Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
Diabetes. 2011 Dec;60(12):3265-70. doi: 10.2337/db11-0162. Epub 2011 Oct 7.
In humans, it is unclear if insulin resistance at the monocyte level is associated with atherosclerosis in vivo. Here we have studied first-degree relatives of patients with type 2 diabetes to investigate whether a reduction in components of the insulin signal transduction pathways, such as the insulin receptor (InsR) or InsR substrate 1 or 2 (IRS1 or IRS2), or a reduction in genetic modifiers of insulin action, such as the TIMP3/ADAM17 (tissue inhibitor of metalloproteinase 3/A disintegrin and metalloprotease domain 17) pathway, is associated with evidence of atherosclerosis.
Insulin sensitivity was analyzed through euglycemic-hyperinsulinemic clamp, and subclinical atherosclerosis was analyzed through intimal medial thickness. Monocytes were isolated through magnetic cell sorting, and mRNA and proteins were extracted and analyzed by quantitative PCR and pathscan enzyme-linked immunosorbent assays, respectively.
In monocyte cells from human subjects with increased risk for diabetes and atherosclerosis, we found that gene expression, protein levels, and tyrosine phosphorylation of IRS2, but not InsR or IRS1, were decreased. TIMP3 was also reduced, along with insulin resistance, resulting in increased ectodomain shedding activity of the metalloprotease ADAM17.
Systemic insulin resistance and subclinical atherosclerosis are associated with decreased IRS2 and TIMP3 expression in circulating monocytes.
在人类中，单核细胞水平的胰岛素抵抗是否与体内动脉粥样硬化有关尚不清楚。在这里，我们研究了 2 型糖尿病患者的一级亲属，以调查胰岛素信号转导通路的组成部分（如胰岛素受体 [InsR]或 InsR 底物 1 或 2 [IRS1 或 IRS2]）的减少，或胰岛素作用的遗传修饰物（如 TIMP3/ADAM17（组织金属蛋白酶抑制剂 3/A 型解整合素和金属蛋白酶域 17）途径）的减少是否与动脉粥样硬化的证据有关。
通过正葡萄糖高胰岛素钳夹分析胰岛素敏感性，通过内膜中层厚度分析亚临床动脉粥样硬化。通过磁细胞分选分离单核细胞，并通过定量 PCR 和 pathscan 酶联免疫吸附测定分别提取和分析 mRNA 和蛋白质。
在具有糖尿病和动脉粥样硬化高风险的人类受试者的单核细胞中，我们发现 IRS2 的基因表达、蛋白水平和酪氨酸磷酸化降低，但 InsR 或 IRS1 没有降低。TIMP3 也减少了，同时伴随着胰岛素抵抗，导致金属蛋白酶 ADAM17 的外显子脱落活性增加。
全身胰岛素抵抗和亚临床动脉粥样硬化与循环单核细胞中 IRS2 和 TIMP3 表达的减少有关。
