Giacconi R, Bonfigli A R, Testa R, Sirolla C, Cipriano C, Marra M, Muti E, Malavolta M, Costarelli L, Piacenza F, Tesei S, Mocchegiani E
Immunology Center (Section Nutrition, Immunity and Ageing), Research Department INRCA, via Birarelli 8, 60121 Ancona, Italy.
Mol Genet Metab. 2008 May;94(1):98-104. doi: 10.1016/j.ymgme.2007.12.006. Epub 2008 Jan 30.
Diabetes mellitus is a chronic disease characterized by an overproduction of reactive oxygen species, which perturbs zinc metabolism and promotes the onset of cardiovascular disease (CVD) in diabetic patients. Metallothioneins (MT) are cysteine-rich metal-binding proteins which, by means of their antioxidant and zinc-buffering properties, might prevent the development of diabetic cardiovascular complications. A recent investigation shows that a polymorphism (+647 A/C) in the human MT-1A gene, affects the intracellular zinc ion release (iZnR) from the proteins and is associated with longevity in Italian population. The aim of the present study is to assess the involvement of +647 A/C and +1245 A/G MT1A polymorphisms with the susceptibility to type 2 diabetes (DM2) and cardiovascular complications. The study included 694 old individuals: 242 old healthy controls, 217 DM2 patients without clinical evidence of CVD (DNC) and 235 diabetic patients with diagnosis of CVD (DCVD). +647 A/C MT1A polymorphism, but not the second SNP, was associated with DM2. C allele carriers were more prevalent in DNC and DCVD patients than in control group (OR=1.37, p=0.034; OR=1.54, p=0.002, respectively). C+ carriers was associated with higher glycemia and glycosylated hemoglobin in DCVD patients, but not in DNC or control subjects. No differences in plasma zinc, but a modulation of MT levels and iZnR in PBMCs were observed in DCVD cohort when related to +647 A/C MT1A polymorphism. In summary, this work provides novel evidence on the association of the +647 A/C MT1A polymorphism with DM2. Moreover, C+ carriers in DCVD patients presented a worse glycemic control, a reduced iZnR and a higher MT levels, suggesting a possible role of MT in diabetic cardiovascular complications.
糖尿病是一种以活性氧过度产生为特征的慢性疾病，活性氧会扰乱锌代谢并促进糖尿病患者心血管疾病（CVD）的发生。金属硫蛋白（MT）是富含半胱氨酸的金属结合蛋白，凭借其抗氧化和锌缓冲特性，可能预防糖尿病心血管并发症的发展。最近的一项研究表明，人类MT-1A基因中的一种多态性（+647 A/C）会影响蛋白质的细胞内锌离子释放（iZnR），并且与意大利人群的长寿有关。本研究的目的是评估+647 A/C和+1245 A/G MT1A多态性与2型糖尿病（DM2）易感性及心血管并发症的关系。该研究纳入了694名老年人：242名健康老年对照、217名无CVD临床证据的DM2患者（DNC）和235名诊断为CVD的糖尿病患者（DCVD）。+647 A/C MT1A多态性而非第二个单核苷酸多态性与DM2相关。C等位基因携带者在DNC和DCVD患者中比对照组更普遍（分别为OR=1.37，p=0.034；OR=1.54，p=0.002）。C+携带者与DCVD患者较高的血糖和糖化血红蛋白相关，但在DNC或对照受试者中无此关联。与+647 A/C MT1A多态性相关时，DCVD队列中血浆锌无差异，但观察到PBMC中MT水平和iZnR有变化。总之，这项工作为+647 A/C MT1A多态性与DM2的关联提供了新证据。此外，DCVD患者中的C+携带者血糖控制较差、iZnR降低且MT水平较高，提示MT在糖尿病心血管并发症中可能发挥作用。
