代谢综合征、肥胖和2型糖尿病全球发病率的急剧升高大大增加了心血管疾病的风险。而胰岛素抵抗和高胰岛素血症是代谢综合征的常见特征。本文讨论了非血管组织中胰岛素抵抗与血管风险，及血管和心脏中胰岛素信号传导受损的后果。胰岛素抵抗通过多种机制导致心血管功能障碍，有研究提示增强胰岛素敏感性将改善心脏和血管功能障碍。关于强化血糖控制对长期心血管预后影响的众多临床研究目前正在进行，其预期结果可望为洞察人类胰岛素增敏治疗和心血管预后关系提供证据。

There has been a dramatic increase in the global incidence of the metabolic syndrome， obesity and type 2 diabetes. These conditions increase the risk for cardiovascular disorders such as atherosclerosis， coronary artery disease， hypertension， dyslipidemia， heart failure and stroke. A common characteristic of the metabolic syndrome is insulin resistance， and hyperinsulinemia. Insulin resistance in skeletal muscle， adipose tissue and liver， and potentially in pancreatic beta cells and the brain， plays an important role in the pathogenesis of type 2 diabetes by contributing to decreasing skeletal muscle glucose uptake， increasing hepatic glucose production， increasing hepatic triglyceride production and altering the secretion of fat cell derived hormones (adipocytokines) such as adiponectin and retinol binding protein 4. Recent studies have suggested that insulin resistance in vascular tissues and the heart might contribute in part to the cardiovascular complications that are associated with insulin resistance and the metabolic syndrome. This brief review will discuss: (1) How insulin resistance in non-vascular tissues can contribute to increased cardiovascular risk. (2) Consequences of impaired insulin signaling in blood vessels (endothelial cells and vascular smooth muscle). (3) Consequences of impaired insulin signaling in the heart.
 
Insulin Resistance in Non Vascular Tissues and Cardiovascular Risk

Insulin resistance in the liver is associated with increased production of triglycerides and secretion of very low-density lipoproteins (VLDL) leading to hypertriglyceridemia. Production of high-density lipoprotein (HDL) is also reduced and this is due in part to increased secretion of and decreased clearance of apolipoprotein B. These changes in lipoprotein metabolism increase the susceptibility to atherosclerosis. Insulin resistance in liver cells and adipocytes is also associated with increased production of plasminogen activator inhibitor (PAI-1)， which increases the risk of hypercoagulability and coronary and vascular thrombosis. Obesity and insulin resistance in adipocytes is associated with increased release of free fatty acids， which contributes in part to abnormal hepatic lipoprotein metabolism. As will be discussed later， increased delivery of free fatty acids and triglycerides to the heart will increase myocardial fatty acid utilization that will have negative effects on cardiac function and tolerance to ischemia. Inflammation promotes atherosclerosis. Insulin resistance in adipocytes is associated with increased secretion of inflammatory cytokines， which could represent another mechanism linking atherosclerosis with insulin resistance. Secretion of adiponectin by adipose tissue is reduced in obesity and insulin resistant states. Low levels of adiponectin are associated with increased incidence of coronary artery disease and animal studies have suggested that adiponectin deficiency leads to increased vascular intimal hyperplasia following vascular injury and adiponectin administration may limit infarct size in experimental animal models of myocardial ischemia. Insulin resistance and obesity is associated with increased generation of angiotensinogen thereby promoting activation of the renin angiotensin system and hyperinsulinemia increases renal absorption of sodium. Both of these phenomena contribute to the increased incidence of hypertension in individuals with the metabolic syndrome.

Consequences of Impaired Insulin Signaling in the Vasculature

The binding of insulin to its receptor activates a series of intracellular signaling events， which diverges to activate either PI3K and protein kinase B (PKB or Akt) or the mitogen activated protein Kinases (MAPKs). The metabolic effects of insulin are largely mediated by activation of PI3 Kinase and PKB/Akt. Moreover in insulin resistant states， insulin resistance at the cellular level is characterized by impaired insulin signaling to PI3K/PKB， while signaling to MAPK is relatively preserved. In the vasculature， insulin-mediated activation of PI3K/PKB leads to activation of endothelial nitric oxide synthase， which promotes vasorelaxation and improved endothelial function. In contrast， insulin-mediated activation of MAPK increases the generation of endothelin 1， which promotes vasoconstriction. Thus in insulin resistant states that are associated with hyperinsulinemia， nitric oxide generation is reduced， but endothelin production is increased because of persistent insulin-mediated activation of MAPK signaling. These changes could contribute to endothelial dysfunction and hypertension， both of which are independent risk factors for vascular complications such as atherosclerosis. Multiple mechanisms lead to impaired insulin signaling in the vasculature in the metabolic syndrome， and include increased metabolism of glucose and fatty acids by endothelial cells， which promote oxidative stress. Oxidative stress also independently impairs the activity of eNOS， which further impairs vascular function.

Consequences of Impaired Insulin Signaling in the Heart

Obesity and diabetes independently increases the risk for heart failure， even after adjusting for underlying coronary artery disease and hypertension. Others and we have shown that insulin resistance develops within cardiac muscle in obesity and other insulin resistant states such as following high-fat feeding. Insulin resistance at the whole body level increases the delivery of fatty acids (FA) to the heart， which augments myocardial FA metabolism. Increased FA utilization leads to oxidative stress and mitochondrial dysfunction. A recent mechanism that has been described is FA-induced mitochondrial uncoupling， which increases oxygen consumption by mitochondria at the expense of ATP production. Thus mitochondrial uncoupling together with the increased oxygen cost of oxidizing FAs increases myocardial oxygen consumption and decreases cardiac efficiency. This metabolic adaptation is deleterious in the context of myocardial ischemia and pressure overload hypertrophy and may accelerated cardiac dysfunction. Using genetically altered mice with disrupted insulin and PI3K/PKB signaling we have shown that insulin signaling in the heart has direct effects to increase cardiac mitochondrial function. In addition， hearts with impaired insulin signaling are unable to maintain normal cardiac function in response to hypertrophic and ischemic insults. This is due in part to increased myocyte and vascular endothelial apoptosis and necrosis leading to an increase in myocardial fibrosis. In addition to mitochondrial dysfunction， insulin signaling is an important regulator of the expression of vascular endothelial growth factor (VEGF)， which plays an important role in promoting angiogenesis in the heart.

Summary/Conclusion

In summary， multiple mechanisms link insulin resistance to cardiovascular dysfunction. Many of the mechanistic insights gained have come from animal studies.  Short-term studies in humans have indicated that pharmacological or non-pharmacological approaches that improve insulin sensitivity will enhance vascular function， and studies in animals have also shown that improving insulin sensitivity may improve  both cardiac and vascular dysfunction. The greater challenge for the future is to demonstrate that improving insuli