瘦素与冠心病

瘦素是肥胖基因编码的一种蛋白质产物,通过与其受体结合发挥抑制食欲、减少能量摄入、增加能量消耗的生物学作用。近来的大量研究显示瘦素与冠心病发生、发展相关,现就近年来发现的瘦素在冠心病中的作用机理作一综述,以期进一步了解冠心病发病机理,为临床治疗冠心病提供帮助。     

瘦素与冠心病发病机制的研究进展

瘦素是肥胖基因编码的一种蛋白质产物,主要由白色脂肪组织分泌,通过与其受体结合发挥抑制食欲、减少能量摄入、增加能量消耗的生物学作用.近年来大量临床研究显示瘦素与冠心痛的发生、发展密切相关,现就瘦素在冠心病发病中的作用机制作一综述.     

瘦素与冠心病发病关系研究进展

自瘦素发现以来,人们对体内脂肪组织进行了大量的基础及临床研究,血清瘦素与冠心病的关系也受到广泛关注。大多数人的研究都支持高血清瘦素与冠心病的发生有密切关系,瘦素可通过多种途径参与,影响冠心病的发生和发展。现就瘦素与冠心病的发病关系作一综述。     

冠心病患者脂联素、瘦素水平及其与hs-CRP、PAI-1关系的研究

目的探讨冠心病患者脂联素、瘦素水平及其与超敏C反应蛋白（hs-CRP）、纤溶酶原激活物抑制物-1（PAI-1）的相关性。方法可疑冠心病患者84例行冠状动脉造影,确诊为冠心病者（冠心病组）62例,冠状动脉造影正常者（对照组）22例,测定两组脂联素、瘦素、hs-CRP、PAI-1水平。结果与对照组相比,冠心病组脂联素水平降低、瘦素水平升高;脂联素与hs—CRP、PAI-1呈负相关,瘦素与hs—CRP、PAI-1呈正相关,脂联素与瘦素呈负相关。结论脂联素可能是冠心病保护因素,瘦素可能是冠心病危险因素;脂联素、瘦素与hs—CRP、PAI-1相互作用可能共同参与了冠心病的发生与发展。     

血清瘦素水平与冠心病的关系

目的 探讨冠心病患者与非冠心病患者之间血清瘦素水平的差异及血清瘦素与血脂、C-反应蛋白(CRP)的相关性.方法 所有被研究者共100例,分为冠心病组与非冠心病组两组.受检者过夜禁食14 h,于清晨空腹卧位抽取肘静脉血,测定胆固醇、甘油三酯、高密度脂蛋白胆固醇和低密度脂蛋白胆固醇,同时离心分离血清,置-20℃冰箱保存备用,集中测定瘦素及CRP.结果 ①冠心病组的血清瘦素水平明显高于非冠心病组[(8.84±4.99)ng/ml和(5.81±3.30)ng/ml,P＜0.05];②冠心病组与非冠心病组血清血脂、CRP水平差别无统计学意义(P＞0.05);③血清瘦素水平与血脂、CRP间无明显相关性.结论 血清瘦素与冠心病的发病明显相关.血清瘦素水平可作为预测冠心病的独立危险因素.     

2型糖尿病合并冠心病患者血清瘦素与血管病变易患因素的关系

目的 研究2型糖尿病合并冠心病患者血清瘦素(Leptin)与血管病变易患因素的关系.方法 测定2型糖尿病组(T2DM)、糖尿病合并冠心病组(DM-CHD)、正常对照组血清瘦素、超敏C反应蛋白(hs-CRP)、血脂系列、空腹血糖(FBG)、糖化血红蛋白(HbAlC)、空腹胰岛素(FINS)并计算胰岛素抵抗指数(HOMA-IR),同时经颈动脉彩色多普勒超声测定颈总动脉内膜-中层厚度(IMT).结果 ①糖尿病合并冠心病组血清瘦素、CRP,IMT,GHbAIC均高于其他两组;②血清瘦素水平在不同性别间差异显著,女性高于男性(P＜0.01);③相关分析显示,血清瘦素浓度与血管病变易患因素腰臀比(WHR)、FINS、hs-CRP、IMT显著相关.多元逐步回归分析显示,性别、FINS、hs-CRP、IMT为影响瘦素最为显著的因素.结论 血清瘦素水平与糖尿病合并冠心病血管易患因素显著相关,提示瘦素可能在糖尿病合并冠心病的血管病变发病中起一定作用,可能为糖尿病大血管病变的重要危险因子.     

血清瘦素、血脂、C-反应蛋白与冠心病发病的相关性研究

目的 研究血清瘦素、血脂、C-反应蛋白水平与冠心病发病的相关性.方法 被研究者共130例,分冠心病组和非冠心病组,检测他们的瘦素、血脂和CRP,进行统计学计算.结果 冠心病患者的血清瘦素水平明显高于非冠心病患者[(8.84±4.99)ng/ml和(5.81±3.30)ng/ml,P＜0.01)];两组血清CRP水平比较差异有统计学意义[(6.12±8.79)mg/L和(2.43±0.93)mg/L,P＜0.01],部分血脂水平两组间差异有统计学意义.结论 血清瘦素、CRP水平与冠心病发病密切相关,检测血清中瘦素、CRP水平可作为预测冠心病的良好指标.     

血清瘦素与早发冠心病及血浆组织因子的关系

目的:探讨血清瘦素与早发冠心病及血浆组织因子的关系。方法:根据冠状动脉造影结果将200例患者分为早发冠心病组(120例)和对照组(80例)。应用酶联免疫吸附法(ELISA法)检测患者血清瘦素、血浆组织因子(TF)及组织因子途径抑制物(TFPI)水平。结果:早发冠心病组血清瘦素、血浆TF、TFPI及TF/TFPI值均高于对照组(均P<0.01);Pearson相关分析显示,血清瘦素水平与早发冠心病患者血浆TF、TFPI、TF/TFPI均呈正相关(均P<0.01);多元逐步回归显示,血清瘦素和早发冠心病患者血浆TF水平呈独立正相关(P<0.01)。结论:早发冠心病患者表现为高瘦素血症,高瘦素水平与TF的表达及早发冠心病的发生有关。     

血清瘦素、脂联素与冠心病病变程度的相关性研究

目的探讨血清瘦素、脂联素(APN)水平与冠心病(CHD)病变程度的相关性。方法应用ELISA法对稳定型心绞痛(SA)组(21例)、不稳定型心绞痛(UA)组(23例)、急性心肌梗死(AMI)组(24例)和正常对照(CO)组(20例)进行血清瘦素、脂联素水平检测,并进行统计学分析。结果血清瘦素水平冠心病各组明显高于正常对照组(P<0.05),UA组及AMI组高于SA组(P<0.05),AMI组高于UA组(P<0.05),血清瘦素水平与冠心病病变程度呈正相关(r=0.60,P<0.05);血清APN水平UA组及AMI组明显低于SAP组和对照组(P<0.05),冠心病各组与正常对照组比较有统计学意义(P<0.05),AMI组与UA组比较有统计学意义(P<0.05),脂联素与冠心病病变程度呈负相关(r=-0.59,P<0.05)。结论血清瘦素、脂联素与冠心病发病密切相关,冠心病患者血清瘦素水平升高,血清瘦素水平与冠心病病变程度呈正相关。冠心病患者血清APN水平下降,血清脂联素与冠心病病变程度呈负相关。     

阿卡波糖对冠心病合并糖耐量减低患者血清脂联素和瘦素水平的影响

目的探讨冠心病合并糖耐量减低患者的血清脂联素(Adiponectin)和瘦素(Leptin)水平及阿卡波糖的干预效果。方法根据口服葡萄糖耐量试验(OGTT),将46例冠心病患者分为冠心病合并IGT组(CHD并IGT组)(n=19)和单纯冠心病组(单纯CHD组)(n=27),33例体检者分为单纯IGT组(n=15)和正常对照组(n=18)。采用酶联免疫吸附法检测受试者血清脂联素和瘦素水平,同时测定OGTT空腹血糖(FBG)和餐后2小时血糖(2hFBG)、空腹胰岛素(Fins)、血脂及超敏C反应蛋白(hs-CRP),并测量身高、体重、腰围,计算体重指数(BMI)、胰岛素抵抗指数(HOMA-IR)。对于冠心病合并IGT组和单纯IGT组均给予阿卡波糖干预3个月后复测上述指标。结果冠心病患者的血清脂联素水平下降,合并IGT时进一步降低,血清脂联素水平与HOMA-IR、HDL-C、SBP及性别相关。IGT患者的血清瘦素水平升高,血清瘦素水平与BMI、腰围相关,女性显著高于男性。血清脂联素和瘦素水平无相关性。经阿卡波糖干预后,BMI、腰围、2hPBG、TC、TG、LDL-C、HOMA-IR水平均下降。血清脂联素水平显著升高,升高的水平与TC的变化相关;血清瘦素水平降低,女性降低水平高于男性。结论阿卡波糖可能通过影响冠心病合并IGT患者血清脂联素和瘦素水平来改善肥胖、餐后高血糖、胰岛素抵抗及血脂紊乱等,进而起到心血管保护作用。     

Opposite effects of insulin-like molecules and leptin in coronary heart disease of type 2 diabetes Preliminary data

INTRODUCTION: Leptin and insulin have been reported to be risk factors for coronary heart disease (CHD) in the general population, but their role in type 2 diabetes still remains unclear. MATERIALS AND METHODS: The role of leptin and insulin upon CHD in type 2 diabetes was assessed in 154 patients, aged 31-77 years, who were treated with oral anti-diabetic agents. Multivariate logistic regression analyses were used with CHD (an established history of CHD or an abnormal treadmill test) as dependent, and leptin, insulin and potential confounders as independent variables. RESULTS: Endogenous insulin was significantly associated with CHD in a model controlling for gender, age, duration of diabetes, body mass index, smoking and leptin (Odds ratio 1.45 per decile, 95% confidence interval 1.11-1.90). Improving control for confounding by replacing body mass index by subcutaneous fat (CT-measured at the L4-L5 level) and height in this model, resulted in a significant negative association between leptin and CHD (OR 0.60, 95% CI 0.37-0.96). DISCUSSION: Leptin might have a beneficial effect on CHD in type 2 diabetes, probably by counteracting the effect of insulin-like molecules or insulin resistance. The effect was elucidated only after careful control for confounding by subcutaneous fat, the main source of leptin production.     

Serum leptin is elevated in Saudi Arabian patients with metabolic syndrome and coronary artery disease.

AIMS: To compare plasma leptin in Saudi subjects with Type 2 diabetes and coronary heart disease (CHD) with non-diabetic control subjects and to examine the relationship of plasma leptin to other CHD risk factors. RESEARCH DESIGN AND METHOD: Serum leptin concentrations were measured in 144 Saudi men. Subjects studied included 59 with Type 2 diabetes mellitus [BMI 27.5 (3.7) kg/m2 mean (sd)], 34 with coronary heart disease [BMI 29.6 (1.8) kg/m2], and 51 non-diabetic controls [BMI 28.0 (3.5) kg/m2]. There was no significant difference in BMI between the groups. Fasting serum leptin, lipids, insulin, apolipoproteins and glucose were measured. BMI, blood pressure; smoking habit and age were also recorded. Insulin resistance was assessed using the HOMA model. RESULTS: Leptin concentrations were significantly higher in diabetic and CHD patients than in controls (P = 0.024 and 0.016, respectively). Multiple regression analysis showed that body weight (P < 0.0006), serum triglyceride concentration (P = 0.046) and systolic blood pressure (P = 0.013) were all significantly related to the logarithm of the serum leptin concentration (R2 = 0.549) in CHD patients. A subgroup analysis, comparing those patients who had the metabolic syndrome, as defined by WHO, with controls, showed higher serum leptin in those with metabolic syndrome (P = 0.05). CONCLUSIONS: Serum leptin is increased in Saudi subjects with diabetes mellitus, metabolic syndrome and CHD. Leptin may be a marker of risk of CHD, at least in men, and contribute to the CHD risk profile in subjects with insulin resistance. Further studies are needed to evaluate this relationship prospectively.     

Plasma leptin concentration in patients with Type 2 diabetes: relationship to cardiovascular disease risk factors and insulin resistance.

AIMS: The aim of this study was to evaluate the relationship of obesity, leptin, insulin resistance and C-reactive protein (CRP) with coronary heart disease (CHD) risk factors in patients with Type 2 diabetes mellitus (DM) with CHD compared with those with Type 2 DM without CHD. METHODS: Leptin, CRP (high sensitivity assay), fasting plasma insulin, glucose, HbA(1c) and full lipid profile were determined in 58 Type 2 diabetic patients with CHD and 87 Type 2 DM patients without CHD. RESULTS: were compared between those with and without CHD. Univariate correlation as well as logistic regression analyses were used to relate these markers with traditional CHD risk factors. RESULTS: Leptin showed significant correlations with BMI (r = 0.59; P < or = 0.0001), waist circumference (r = 0.45; P < 0.0001), CRP (r = 0.36; P < 0.0001), and fasting insulin (r = 0.53; P < 0.0001) as well as with systolic (r = 0.23; P = 0.007) and diastolic (r = 0.23; P = 0.007) blood pressure. However, when those with and without CHD were compared only age (P < 0.0001), duration of diabetes (P < 0.001) and degree of microalbuminuria (P = 0.02) were significantly higher in patients with CHD. Leptin (P = 0.49), CRP (P = 0.19) and lipid parameters were not significantly different between the two groups. CONCLUSION: Our study confirms a relationship between leptin and CRP with CHD risk factors. The lack of significant difference when patients with and without CHD are compared may be due to the potential confounding effects of treatment with aspirin and statins.     

Leptin and coronary heart disease: A systematic review and meta-analysis

Introduction

Leptin, an adipose tissue-derived hormone, plays a central role in regulating human energy homeostasis. The role of leptin in regulating blood pressure, activating the sympathetic nervous system, insulin resistance, platelet aggregation, arterial thrombosis, angiogenesis, and inflammatory vascular responses suggests that leptin may have a close relationship with the development of coronary heart disease (CHD). However, no conclusive data are available to determine the association between leptin and CHD.

Methods

The PubMed, EMBASE and Cochrane databases were surveyed for original studies describing the association between leptin and CHD outcome from the date of publication of each database through March 2013. The data were extracted by two investigators independently.

Results

The meta-analysis reported here was comprised of eight original articles with a total of 21,064 participants (10,842 men, 10,222 women) and 2053 CHD events. The odds ratio for the sociodemographic-adjusted study reported here was 1.57 (95% confidence interval, 1.14–2.16) and 1.72 (95% confidence internal, 1.03–2.87) in males and females, respectively. Further adjustment for additional cardiovascular risk factors resulted in an odds ratio of 1.36 (95% confidence interval, 0.98–1.88) in males and 1.50 (95% confidence interval, 0.93–2.42) in females. Sensitivity analysis restricted to sociodemographics-adjusted studies with high methodological quality indicated an estimate of 1.47 (95% confidence internal, 1.06–2.04) in males and 1.85 (95% confidence internal, 0.61–5.63) in females. Sensitivity analysis restricted to cardiovascular risk factor-adjusted studies showed no significant differences in both males and females.

Conclusion

The results of the meta-analysis represents the most precise and accurate estimate of the relationship between leptin and CHD. Although the associations of leptin and CHD were not statistically significant both in male and female overall, males with high levels of leptin should be paid more attention to. Our findings highlight the need for additional well-designed and gender-specific prospective studies to evaluate the role of leptin on the development of CHD.     

Possible role of placental leptin in pregnancy: a review

Leptin was initially identified as an adipocyte-derived hormone that decreases food intake and body weight via its receptor in the hypothalamus. Subsequent animal studies revealed various physiologic functions of leptin. Leptin plays an essential role in reproduction by regulating gonadotropin-releasing hormone secretion from the hypothalamus. It also modulates glucose metabolism by increasing insulin sensitivity and activates the sympathetic nervous system. In humans, leptin is also produced by placental trophoblasts and is secreted into both the maternal and fetal circulation. Leptin production in the placenta is increased in pregnancies complicated with several pathologic conditions. Leptin gene expression in the placenta is augmented in severe preeclampsia, and maternal plasma leptin levels in severe preeclampsia are significantly higher than those in normotensive pregnant women. Leptin production in the placenta is also increased in diabetic pregnancy with insulin treatment. Furthermore, leptin is proposed to play a functional role in implantation by virtue of its stimulatory effect on matrix metalloproteinase expression in cytotrophoblast. Dysregulation of leptin metabolism and/or function in the placenta may be implicated in the pathogenesis of various disorders during pregnancy, such as recurrent miscarriage, gestational diabetes, intrauterine growth retardation, and preeclampsia. In this review, possible roles of placental leptin are discussed.     

Expression of leptin and leptin receptor during the development of liver fibrosis and cirrhosis.

Leptin is involved in the regulation of food intake and is mainly secreted by adipocytes. Major secretagogues are cytokines such as TNF-alpha or IL-1. Leptin in turn upregulates inflammatory immune responses. Elevated leptin serum levels have been detected in patients with liver cirrhosis, a disease frequently associated with elevated levels of circulating cytokines as well as hypermetabolism and altered body weight. Recently, leptin has been detected in activated hepatic stellate cells in vitro and an involvement of leptin in liver fibrogenisis has been suggested. The current study was designed to further clarify the role of leptin in liver disease by characterizing leptin and leptin receptor expression in the development and onset of experimental liver fibrosis. Liver fibrosis and cirrhosis was induced in rats by use of phenobarbitone and increasing doses of CCl (4). Leptin and leptin receptor mRNA expression was determined by semiquantitative RT-PCR, protein expression by Western blot analysis and localization of leptin and its receptor by immunohistochemistry. Normal liver tissue does not express leptin, but leptin receptor mRNA. Increasing levels of leptin mRNA were detected in fibrotic and cirrhotic livers correlated to the degree of fibrosis. Leptin receptor mRNA expression was not significantly altered in damaged livers. Increasing levels of leptin were detected in fibrotic and cirrhotic livers, whereas protein expression of the receptor remained unchanged. Throughout different stages of liver fibrosis, leptin immunoreactivity was localized in activated hepatic stellate cells only, whereas immunoreactivity for the receptor was mainly seen on hepatocytes. In conclusion, leptin is expressed at increasing levels in activated hepatic stellate cells in vivo, which may therefore be a source of increased leptin tissue and serum levels contributing to the pathophysiology and morphological changes of chronic liver disease.     

Interaction between leptin and sympathetic nervous system in hypertension

Leptin is a protein produced by adipose tissue that acts in the central nervous system (CNS) to decrease appetite and increase energy expenditure. Leptin thus functions as the afferent component of a negative feedback loop that maintains stable adipose tissue mass. Intravenous leptin increases norepinephrine turnover and sympathetic nerve activity to thermogenic brown adipose tissue. Leptin also increases sympathetic nerve activity to tissues not usually considered thermogenic, including the kidney, hindlimb, and adrenal gland. Chronic systemic CNS administration of leptin increases arterial pressure and heart rate in conscious animals. However, leptin has additional cardiovascular actions that may act to oppose sympathetically mediated vasoconstriction. These actions include natriuresis, insulin sensitization, endothelium-dependent dilatation, and angiogenesis. Thus, the overall effect of leptin on arterial pressure has been unclear. Recent studies have demonstrated that leptin-deficient ob/ob obese mice have lower arterial pressure than lean controls with normal leptin levels. These studies suggest that leptin contributes physiologically to maintenance of arterial pressure. Leptin expression and plasma leptin concentrations are elevated in obese humans. Abnormalities in the generation or actions of leptin may, therefore, have implications for the sympathetic, cardiovascular, and renal changes associated with obesity.     

Obesity, leptin resistance, and the effects of insulin reduction

Leptin resistance is a hallmark of obesity, but its etiology is unknown, and its clinical measurement is elusive. Leptin-sensitive subjects have normal resting energy expenditure (REE) at a low leptin concentration, while leptin-resistant subjects have a normal REE at a higher leptin concentration; thus, the ratio of REE:Leptin may provide a surrogate index of leptin sensitivity. We examined changes in REE and leptin in a cohort of 17 obese subjects during experimental weight loss therapy with the insulin-suppressive agent octreotide-LAR, 40 mg i.m. q28d for 6 months. Six subjects lost significant weight (>10%) and BMI (>-3 kg/m(2)) with a 34% decline in leptin and a 46% decrease in insulin area under the curve (IAUC) to oral glucose tolerance testing. These subjects maintained their pretreatment REE, and thus exhibited a rise in REE:Leptin, while the other 11 showed minimal changes in each of these parameters. For the entire cohort, the change in IAUC correlated negatively with the change in REE:Leptin. These results suggest that the REE:Leptin ratio, while derivative, may serve as a useful clinical indicator of changes in leptin sensitivity within obese subjects. They also support the possibilities that hyperinsulinemia may be a proximate cause of leptin resistance, and that reduction of insulinemia may promote weight loss by improving leptin sensitivity.     

The role of leptin in the regulation of neuroendocrine function and CNS development

Leptin, a hormone produced by adipocytes in proportion to fat stores, signals the sufficiency of energy reserves to the brain to control feeding and metabolism. Leptin represents a vital link between metabolic and neuroendocrine pathways, and adequate circulating leptin levels are required to permit the expenditure of energy on reproduction, growth, and other energy-intensive endocrine outputs. Leptin mediates its effects by acting upon a distributed network of CNS neurons that express the signaling form of the leptin receptor (LRb). Nutritional status early in development influences a lifelong metabolic program that modulates risk for diabetes, obesity and other elements of the metabolic syndrome. Recent evidence has demonstrated a number of important roles for leptin in the regulation of neural development and metabolic programming. In this review, we discuss leptin action, the neural circuits on which leptin acts, and our nascent understanding of how early leptin exposure may influence neural development and the predisposition to metabolic diseases.