Academic Medical Center, Department of Vascular Medicine, Amsterdam, The Netherlands.
Atherosclerosis. 2012 May;222(1):208-15. doi: 10.1016/j.atherosclerosis.2012.01.035. Epub 2012 Jan 28.
Exogenous insulin use in patients with type 2 diabetes (DM2) has been associated with an increased risk of cardiovascular events. Through which mechanisms insulin may increase atherosclerotic plaque vulnerability is currently unclear. Because insulin has been suggested to promote angiogenesis in diabetic retinopathy and tumors, we hypothesized that insulin enhances intra-plaque angiogenesis.
An in vitro model of pathological angiogenesis was used to assess the potential of insulin to enhance capillary-like tube formation of human microvascular endothelial cells (hMVEC) into a three dimensional fibrin matrix. In addition, insulin receptor expression within atherosclerotic plaques was visualized in carotid endarterectomy specimens of 20 patients with carotid artery stenosis, using immunohistochemical techniques. Furthermore, microvessel density within atherosclerotic plaques was compared between 68 DM2 patients who received insulin therapy and 97 DM2 patients who had been treated with oral glucose lowering agents only.
Insulin, at a concentration of 10(-8)M, increased capillary-like tube formation of hMVEC 1.7-fold (p<0.01). Within human atherosclerotic plaques, we observed a specific distribution pattern for the insulin receptor: insulin receptor expression was consistently higher on the endothelial lining of small nascent microvessels compared to more mature microvessels. There was a trend towards an increased microvessel density by 20% in atherosclerotic plaques derived from patients using insulin compared to plaques derived from patients using oral glucose lowering agents only (p=0.05).
Exogenous insulin use in DM2 patients may contribute to increased plaque vulnerability by stimulating local angiogenesis within atherosclerotic plaques.
在 2 型糖尿病（DM2）患者中使用外源性胰岛素与心血管事件风险增加有关。目前尚不清楚胰岛素通过哪些机制增加动脉粥样硬化斑块的脆弱性。因为胰岛素被认为可以促进糖尿病视网膜病变和肿瘤中的血管生成，所以我们假设胰岛素可以增强斑块内的血管生成。
使用体外病理性血管生成模型来评估胰岛素增强人微血管内皮细胞（hMVEC）在三维纤维蛋白基质中形成毛细血管样管状结构的潜力。此外，使用免疫组织化学技术在 20 例颈动脉狭窄患者的颈动脉内膜切除术标本中观察到胰岛素受体在动脉粥样硬化斑块中的表达。此外，将接受胰岛素治疗的 68 例 DM2 患者与仅接受口服降血糖药物治疗的 97 例 DM2 患者的斑块内微血管密度进行比较。
胰岛素浓度为 10(-8)M 时，可使 hMVEC 的毛细血管样管状结构形成增加 1.7 倍（p<0.01）。在人类动脉粥样硬化斑块中，我们观察到胰岛素受体的特定分布模式：与更成熟的微血管相比，小新生微血管内皮细胞上的胰岛素受体表达始终更高。与仅接受口服降血糖药物治疗的患者相比，使用胰岛素的患者的斑块内微血管密度增加了 20%（p=0.05）。
DM2 患者使用外源性胰岛素可能通过刺激动脉粥样硬化斑块内的局部血管生成，导致斑块脆弱性增加。
