Jandeleit-Dahm Karin A M, Tikellis Christos, Reid Christopher M, Johnston Colin I, Cooper Mark E
Danielle Alberti Centre for Diabetes Complications, Vascular Division, Wynn Domain, Baker Heart Research Institute, Melbourne, Victoria, Australia.
J Hypertens. 2005 Mar;23(3):463-73. doi: 10.1097/01.hjh.0000160198.05416.72.
Recent trials have suggested that inhibitors of the renin-angiotensin system (RAS), such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), may reduce the incidence of new-onset diabetes in patients with or without hypertension and at high risk of developing diabetes. In this review, we critically evaluate the evidence from recent clinical trials for such a potential preventive effect of ACE inhibitors and ARBs, including a meta-analysis of these recent trials. The reduced incidence of diabetes in patients at high risk of developing diabetes by ACE inhibitors or ARBs has been explained by haemodynamic effects, such as improved delivery of insulin and glucose to the peripheral skeletal muscle, and non-haemodynamic effects, including direct effects on glucose transport and insulin signalling pathways, all of which decrease insulin resistance. There is now evidence that the pancreas may contain an in situ active RAS, which appears to be upregulated in an animal model of type 2 diabetes. Thus, ACE inhibitors and ARBs may act by attenuating the deleterious effect of angiotensin II on vasoconstriction, fibrosis, inflammation, apoptosis and beta-cell death in the pancreas, thereby protecting a critical beta-cell mass essential for insulin production. New evidence is presented that ACE inhibitors and ARBs may delay or prevent the development of insulin resistance and diabetes, for which novel mechanisms are suggested. The actions of agents that interrupt the RAS on insulin resistance, obesity and diabetes warrant further investigation in other animal models. Prospective clinical studies with the primary endpoint of the prevention of diabetes are now indicated to (i) further explore whether the inhibitors of the RAS are superior compared to other antihypertensive agents such as calcium channel blockers (CCBs) and (ii) to evaluate the potential beneficial effects of combination antihypertensive regimens on the development of diabetes.
近期试验表明，肾素 - 血管紧张素系统（RAS）抑制剂，如血管紧张素转换酶（ACE）抑制剂和血管紧张素II受体阻滞剂（ARB），可能会降低有或无高血压且患糖尿病风险较高的患者新发糖尿病的发生率。在本综述中，我们严格评估了近期临床试验中关于ACE抑制剂和ARB这种潜在预防作用的证据，包括对这些近期试验的荟萃分析。ACE抑制剂或ARB使糖尿病高危患者糖尿病发生率降低，这一现象可通过血流动力学效应来解释，如改善胰岛素和葡萄糖向周围骨骼肌的输送，以及非血流动力学效应，包括对葡萄糖转运和胰岛素信号通路的直接作用，所有这些均可降低胰岛素抵抗。现在有证据表明胰腺可能含有原位活性RAS，在2型糖尿病动物模型中其似乎上调。因此，ACE抑制剂和ARB可能通过减弱血管紧张素II对胰腺血管收缩、纤维化、炎症、细胞凋亡和β细胞死亡的有害作用来发挥作用，从而保护对于胰岛素产生至关重要的关键β细胞群。新证据表明，ACE抑制剂和ARB可能延迟或预防胰岛素抵抗和糖尿病的发生，并提出了新的机制。干扰RAS的药物对胰岛素抵抗、肥胖和糖尿病的作用值得在其他动物模型中进一步研究。目前需要开展以预防糖尿病为主要终点的前瞻性临床研究，以（i）进一步探究RAS抑制剂是否优于其他抗高血压药物，如钙通道阻滞剂（CCB），以及（ii）评估联合抗高血压方案对糖尿病发生的潜在有益作用。
