人類細胞色素P450酶2J2 (CYP2J2)在cis-epoxyeicosatrienoic acids（EETs）的生物合成中扮演重要的角色。細胞色素P450酶2J2*7之基因多型性，是在轉録起始位的基因變異，它是一種在-50的位置由G變成T的基因表現變異，此基因的變異會使參與花生四烯酸（arachidonic acid）代謝之細胞色素P450酶2J2酵素活性降低，進而影響EETs的生合成。研究指出低濃度的5, 6-EETs會刺激胰島素的分泌，然而，8, 9-， 11, 12-， 14, 15-EETs在胰臟可以刺激昇糖激素的分泌。EETs的研究最近也發現參與PPAR（peroxisome proliferator-activated receptor）-α及PPARγ的調控，而PPARα及PPARγ的調節是已知胰島素抗性發生的主要機轉之一，因此EETs在糖尿病的致病機轉中可能扮演某種致病的角色。本研究假設人類細胞色素P450酶2J2基因變異，可能在糖尿病的致病機轉扮演一重要的角色。研究中收集了2,073位第二型糖尿病之病人和704位非糖尿病對照組。細胞色素P450酶2J2*7基因多型性以PCR-RFLP和Real-time PCR方法測定。在此兩個研究族群之基因多型性表現頻率的分佈符合哈溫平衡。研究結果顯示細胞色素P450酶2J2*7基因型分佈和對偶基因的表現頻率在第二型糖尿病疾病組和對照組之間沒有顯著的差異。然而，將第二型糖尿病依發病年齡分成≦35歲的早發型第二型糖尿病和＞35歲的遲發型第二型糖尿病疾病組與對照組的比較結果發現，早發型第二型糖尿病比遲發型第二型糖尿病疾病組和對照組有顯著較高頻率之變異型T對偶基因的表現( GG / GT + TT = 84.2% / 15.8% vs. 90.3% / 9.7% vs. 91.3% / 8.7%；p = 0.018，p = 0.027 )。細胞色素P450酶2J2*7基因型與第二型糖尿病的發病年齡分佈有統計學上的相關性( p for trend = 0.042 )。進一步分析胰島素分泌抗性指數（HOMA-IR）和胰臟β-細胞分泌指數（HOMA-β）與細胞色素P450酶2J2*7基因型的相關性，發現年輕發病族群之HOMA-IR及HOMA-β皆較遲發型糖尿病病人為高。在早發年輕發病糖尿病疾病組及對照組細胞色素P450酶2J2*7基因型與HOMA-IR有差異，具變異型T對偶基因型者有較高的胰島素抗性指數（早發型糖尿病族群：GG / GT + TT = 8.9 ± 6.1 / 6.4 ± 3.8, p = 0.045；對照組：GG / GT + TT = 2.6 ± 1.1 / 2.1 ± 0.8, p = 0.007）。本研究發現細胞色素P450酶2J2*7基因多型性可能經由胰島素作用的調節在年輕型和有家族史的第二型糖尿病患者的致病機轉上可能扮演重要的角色。

Cytochrome P450（CYP）2J2, the single member of human cytochromes P450 II J subfamily, plays an important role in the biosynthesis of biologically active cis-epoxyeicosatrienoic acids. An allelic variant named CYP 2J2*7, a relatively frequent G→T substitution at position-50 relative to the transcription start site, which interrupts a critical Sp1 binding site, results in both decreased promoter activity in vitro and reduced circulating levels of CYP2J2 epoxygenase metabolites. Epoxyeicosatrienoic acid (EETs) are endogenously produced and incorporated into membrane phospholipids in the pancreas. Low concentrations of 5,6-EETs stimulate insulin secretion, whereas 8,9-, 11,12-, and 14,15-EETs stimulate glucagon secretion from the pancreas. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. EETs increased PPAR-α and PPAR-γ transcription activity. PPAR-α and PPAR-γ play a key role in the regulation of adipogenesis, lipid metabolism, insulin sensitivity and inflammation. Thus, genetic abnormalities in the function or expression of CYP2J2, the pathogenetic of enzymes may play a role in diabetes. The present study investigates whether CYP 2J2*7 gene polymorphism can be associated with type 2 diabetes in a Chinese population. We studied 2,073 Chinese type 2 diabetes patients and 704 control subjects without. CYP 2J2*7 gene polymorphism was determined by PCR-RFLP and real-time PCR. In both study groups, the genotype frequency distributions of this polymorphism were in Hardy-Weinberg equilibrium. The CYP2J2*7 genotype distribution or allele frequencies were not different between type 2 diabetes and control subjects. Diabetics with young age of onset（≦35 years old） had a higher frequency of T variant than that of the age of onset of greater than 35 years old and controls ( GG / GT + TT = 84.2% / 15.8% vs. 90.3% / 9.7% vs. 91.3% / 8.7%；p = 0.018，p = 0.027 ). CYP2J2*7 genotype had a statistically significant association with age of onset ( p for trend = 0.042 ). The HOMA-IR and HOMA-β values were significantly higher in diabetic patients with young age of onset compared to those of late onset diabetics and controls. CYP2J2*7 polymorphism was associated with HOMA-IR and HOMA-β in diabetics with young age of onset and controls, subjects and T variants had significant higher value of HOMA-IR and HOMA-β（early onset diabetics：GG / GT + TT = 8.9 ± 6.1 / 6.4 ± 3.8, p=0.045；controls：GG / GT + TT = 2.6 ± 1.1 / 2.1 ± 0.8, p = 0.007）.These findings suggest that CYP 2J2*7 polymorphism may play a role in the pathogenesis of young onset type 2 diabetes and family diabetic history.

中文摘要..................................................1
英文摘要..................................................3
第一章 緒論..............................................5 第一節 國人第二型糖尿病疾病流行病學.......................5
第二節 第二型糖尿病與胰島素抗性…………………………………8
第三節 易感性基因對疾病影響的相關研究...................15
第四節 人類細胞色素P450酶2J2相關文獻探討…………………17
第二章 研究目的與重要性..................................22
第三章 實驗材料及方法....................................23
第一節 研究族群及收集時間………………………………………23
第二節 臨床生理及生化檢查……………………………………..24
第三節 胰島素酵素免疫分析………………………………………29
第四節 基因型的檢测…………………………………………....31
第五節 統計分析…………………………………………………..35
第四章 研究結果………………………………………………………37
第五章 討論……………………………………………………………42
第六章 結論與未來展望………………………………………………46
參考文獻………………………………………………………………48

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