM患者中占总肌肉HK活性的28±5%，在对照组中占40±5%（P = 0.08）；当在0.11 mmol/升葡萄糖中测量时，分别为31±4%和47±7%（P = 0.02）。NIDDM患者的HKII mRNA、HKII免疫反应蛋白水平和HKII活性显著降低（分别为P < 0.0001、P = 0.03和P = 0.02），同时糖原合酶mRNA水平和总糖原合酶活性也显著降低（分别为P = 0.02和P = 0.02）。在整个研究人群中，在0.11 mM和11.0 mM葡萄糖下估计的HKII活性与空腹血浆葡萄糖浓度呈负相关（r = -0.45，P = 0.004；r = -0.54，P < 0.0001），与空腹血浆非酯化脂肪酸浓度也呈负相关（r = -0.46，P = 0.003；r = -0.37，P = 0.02）。总之，NIDDM患者的特征是肌肉中HKII活性降低和基因表达减少，这可能是代谢紊乱的继发结果。HKII在人股外侧肌上清液中的活性约占总HK活性的三分之一。
