Division of Endocrinology, Diabetes, Metabolism and the Clinical Research Center, Temple University School of Medicine, Philadelphia, PA, USA.
Curr Pharm Des. 2013;19(32):5678-83. doi: 10.2174/1381612811319320003.
Insulin resistance and inflammation are recognized as important links between obesity and cardiovascular disease (CVD). Plasma free fatty acids (FFA), either released from the abnormally enlarged adipose tissue or as part of the excessive nutrient intake, produce insulin resistance and inflammation. Both insulin resistance and inflammation are tightly linked to several independent CVD risk factors such as type 2 diabetes (T2DM), hypertension, dyslipidemia and disorders of blood coagulation. Several hypotheses have been proposed to explain how increased plasma FFA levels can cause insulin resistance including a) the lipid metabolite hypothesis, b) the inflammation hypothesis, c) the hyperinsulinemia hypothesis and d) the endoplasmic reticulum (ER) stress hypothesis. The latter does not require presence of elevated plasma FFA levels and thus provides a mechanism to explain the development of insulin resistance and inflammation in all obese individuals, i.e., those with and without elevated plasma FFA levels. Hyperinsulinemia per se has been suspected to cause CVD based on epidemiologic studies which have associated chronic hyperinsulinemia with CVD without, however, establishing a cause and effect relationship. There are, however, newer results which support the hypothesis that chronic hyperinsulinemia per se can promote the development of CVD. For instance, hyperinsulinemia can activate triglyceride formation, several matrix metalloproteinases (MMP), and the tissue factor pathway of blood coagulation, all of which are known to be associated with CVD, even in the presence of "metabolic insulin resistance".
胰岛素抵抗和炎症被认为是肥胖与心血管疾病（CVD）之间的重要联系。血浆游离脂肪酸（FFA），要么是从异常增大的脂肪组织中释放出来的，要么是作为过量营养摄入的一部分，都会导致胰岛素抵抗和炎症。胰岛素抵抗和炎症都与几种独立的 CVD 风险因素紧密相关，如 2 型糖尿病（T2DM）、高血压、血脂异常和凝血紊乱。已经提出了几种假设来解释为什么增加的血浆 FFA 水平会导致胰岛素抵抗，包括 a）脂质代谢物假说、b）炎症假说、c）高胰岛素血症假说和 d）内质网（ER）应激假说。后者不需要存在升高的血浆 FFA 水平，因此提供了一种机制来解释所有肥胖个体中胰岛素抵抗和炎症的发展，即那些有和没有升高的血浆 FFA 水平的个体。基于流行病学研究，高胰岛素血症本身就被怀疑会导致 CVD，这些研究将慢性高胰岛素血症与 CVD 联系起来，但并未建立因果关系。然而，有更新的结果支持慢性高胰岛素血症本身可以促进 CVD 发展的假说。例如，高胰岛素血症可以激活甘油三酯形成、几种基质金属蛋白酶（MMP）和凝血组织因子途径，所有这些都与 CVD 有关，即使存在“代谢性胰岛素抵抗”。
