IDENTIFICATION OF 4 AMINO-ACID SUBSTITUTIONS IN HEXOKINASE-II AND STUDIES OF RELATIONSHIPS TO NIDDM, GLUCOSE EFFECTIVENESS, AND INSULIN SENSITIVITY
IDENTIFICATION OF 4 AMINO-ACID SUBSTITUTIONS IN HEXOKINASE-II AND STUDIES OF RELATIONSHIPS TO NIDDM, GLUCOSE EFFECTIVENESS, AND INSULIN SENSITIVITY
复制标题
DOI：
10.2337/diabetes.44.3.347
复制
发表时间：
1995-03-01
期刊：
影响因子：
7.7
通讯作者：
PEDERSEN, O
中科院分区：
文献类型：
--
作者：
ECHWALD, SM;BJORBAEK, C;PEDERSEN, O
人类己糖激酶（HX） II是一种在肌肉组织中的葡萄糖磷酸化酶，在葡萄糖代谢中起核心作用。由于在非胰岛素依赖型糖尿病（pre-NIDDM）和NIDDM受试者中已证实胰岛素刺激的葡萄糖摄取减少和肌肉中葡萄糖-6-磷酸含量减少，我们检查了NIDDM患者中HKII基因的编码区，以确定这些患者是否表现出与该疾病相关或促成该疾病的遗传多态性。初步对38例胰岛素抵抗型NIDDM患者和5例健康对照者的HKII基因全编码区进行单链构象多态性分析和核苷酸测序。该分析揭示了密码子142 （Gln到His）、148 （Leu到Phe）、497 （Arg到Gln）和844 （Arg到Lys）上的4个错义突变，以及另外6个外显子多态性，这些多态性并不预测蛋白质氨基酸组成的任何变化。在NIDDM患者中发现1个纯合型和9个杂合型密码子142突变携带者。密码子148,497,844的突变分别在1例糖尿病患者中发现，且仅在1个等位基因上。未发现复合杂合突变的携带者。随后对301名NIDDM患者和151名健康对照者的研究显示，密码子148、497和844处没有额外的突变。对照组和NIDDM患者的142号密码子总突变频率分别为18.9%和17.0% （chi(2) = 0.56, P = 0.45）。对383名无血缘关系的年轻健康白种人进行了静脉葡萄糖和甲磺丁胺联合检测，以确定密码子142氨基酸多态性是否与葡萄糖有效性或胰岛素敏感性的改变有关。然而，没有证据可以提供全身胰岛素作用和葡萄糖周转的两种估计与基因变异之间的明显关系。总之，在人类HKII基因中发现了4个氨基酸替换。虽然密码子142的广泛突变似乎与NIDDM易感性增加或全身葡萄糖有效性或胰岛素敏感性的重大异常无关，但需要进一步的研究来解决HKII突变在细胞内能量代谢中的潜在作用。
Human hexokinase (HX) II, a glucose phosphorylating enzyme in muscle tissue, plays a central role in glucose metabolism. Since reduced insulin-stimulated glucose uptake and reduced glucose-6-phosphate content in muscle have been demonstrated in pre-non-insulin-dependent diabetes mellitus (pre-NIDDM) and NIDDM subjects, we have examined the coding region of the HKII gene in NIDDM patients to determine whether these patients show genetic polymorphisms that are associated with or contribute to the disease. Single-strand conformational polymorphism analysis and nucleotide sequencing were initially performed on the entire coding region of the HKII gene of 38 insulin-resistant NIDDM patients and 5 healthy control subjects. This analysis revealed four missense mutations at codons 142 (Gln to His), 148 (Leu to Phe), 497 (Arg to Gln), and 844 (Arg to Lys) and an additional six exon polymorphisms that did not predict any change in amino acid composition of the protein. One homozygous and nine heterozygous carriers of the codon 142 mutation were found among the NIDDM patients. The mutations at codons 148, 497, and 844 were each found in one diabetic subject and only on one allele. There were no carriers of compound heterozygous mutations. A subsequent study of 301 patients with NIDDM and 151 healthy control subjects revealed no additional mutations at codons 148, 497, or 844. The total frequency of the mutated allele at codon 142 was 18.9% among the control subjects and 17.0% among the NIDDM patients (chi(2) = 0.56, P = 0.45). A population-based sample of 383 unrelated young healthy Caucasians was examined during a combined intravenous glucose and tolbutamide test to address whether the codon 142 amino acid polymorphism was associated with alterations in glucose effectiveness or insulin sensitivity. No evidence could, however, be provided for obvious relationships between the two estimates of whole-body insulin action and glucose turnover and the gene variant. In conclusion, four amino acid substitutions have been identified in the human HKII gene. Although the widespread mutation at codon 142 does not seem to be associated with an increased susceptibility to NIDDM or major abnormalities in whole-body glucose effectiveness or insulin sensitivity, further studies are needed to address the potential roles of the HKII mutations in intracellular energy metabolism.