炎性反应——肥胖和胰岛素抵抗的重要特征

肥胖和胰岛素抵抗呈现一种慢性炎性反应状态,表现为白细胞介素-6、白细胞介素-1β、巨噬细胞趋化因子等炎性反应因子水平升高.其原因在于能量代谢不平衡导致脂肪细胞肥大、增生、内质网应激和线粒体功能障碍,c-Jun氨基末端激酶(JNK)/激活蛋白(AP)-1和核因子(NF)-KB抑制蛋白激酶(IKK)β/NF-κKB两条信号通路活化,脂肪因子、游离脂肪酸和其他炎性反应介质表达增高,进而影响了全身各器官如肝脏、胰岛β细胞和骨骼肌.单核细胞和巨噬细胞是炎性反应因子另一个重要的来源.肥胖导致的JNK活化通过胰岛素受体底物-1的丝氨酸磷酸化影响胰岛素信号转导.饮食、运动、降低体重和药物可以改变炎性反应因子的水平.炎性反应理论为代谢性疾病的临床干预提供了重要的方向.     

C反应蛋白与2型糖尿病及其血管并发症

2型糖尿病的主要病理生理改变为从以胰岛素抵抗(IR)为主伴胰岛素分泌不足到以胰岛素分泌不足为主伴胰岛素抵抗.目前研究认为IR是一种系统性慢性炎性反应,C反应蛋白(CRP)作为非特异性急性期反应蛋白,在IR各阶段普遍升高.升高的CRP又加重糖、脂代谢紊乱,加重内皮功能失调,促进动脉粥样硬化形成,从而促进2型糖尿病及其并发症的发生、发展.因此,研究CRP与2型糖尿病的关系有助于糖尿病并发症的预测及治疗.     

C反应蛋白与2型糖尿病及其血管并发症

2型糖尿病的主要病理生理改变为从以胰岛素抵抗(IR)为主伴胰岛素分泌不足到以胰岛素分泌不足为主伴胰岛素抵抗.目前研究认为IR是一种系统性慢性炎性反应,C反应蛋白(CRP)作为非特异性急性期反应蛋白,在IR各阶段普遍升高.升高的CRP又加重糖、脂代谢紊乱,加重内皮功能失调,促进动脉粥样硬化形成,从而促进2型糖尿病及其并发症的发生、发展.因此,研究CRP与2型糖尿病的关系有助于糖尿病并发症的预测及治疗.     

C反应蛋白与2型糖尿病及其血管并发症

2型糖尿病的主要病理生理改变为从以胰岛素抵抗(IR)为主伴胰岛素分泌不足到以胰岛素分泌不足为主伴胰岛素抵抗.目前研究认为IR是一种系统性慢性炎性反应,C反应蛋白(CRP)作为非特异性急性期反应蛋白,在IR各阶段普遍升高.升高的CRP又加重糖、脂代谢紊乱,加重内皮功能失调,促进动脉粥样硬化形成,从而促进2型糖尿病及其并发症的发生、发展.因此,研究CRP与2型糖尿病的关系有助于糖尿病并发症的预测及治疗.     

脂肪固有免疫细胞与胰岛素抵抗

胰岛素抵抗是指外周组织对胰岛素敏感性及反应性降低,肥胖是胰岛素抵抗的主要原因.近年来研究显示,脂肪组织内的炎性反应状态与胰岛素抵抗及2型糖尿病等代谢疾病之间存在密切关系,而脂肪组织中的巨噬细胞、肥大细胞、中性粒细胞、树突状细胞、嗜酸性粒细胞以及自然杀伤T细胞等多种固有免疫细胞通过活化和释放炎性反应介质,参与炎性反应,从而促进机体胰岛素抵抗的形成.进一步深入阐明固有免疫细胞在脂肪组织炎性反应和胰岛素抵抗方面的作用,可以为糖尿病基础研究和治疗提供新的方向和思路.     

胰岛素抗炎机制研究进展

胰岛素是体内唯一降低血糖的激素,目前,临床上主要使用胰岛素治疗糖尿病.然而,胰岛素不仅是一个重要的代谢调节激素,而且是一个重要的抗炎因子.其发挥抗炎作用的具体机制可能为:直接调节炎性反应因子,抑制氧化应激,调节一氧化氮的表达,在血管水平发挥抗炎作用,促进辅助性T细胞(Th)-2的转化,抑制白细胞介素-6-信号转导与转录激活因子(IL-6-STAT)炎性反应通路,降低C反应蛋白水平,下调Toll样受体等.     

乌司他丁对代谢综合征患者胰岛素抵抗的影响

目的探讨乌司他丁对代谢综合征患者胰岛素抵抗的影响及其机制。方法 84名代谢综合征患者随机分为对照组及观察组,两组患者给予相同的基础治疗,对照组另给予乌司他丁100 000 U/d,连续应用2 w,观察两组患者血清C反应蛋白(CRP)、肿瘤坏死因子-α(TNF-α)表达水平变化及胰岛素抵抗指数变化。结果治疗前两组血清CRP、TNF-α表达水平及胰岛素抵抗指数无统计学差异。治疗2 w后观察组血清CRP、TNF-α表达水平低于对照组;观察组胰岛素抵抗指数低于对照组(P<0.05)。结论乌司他丁能够减轻代谢综合征患者的胰岛素抵抗,其可能通过减少炎症介质的表达及炎性反应发挥作用。     

行冠状动脉支架术的非糖尿病患者的胰岛素抵抗及护理

目的:观察行冠状动脉支架术冠心病未合并糖尿病患者的胰岛素抵抗(IR)状态,术后的炎性反应,并探讨护理对策。方法:术前测量32例行冠状动脉支架术的非糖尿病患者的空腹血糖和胰岛素水平,计算胰岛素敏感指数(IAI,以IAI≤4.57为IR);测量术前,术后24 h和一周血高敏C反应蛋白(hsCRP)及白细胞介素(IL)-6水平。结果:冠心病未合并糖尿病患者34.8%(11/32)存在IR,其术前CRP,TNF和IL-6水平显著高于无IR者(P< 0.01);IAI与CRP、TNF和IL-6呈负相关(r=-0.73,-0.58,-0.53);术后24 h内,所有患者CRP,TNF和IL-6水平升高(P<0.001),但IR组升高尤为显著(P<0.001);术后一周,IR组CRP,TNF、和IL-6仍维持较高水平,而对照组已恢复正常。结论:(1)超过30%的非糖尿病支架术冠心病患者存在IR;(2)支架术后,IR者的炎性反应较剧烈,持续时间较长,可能是其术后再狭窄的原因。     

脑梗死患者血清胰岛素样生长因子-1和C反应蛋白检测的临床意义

目的探讨急性脑梗死患者血清胰岛素样生长因子-1(IGF-1)和C反应蛋白(CRP)检测的临床意义。方法选择急性脑梗死患者50例,另选择年龄、性别、传统血管危险因素匹配的健康体检者50例为对照组。所有研究对象均测定空腹血清IGF-1和CRP水平。结果脑梗死组血清IGF-1水平较对照组显著降低,而血清CRP水平显著升高,差异均有统计学意义(P0.01)。脑梗死组血清IGF-1和CRP水平呈负相关(r=-0.72,P0.01)。结论脑梗死患者存在低度炎性反应,血清低IGF-1与高CRP水平提示了脑梗死的一些可能的病理生理机制。     

2型糖尿病的抗炎治疗

胰岛素抵抗与胰岛β细胞功能障碍是2型糖尿病发病的主要病理生理基础,而炎性反应因子介导的慢性非特异性低度炎性反应状态与胰岛素抵抗及β细胞功能障碍密切相关.传统意义上的降糖药物如二甲双胍、噻唑烷二酮类药物、胰岛素、胰高血糖素样肽-1以及他汀类降脂药都具有抗炎效应.新型的抗炎药物如白细胞介素1受体拮抗剂、白藜芦醇、姜黄素等可以通过多种途径改善炎性反应状态而降低血糖.因此,针对炎性反应因子的抗炎治疗有望成为一种崭新的糖尿病治疗u方法.     

Association between C-reactive protein and insulin resistance in a Japanese population: the Minoh Study

OBJECTIVE: To investigate the association between C-reactive protein (CRP) and insulin resistance. MATERIALS AND METHODS: This study included 1,624 Japanese participants (652 men and 972 women) aged 40 to 69 years who were non-diabetics or did not have medication for hypertension or dyslipidemia, a history of cardiovascular disease or CRP levels >10 mg/l. Serum CRP level, fasting glucose level, and fasting insulin level were measured, and the degree of insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Categories of CRP were defined by the following tertiles: <0.25 mg/l, 0.25-0.59 mg/l, and > or = 0.60 mg/l. RESULTS: Elevated CRP levels were associated with increased fasting insulin levels, fasting glucose levels, and HOMA-IR in both men and women. Although the adjustment for body mass index in addition to age, cigarette smoking, and alcohol consumption attenuated the associations between CRP and fasting insulin, fasting glucose, and HOMA-IR, elevated CRP levels were associated with increased insulin levels and HOMA-IR in both sexes. Stratified analyses by CRP level and obesity showed that obesity status was associated with increased fasting insulin levels, fasting glucose levels, and HOMA-IR in both sexes and that fasting insulin levels, fasting glucose levels, and HOMA-IR were higher among obese individuals than among non-obese individuals at the same level of CRP. CONCLUSION: These results suggest a possible role of subclinical inflammation in insulin resistance and glucose intolerance in Japanese, but it only partly explains the link between obesity and impaired glucose homeostasis.     

C-reactive protein is elevated 30 years after eclamptic pregnancy

Women with a history of preeclampsia or eclampsia (seizure during preeclamptic pregnancy) are at increased risk for cardiovascular disease after pregnancy for reasons that remain unclear. Prospective studies during pregnancy suggest that inflammation, dyslipidemia, and insulin resistance are associated with increased risk of preeclampsia. Elevated serum C-reactive protein (CRP >3 mg/L) is an indicator of inflammation and cardiovascular risk. We hypothesized that Icelandic postmenopausal women with a history of eclampsia would manifest higher concentrations of serum CRP than Icelandic postmenopausal controls with a history of uncomplicated pregnancies. We also asked whether elevated CRP is associated with the dyslipidemia and insulin resistance previously identified in this cohort. CRP, measured by high-sensitivity enzyme-linked immunoassay, was higher in women with prior eclampsia (n=25) than controls (n=28) (median mg/L [interquartile range]: 9.0 [0.9 to 13.2] versus 2.0 [0.3 to 5.1]; P<0.03). This difference remained significant after adjustment for body mass index, smoking, hormone replacement, and current age. Women with prior eclampsia clustered into either high CRP (range 8.97 to 40.6 mg/L, n=13) or lower CRP (median 1.0, range 0.05 to 3.77, n=12) subsets. The prior eclampsia/high CRP subset displayed significantly elevated systolic blood pressures, lower high-density lipoprotein (HDL) cholesterol, higher apolipoprotein B, and higher fasting insulin and homeostasis model of insulin resistance (HOMA) values compared to controls, whereas the prior eclampsia/low CRP subset differed from controls only by marginally increased apolipoprotein B. The triad of inflammation, low HDL, and insulin resistance may elevate risk for both preeclampsia/eclampsia and cardiovascular disease in later life.     

Preliminary evidence for obesity-associated insulin resistance in adolescents without elevations of inflammatory cytokines

ABSTRACT: BACKGROUND: To ascertain whether the associations between obesity, inflammation, and insulin resistance established in human adult studies are found among adolescents. METHODS: We contrasted 36 obese and 24 lean youth on fasting glucose, insulin levels, lipid profile, hemoglobin A1C, markers of hepatic function, white blood cell count, C-reactive protein (CRP) and fibrinogen levels. The cytokines IL-6, TNF-alpha, IFN-gamma, IL-10 and IL-4 and the adipokines leptin, resistin, and adiponectin were also compared between the two groups. The fasting glucose and insulin values were used to estimate the degree of insulin resistance with the homeostatic model assessment of insulin resistance (HOMA-IR). T-tests and correlations were run to examine group differences and associations between groups. In addition, regression analyses were used to ascertain whether the markers of inflammation were predictive of the degree of insulin resistance. RESULTS: Although obese adolescents had clear evidence of insulin resistance, only CRP, fibrinogen and leptin were elevated; there were no group differences in pro- or anti-inflammatory cytokines nor adiponectin and resistin. Anthropometric measures of obesity and level of insulin resistance were highly correlated to the acute phase reactants CRP and fibrinogen; however, the degree of insulin resistance was not predicted by the pro- or anti-inflammatory cytokine markers. Obese adolescents had higher white blood cell counts. In addition they had higher circulating alanine aminotransferase concentrations and lower circulating albumin and total protein than lean adolescents, possibly as a result of hepatocyte damage from fatty liver. CONCLUSION: Unlike rodent or adult studies, we found that wide-spread systemic inflammation is not necessarily associated with insulin resistance among adolescents. This finding does not support the current paradigm that the associations between obesity and insulin resistance are, to a significant degree, mediated by low grade systemic inflammation. These data support the need for further adolescent studies to explore these associations.     

Insulin resistance is associated with C-reactive protein independent of abdominal obesity in nondiabetic Taiwanese

Insulin resistance, which plays a fundamental role in the pathogenesis of metabolic syndrome and type 2 diabetes mellitus, is associated with serum levels of inflammatory markers and abdominal obesity. Whether insulin resistance is caused by inflammation or is an epiphenomenon of obesity remains unresolved. We therefore conducted a cross-sectional study to investigate whether the association between insulin resistance and C-reactive protein (CRP) levels is independent of abdominal obesity in a nondiabetic Taiwanese population. The study included 574 Taiwanese participants (300 men and 274 women) who were nondiabetic persons with CRP levels not exceeding 10 mg/L and who did not have a history of cardiovascular disease or were taking medication for dyslipidemia. All participants were of Han-Chinese origin. The degree of insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). The CRP levels were categorized into quartiles from the lowest to the highest concentrations (Q1-Q4). Blood pressure, fasting glucose level, triglycerides level, waist circumference, and HOMA-IR were all found to be significantly higher in Q3 and Q4 than in Q1 and Q2. Stratified analysis by sex and abdominal obesity showed that HOMA-IR was significantly associated with CRP levels in both sexes in either obese or nonobese populations. Multiple linear regression analysis adjusting for age, smoking, components of metabolic syndrome, and waist circumference showed that the association between HOMA-IR and CRP levels remained significant in both men and women (P = .029 for men and P < .001 for women). These findings confirm that insulin resistance is strongly associated with CRP levels independent of abdominal obesity in nondiabetic Taiwanese. Factors other than abdominal obesity, such as polymorphisms in the CRP gene, may influence the association of insulin resistance with CRP levels in different ethnic populations.     

Inflammation, insulin resistance and carotid IMT in first degree relatives of north Indian type 2 diabetic subjects

Inflammation is associated with insulin resistance, atherosclerosis and type 2 diabetes but whether it causes insulin resistance and accelerated atherosclerosis or an epiphenomena of insulin resistance is not clear. Thirty-eight young normoglycemic, non-obese, first degree relatives of type 2 diabetic subjects (FH(+)) and 38 control subjects without family history of diabetes (FH(-)) (age and sex matched), were studied to determine difference in inflammatory markers, insulin resistance and carotid intima-media thickness (IMT). Plasma glucose, insulin (fasting and 2h after 75gm oral glucose) lipids and serum levels of C-reactive protein (CRP), tumour necrosis factor (TNF)-alpha and fibrinogen were measured after an overnight fast of 10-12h. First degree relative group (FH(+)) have higher BMI (p<0.05), composite IMT (p<0.05) and CRP level (p<0.05), however, after adjustment for BMI, the two groups did not significantly differ. Fibrinogen was not significantly correlated with composite IMT in FH(+) group after controlling with BMI. In FH(+) group composite IMT was significantly correlated with systolic blood pressure (p<0.05), LDL-cholesterol (p<0.05), postprandial insulin level (p<0.05) and HOMA-IR (p<0.05) after adjustment of BMI. Thus insulin resistance is a major determinant of atherosclerosis in subjects with high risk of type 2 diabetes showing the strong relationship between inflammation, obesity and insulin resistance.     

C-reactive protein, its role in inflammation, Type 2 diabetes and cardiovascular disease, and the effects of insulin-sensitizing treatment with thiazolidinediones.

Increased concentrations of the marker of inflammation, C-reactive protein (CRP), are associated with insulin resistance, Type 2 diabetes and the development of cardiovascular disease. In particular, inflammation is closely associated with endothelial dysfunction and is recognized as one of the cardiovascular risk factors clustering in the Insulin Resistance Syndrome or Metabolic Syndrome. The exact mechanisms linking insulin resistance and inflammation remain unclear. However, the close association between insulin resistance and inflammation in atherogenesis suggests that therapies that address both parameters may have benefits in reducing diabetes-related macrovascular complications. The thiazolidinedione class of oral anti-diabetic agents are powerful insulin sensitizers that also have anti-inflammatory properties. Treatment with these agents has a range of anti-atherogenic effects, including reduced levels of CRP, plasminogen activator inhibitor-1 (PAI-1), TNF-alpha and reactive oxygen species. Additionally, the insulin-sensitizing effect of thiazolidinediones improves other factors of the Insulin Resistance Syndrome, including dyslipidaemia and hypertension. Outcome studies are underway to determine if the effects of improving insulin sensitivity and reducing inflammation will translate into clinical benefits and reduce the cardiovascular morbidity and mortality associated with insulin resistance and Type 2 diabetes.     

Adiponectin in childhood and adolescent obesity and its association with inflammatory markers and components of the metabolic syndrome

CONTEXT: Adiponectin levels are lower in obese children and adolescents, whereas markers of inflammation and proinflammatory cytokines are higher. Hypoadiponectinemia may contribute to the low-grade systemic chronic inflammatory state associated with childhood obesity. OBJECTIVE: We investigated whether C-reactive protein (CRP), the prototype of inflammation, is related to adiponectin levels independently of insulin resistance and adiposity. DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME MEASURES: In a multiethnic cohort of 589 obese children and adolescents, we administered a standard oral glucose tolerance test and obtained baseline measurements for adiponectin, plasma lipid profile, CRP, IL-6, and leptin. RESULTS: Stratifying the cohort into quartiles of adiponectin levels and adjusting for potential confounding variables, such as age, gender, ethnicity, body mass index z-score, pubertal status, and insulin sensitivity, the present study revealed that low levels of adiponectin are associated not only with higher CRP levels, but also with components of the metabolic syndrome, such as low high-density lipoprotein cholesterol and a high triglyceride-to-high-density-lipoprotein ratio. CONCLUSIONS: The link between adiponectin levels and a strong marker of inflammation, CRP, is independent of insulin resistance and adiposity in obese children and adolescents. Adiponectin may be one of the signals linking inflammation and obesity. Thus, adiponectin may function as a biomarker of the metabolic syndrome in childhood obesity.     

Humoral markers of inflammation and endothelial dysfunction in relation to adiposity and in vivo insulin action in Pima Indians

Several studies have shown that humoral markers of inflammation and endothelial dysfunction are predictive of macrovascular events, and correlated with indirect measures of adiposity and insulin action, thus providing a possible link between obesity, insulin resistance and atherosclerosis. We examined the relationship between humoral markers of inflammation and endothelial dysfunction and direct measures of adiposity and insulin action in Pima Indians, a population with a very high prevalence of obesity and insulin resistance, but a relatively low propensity for atherosclerotic disease. Fasting plasma concentrations of the inflammatory markers C-reactive protein (CRP), secretory phospholipase A2 (sPLA2) and soluble intercellular adhesion molecule-1 (sICAM-1) and of the endothelial markers E-selectin and von Willebrand factor (vWF) were measured in 32 non-diabetic Pima Indians (18 M/14 F, age 27+/-1 years) in whom percent body fat and insulin-stimulated glucose disposal (M) were assessed by DEXA and a hyperinsulinemic clamp, respectively. CRP, sPLA2, and sICAM-1 were all positively correlated with percent body fat (r=0.71, 0.57, and 0.51, all P<0.01). E-selectin and vWF were not correlated with percent body fat, but were negatively correlated with M (r= -0.65 and -0.46, both P<0.001) and positively correlated with CRP (r=0.46, and 0.33, both P<0.05). These findings indicate that humoral markers of inflammation increase with increasing adiposity in Pima Indians whereas humoral markers of endothelial dysfunction increase primarily in proportion to the degree of insulin resistance and inflammation. Thus, obesity and insulin resistance appear to be associated with low-grade inflammation and endothelial dysfunction, respectively, even in an obesity- and diabetes-prone population with relatively low propensity for atherosclerosis.