Trombetta M, Dauriz M, Bonetti S, Travia D, Boselli L, Santi L, Bonora E, Bonadonna R C
Department of Medicine, University of Verona, Verona, Italy; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital Trust of Verona, Verona, Italy.
Department of Medicine, University of Verona, Verona, Italy.
Nutr Metab Cardiovasc Dis. 2016 Mar;26(3):232-8. doi: 10.1016/j.numecd.2016.01.002. Epub 2016 Jan 14.
Insulin resistance is a hallmark of type 2 diabetes (T2DM), it is often accompanied by defective beta-cell function (BF) and is involved in the pathophysiology of cardiovascular disease (CVD). Commonalities among these traits may recognize a genetic background, possibly involving the genetic variation of insulin signaling pathway genes. We conducted an exploratory analysis by testing whether common genetic variability at IRS1, ENPP1 and TRIB3 loci is associated with cardiovascular risk traits and metabolic phenotypes in T2DM.
In 597 drug-naïve, GADA-negative, newly-diagnosed T2DM patients we performed: 1) genotyping of 10 independent single-nucleotide polymorphisms covering ∼ 90% of common variability at IRS1, ENPP1 and TRIB3 loci; 2) carotid artery ultrasound; 3) standard ECG (n = 450); 4) euglycaemic insulin clamp to assess insulin sensitivity; 5) 75 g-OGTT to estimate BF (derivative and proportional control) by mathematical modeling. False discovery rate of multiple comparisons was set at 0.20. After adjustment for age, sex and smoking status, rs4675095-T (IRS1) and rs4897549-A (ENPP1) were significantly associated with carotid atherosclerosis severity, whilst rs7265169-A (TRIB3) was associated with ECG abnormalities. Rs858340-G (ENPP1) was significantly associated with decreased insulin sensitivity, independently of age, sex and body-mass-index. No consistent relationships were found with BF.
Some associations were found between intermediate phenotypes of CVD and common genetic variation of gatekeepers along the insulin signaling pathway. These results need be replicated to support the concept that in T2DM the CVD genetic risk clock may start ticking long before hyperglycemia appears. ClinicalTrials.gov Identifier: NCT01526720.
胰岛素抵抗是2型糖尿病（T2DM）的一个标志，常伴有β细胞功能缺陷（BF），并参与心血管疾病（CVD）的病理生理过程。这些特征之间的共性可能存在遗传背景，可能涉及胰岛素信号通路基因的遗传变异。我们通过测试IRS1、ENPP1和TRIB3基因座的常见遗传变异性是否与T2DM患者的心血管风险特征和代谢表型相关，进行了一项探索性分析。
在597例未服用药物、谷氨酸脱羧酶抗体（GADA）阴性、新诊断的T2DM患者中，我们进行了以下操作：1）对10个独立的单核苷酸多态性进行基因分型，这些多态性覆盖了IRS1、ENPP1和TRIB3基因座约90%的常见变异性；2）颈动脉超声检查；3）标准心电图检查（n = 450）；4）正常血糖胰岛素钳夹试验以评估胰岛素敏感性；5）口服75 g葡萄糖耐量试验（OGTT），通过数学模型估计BF（导数和比例控制）。多重比较的错误发现率设定为0.20。在调整年龄、性别和吸烟状态后，rs4675095 - T（IRS1）和rs4897549 - A（ENPP1）与颈动脉粥样硬化严重程度显著相关，而rs7265169 - A（TRIB3）与心电图异常相关。Rs858340 - G（ENPP1）与胰岛素敏感性降低显著相关，独立于年龄、性别和体重指数。未发现与BF有一致的关系。
在CVD的中间表型与胰岛素信号通路中关键基因的常见遗传变异之间发现了一些关联。这些结果需要重复验证，以支持在T2DM中CVD遗传风险时钟可能在高血糖出现之前很久就开始计时的概念。临床试验.gov标识符：NCT01526720。
