Knowles Joshua W, Xie Weijia, Zhang Zhongyang, Chennamsetty Indumathi, Assimes Themistocles L, Paananen Jussi, Hansson Ola, Pankow James, Goodarzi Mark O, Carcamo-Orive Ivan, Morris Andrew P, Chen Yii-Der I, Mäkinen Ville-Petteri, Ganna Andrea, Mahajan Anubha, Guo Xiuqing, Abbasi Fahim, Greenawalt Danielle M, Lum Pek, Molony Cliona, Lind Lars, Lindgren Cecilia, Raffel Leslie J, Tsao Philip S, Schadt Eric E, Rotter Jerome I, Sinaiko Alan, Reaven Gerald, Yang Xia, Hsiung Chao A, Groop Leif, Cordell Heather J, Laakso Markku, Hao Ke, Ingelsson Erik, Frayling Timothy M, Weedon Michael N, Walker Mark, Quertermous Thomas
J Clin Invest. 2015 Apr;125(4):1739-51. doi: 10.1172/JCI74692. Epub 2015 Mar 23.
Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.
胰岛素敏感性降低，也称为胰岛素抵抗（IR），是2型糖尿病患者的一种基本异常情况，也是心血管疾病的一个危险因素。虽然IR易感性具有遗传性，但其遗传基础在很大程度上仍不清楚。胰岛素敏感性遗传学联盟对2764名欧洲个体进行了全基因组关联研究（GWAS），以直接测量胰岛素敏感性，如正常血糖钳夹试验或胰岛素抑制试验，并在另外2860名个体中进行了重复验证。N-乙酰转移酶2（NAT2）的一个非同义变体[rs1208（803A>G，K268R）]的存在与独立于体重指数（BMI）的胰岛素敏感性降低密切相关。rs1208“A”等位基因与IR相关特征名义上相关，包括空腹血糖升高、糖化血红蛋白、总胆固醇和低密度脂蛋白胆固醇、甘油三酯以及冠状动脉疾病。NAT2可使芳胺和肼类药物及致癌物乙酰化，但预测的乙酰化NAT2表型与胰岛素敏感性无关。在小鼠脂肪细胞系中，沉默NAT2直系同源基因Nat1可降低胰岛素介导的葡萄糖摄取，增加基础和异丙肾上腺素刺激的脂解作用，并减少脂肪细胞分化，而Nat1过表达则产生相反的效果。通过葡萄糖和胰岛素耐量试验测量，Nat1缺陷小鼠的空腹血糖、胰岛素和甘油三酯升高，胰岛素敏感性降低，在Nat1杂合子小鼠中具有中等效应。我们的结果支持NAT2在胰岛素敏感性中发挥作用。
