Adverse hepatic and cardiac responses to rosiglitazone in a new mouse model of type 2 diabetes: Relation to dysregulated phosphatidylcholine metabolism
Adverse hepatic and cardiac responses to rosiglitazone in a new mouse model of type 2 diabetes: Relation to dysregulated phosphatidylcholine metabolism
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DOI：
10.1016/j.vph.2005.11.011
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发表时间：
2006-07-01
影响因子：
4
通讯作者：
Leiter, Edward H.
中科院分区：
文献类型：
--
作者：
Pan, Huei-Ju;Lin, Yiming;Leiter, Edward H.
鉴于代谢功能障碍与胰岛素抵抗和2型糖尿病（T2D）相关的异质性，一种药物不能期望为所有患者提供无并发症的治疗。噻唑烷二酮类（TZD）增加胰岛素敏感性，降低血糖，改善心血管参数。然而，除了增加脂肪量外，TZD在某些个体中有可能加剧潜在的肝骨化病和糖尿病性心肌病。药理学应该允许患者选择最大化治疗和最小化风险。为此，我们将两个遗传多样性的自交系NON/Lt和NZO/Lt组合在一起，产生了“负杂种优势”，增加了F1雄性T2D的频率。与T2D患者一样，用罗格列酮（rosiglitazone，一种过氧化物酶体增殖物激活γ受体（PPAR γ）的激动剂）治疗糖尿病和高脂血症F1男性，可以逆转这些疾病的表型。然而，杂交基因组扰乱了肝脏中磷脂酰胆碱（PC）生物合成的两条主要途径，并显著改变了心脏线粒体中心磷脂的组成，这些代谢缺陷严重加剧了潜在的肝骨化病，并增加了脂肪因子、纤溶酶原激活物抑制剂-1 （PAI-1）的水平，这是心血管事件的危险因素。这个模型系统展示了如何利用小鼠遗传学的力量来识别可能容易产生药物副作用的个体的代谢特征。(c) 2006爱思唯尔公司版权所有。
Given the heterogeneous nature of metabolic dysfunctions associated with insulin resistance and type 2 diabetes (T2D), a single pharmaceutical cannot be expected to provide complication-free therapy in all patients. Thiazolidinediones (TZD) increase insulin sensitivity, reduce blood Glucose and improve cardiovascular parameters. However, in addition to increasing fat mass, TZD have the potential in certain individuals to exacerbate underlying hepatosteatosis and diabetic cardiomyopathy. Pharmacogenctics should allow patient selection to maximize therapy and minimize risk. To this end, we have combined two genetically diverse inbred strains, NON/Lt and NZO/Lt, to produce a "negative heterosis" increasing the frequency of T2D in F1 males. As in humans with T2D, treatment of diabetic and hyperlipemic F1 males with rosiglitazone (Rosi), an agonist of peroxisome proliferator-activated gamma receptor (PPAR gamma), reverses these disease phenotypes. However, the hybrid genome perturbed both major pathways for phosphatidylcholine (PC) biosynthesis in the liver, and effected remarkable alterations in the composition of cardiolipin in heart mitochondria, These metabolic defects severely exacerbated an underlying hepatosteatosis and increased levels of the adipokine, plasminogen activator inhibitor-1 (PAI-1), a risk factor for cardiovascular events. This model system demonstrates how the power of mouse genetics can be used to identify the metabolic signatures of individuals who may be prone to drug side effects. (c) 2006 Elsevier Inc. All rights reserved.