Inflammation, insulin resistance, and atherosclerosis

Until recently, atherosclerosis was thought to be a passive process of lipid deposition in the arterial wall, followed by progressive occlusion of the lumen, and finally plaque rupture and thrombosis. Recent data suggest the contrary-atherosclerosis is a dynamic process developing over many years, characterized by active uptake of lipids and smooth muscle proliferation, "molding" of plaque, and subject to the influence of many environmental and genetic factors. Central to these processes, both at initiation and propagation, are factors associated with inflammation. Insulin resistance (IR), the underlying cause of type 2 diabetes mellitus (DM), is also associated with elevated levels of inflammatory factors, such as C reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), and fibrinogen. Recent studies indicate that these same factors precede and predict DM. These findings have led to the notion that the strong association of IR/DM with cardiovascular disease (CVD) may be through inflammation pathways. In this article, we review what is known about the association of inflammation with IR and atherosclerosis. We show that many of the same inflammatory factors associated with IR are present in atherosclerosis. We also discuss the underlying determinants of inflammation in these conditions.     

Perilipin与肥胖及胰岛素抵抗

Perilipin是一种脂滴相关蛋白,包被于脂肪细胞和甾体生成细胞的脂滴表面.因其独特的组织分布和分子结构,Perilipin具有双向调控脂肪分解的功能.目前许多研究表明,Perilipin在肥胖和胰岛素抵抗中占有重要作用.Perilipin基因的缺失和基因多态性与肥胖、胰岛素抵抗的发生、发展及易感性密切相关.其可能成为治疗这些相关疾病的新靶点.     

Glypican-4与肥胖及胰岛素抵抗

Glypican-4是一种新的脂肪细胞因子,其在皮下和内脏脂肪组织中差异表达,并与体重指数、腰臀比密切相关.Glypican-4通过直接与胰岛素受体结合,发挥类似胰岛素的作用,促进葡萄糖的摄取和前脂肪细胞的分化.在肥胖和糖尿病等具有胰岛素抵抗的患者中,glypican-4可通过代偿性分泌增加,维持机体血糖水平正常.Glypican-4是第一个被发现能直接与胰岛素受体结合,发挥增强胰岛素信号转导作用的脂肪细胞因子.研究其在胰岛素信号转导方面的功能将可能为肥胖和糖尿病的诊治带来新的契机.     

网膜素与肥胖及胰岛素抵抗的关系

网膜素是新近发现的一种脂肪细胞因子,特异性表达于内脏脂肪组织.目前研究表明,网膜素能促进皮下和网膜脂肪细胞胰岛素刺激的葡萄糖转运和蛋白激酶B磷酸化,且与肥胖相关,在调节糖代谢中具有一定作用.因此,对网膜素的表达、作用机制及生物学功能的深入研究,有助于进一步阐明肥胖、代谢综合征及糖尿病等的发病机制,从而为这些疾病的治疗提供新的方向.     

网膜素与肥胖及胰岛素抵抗的关系

网膜素是新近发现的一种脂肪细胞因子,特异性表达于内脏脂肪组织.目前研究表明,网膜素能促进皮下和网膜脂肪细胞胰岛素刺激的葡萄糖转运和蛋白激酶B磷酸化,且与肥胖相关,在调节糖代谢中具有一定作用.因此,对网膜素的表达、作用机制及生物学功能的深入研究,有助于进一步阐明肥胖、代谢综合征及糖尿病等的发病机制,从而为这些疾病的治疗提供新的方向.     

网膜素与肥胖及胰岛素抵抗的关系

网膜素是新近发现的一种脂肪细胞因子,特异性表达于内脏脂肪组织.目前研究表明,网膜素能促进皮下和网膜脂肪细胞胰岛素刺激的葡萄糖转运和蛋白激酶B磷酸化,且与肥胖相关,在调节糖代谢中具有一定作用.因此,对网膜素的表达、作用机制及生物学功能的深入研究,有助于进一步阐明肥胖、代谢综合征及糖尿病等的发病机制,从而为这些疾病的治疗提供新的方向.     

Relationship between insulin resistance, insulin secretion and insulin metabolism in simple obesity

The study was designed to evaluate whether the correlation occurring in simple obesity between insulin resistance and peripheral hyperinsulinemia corresponds to a relationship between insulin resistance and insulin overproduction by the pancreas. In addition, the study investigated the relation existing in simple obesity between insulin resistance and insulin metabolism. For these purposes, we measured and correlated: (1) insulin sensitivity, estimated by glucose disappearance rate from plasma after intravenous insulin injection; (2) insulin secretion by the pancreas, estimated by fasting C-peptide levels in peripheral blood; (3) insulin metabolism, estimated by means of C-peptide: insulin molar ratio in peripheral blood. Twenty-five subjects (20 females, five males) aged 21 to 59 years were studied. All were obese and had a normal glucose tolerance. Glucose disappearance rate from plasma after i.v. insulin injection averaged 3.65 +/- 0.42 mg/dl/min (mean +/- s.e.m.). Fasting C-peptide was 0.90 +/- 0.09 nmol/l. Fasting C-peptide: insulin molar ratio averaged 5.94 +/- 0.48. Negative correlations were found between glucose disappearance rates after i.v. insulin injection, ie, insulin sensitivity, and fasting concentrations of both insulin (r = -0.806, P less than 0.001) and C-peptide (r = -0.525, P less than 0.01). A positive relationship was found between glucose disappearance rate from plasma after i.v. insulin injection and fasting C-peptide: insulin molar ratio, ie, insulin metabolism (r = 0.707, P less than 0.001). We conclude that in simple obesity insulin overproduction by the pancreas is negatively related to insulin resistance, and insulin resistance and impaired insulin metabolism are strictly related phenomena.     

老问题新认识:对脂肪酸与肥胖和胰岛素抵抗关系的再评价

美国牛津糖尿病中心的Karpe F等近期发表的"Fatty acids,obesity,and insulin resistance:time for a reevaluation"(Diabetes,2011,60:2441)。根据他们自己的研究和文献对脂肪酸(FA)在肥胖和IR中的关系撰文提出新认识。首先,非酯化脂肪酸(NEFA)的基本功能现在认为NEFA是将储存在脂肪组织的TG转运到其利用处的转运工具,而不只是供肝、心肌等利用。第二,上身和腹部皮下脂肪堆积是NEFA主要来源,不同于普遍认为只有一小部分NEFA来自腹内脂肪组织。第三,空腹血浆NEFA几乎全部来自脂肪细胞内TG水解,但餐后血浆NEFA约40%～50%来自食物脂肪乳糜颗粒中的TG被LPL水解,脂肪利用被胰岛素抑制,在富含碳水化合物餐后NEFA浓度下降。第四,NEFA升高伴急性IR,常见于肥胖,控制不良的糖尿病患者,IR伴异位脂肪——脂肪组织以外的胰岛素效应组织如骨骼肌细胞脂质增加(细胞TG),反映脂肪清除损害甚于摄取。现撷其精要摘译并如以评论,供广大读作者参考。     

Postmenopausal hypertension,abdominal obesity,apolipoprotein and insulin resistance

This study aimed to evaluate the association of abdominal obesity, apolipoprotein and insulin resistance (IR) with the risk of hypertension in postmenopausal women. We analyzed a total of 242 women aged between 35 and 70 years. Blood pressure (BP), anthropometric indices, lipid profile, fasting glucose, insulin, C-reactive protein (CRP) and apolipoprotein concentrations were measured. Homeostasis model assessment (HOMA) was used to assess IR. Hypertension was defined as a systolic BP (SBP) ≥140 mmHg and/or diastolic BP (DBP) ≥90 mmHg or current treatment with antihypertensive drugs. Women with hypertension showed significantly higher mean values of age, SBP and DBP, waist circumference (WC), fasting plasma glucose (FPG), insulin, HOMAIR and the apolipoprotein B (apoB). When analyses were done according to the menopausal status, higher prevalence of hypertension was observed in postmenopausal women (72.8% vs. 26.0%, p < 0.001) compared to their premenopausal counterparts. Postmenopausal women showed also significantly higher mean values of SBP and DBP, WC, HOMAIR and apoB. Multivariate linear regression analysis revealed that SBP was significantly affected by WC (p = 0.034), apoB (p = 0.038) and log HOMAIR (p = 0.007) in postmenopausal women. The interaction models revealed significant interaction between WC, apoB and log HOMAIR (WC×apoB×log HOMAIR) on SBP (p = 0.001) adjusted for age. In a multivariate logistic regression, adjusting for age and apoB, WC (p = 0.001), log HOMAIR (p = 0.007) and menopause (p = 0.008) were significantly associated with higher risk for hypertension. These results suggest that changes in WC, apoB and IR accompanying menopause lead to a greater prevalence of hypertension in postmenopausal women.     

Low-grade inflammation, obesity, and insulin resistance in adolescents

CONTEXT: Low-grade inflammation is associated with insulin resistance and precedes the onset of type 2 diabetes mellitus in adults, but there are no comparable data in youth. OBJECTIVE: The objective of the study was to characterize the pattern of subclinical immune activation that is associated with indices of obesity and insulin resistance in youth and analyze whether this association is explained by obesity. DESIGN: This was a cross-sectional study. SETTING: Medical check-up of schoolchildren was conducted by the Public Health Office in Düsseldorf (Germany). PARTICIPANTS: Participants included 519 adolescents (mean age 15.5 +/- 0.8 yr). MAIN OUTCOME MEASURES: Measures included body mass index (BMI) and waist circumference (WC) as indices of obesity; fasting glucose, insulin, and homeostasis model assessment of insulin resistance; serum concentrations of TNFalpha, IL-6, IL-8, IL-18, monocyte chemoattractant protein-1, interferon-gamma-inducible protein (IP)-10 and adiponectin as immunological variables. RESULTS: In age-, sex-, and lipid-adjusted analyses, IL-6, IL-18, IP-10, and adiponectin (inversely) were associated with both BMI and WC (all P 相似文献   

Pathophysiological connections between gallstone disease,insulin resistance,and obesity

Obesity and cholesterol gallstone disease (GSD) are frequently coexisting diseases; therefore and considering the current worldwide obesity epidemics, a precise understanding of the pathophysiological relationships between GSD and insulin resistance (IR) is important. Classically, obesity has been understood as a risk factor for GSD and the gallbladder (GB) viewed as a simple bile reservoir, with no metabolic roles whatsoever. However, consistent evidence has showed that both GSD and cholecystectomy associates with fatty liver and IR, raising the possibility that the GB is indeed an organ with metabolic regulatory roles. Herein, we review the pathophysiological mechanisms by which GSD, IR, and obesity are interconnected, with emphasis in the actions of the GB as a regulator of bile acids kinetics and a hormone secreting organ, with metabolic actions at the systemic level. We also examine the relationships between increased hepatic lipogenic in IR states and GSD pathogenesis. We propose a model in which GSD and hepatic IR mutually interact to determine a state of dysregulated lipid and energy metabolism that potentiate the metabolic dysregulation of obesity.     

Fast food, central nervous system insulin resistance, and obesity

Rates of obesity and insulin resistance have climbed sharply over the past 30 years. These epidemics are temporally related to a dramatic rise in consumption of fast food; until recently, it was not known whether the fast food was driving the obesity, or vice versa. We review the unique properties of fast food that make it the ideal obesigenic foodstuff, and elucidate the mechanisms by which fast food intake contributes to obesity, emphasizing its effects on energy metabolism and on the central regulation of appetite. After examining the epidemiology of fast food consumption, obesity, and insulin resistance, we review insulin's role in the central nervous system's (CNS) regulation of energy balance, and demonstrate the role of CNS insulin resistance as a cause of leptin resistance and in the promotion of the pleasurable or "hedonic" responses to food. Finally, we analyze the characteristics of fast food, including high-energy density, high fat, high fructose, low fiber, and low dairy intake, which favor the development of CNS insulin resistance and obesity.     

Sex steroid hormones,upper body obesity,and insulin resistance

Low plasma levels of SHBG and free testosterone have been associated with increased insulin resistance and risk for type 2 diabetes in males. As truncal obesity, a condition accompanied by increased insulin resistance, is also associated with low SHBG and testosterone levels, the independent association of low free testosterone and SHBG with excessive insulin resistance remains to be determined. In this study we evaluated whether in normogonadic men, plasma levels of SHBG and free testosterone are primarily related to insulin resistance or to generalized and regional adiposity. Hyperinsulinemic-euglycemic clamps and iv glucose tolerance tests were performed in 24 healthy volunteer and 33 patients with mild type 2 diabetes. The 2 groups were chosen to have similar body mass index and were found to have similar body composition and fat distribution, assessed by underwater weighing, skinfold thickness, and magnetic resonance imaging of the abdomen. In the 2 groups combined, plasma levels of SHBG correlated inversely with fat accumulation in both sc and intraabdominal areas. Plasma levels of free testosterone correlated inversely with both truncal and peripheral skinfold thickness only in the nondiabetic men. No associations between plasma levels of sex steroid hormones and insulin resistance, hepatic glucose output, or insulin secretion were found to be independent of adiposity. Furthermore, although patients with diabetes were more insulin resistant than those without diabetes, the 2 groups had similar plasma concentrations of free testosterone (55 +/- 14 and 67 +/- 27 pmol/liter, respectively), SHBG (19 +/- 13 and 19 +/- 13 nmol/liter), estradiol (83 +/- 5 and 81 +/- 21 pmol/liter), and dehydroepiandrosterone sulfate (3.6 +/- 2.2 and 2.8 +/- 1.7 nmol/liter). We conclude that in normogonadal nondiabetic males, the variability in plasma bioavailable testosterone concentrations is predictive of the variability in fat deposition in the sc adipose tissue compartments of both truncal and peripheral areas. Low plasma levels of bioavailable testosterone do not independently predict excessive insulin resistance, beta-cell dysfunction, or hepatic glucose output in normogonadal men.     

Upper abdominal obesity, insulin resistance and breast cancer risk

PURPOSE: A majority of prospective studies show breast cancer risk to be higher in obese postmenopausal women with upper abdominal adiposity than in those with overall adiposity. The evidence is more limited and inconsistent in the case of premenopausal women. The review examines evidence that aberrant insulin signalling may be involved in the promotion of mammary carcinogenesis. The aetiology and concomitants of abdominal visceral obesity are examined. MECHANISMS: Clinical and experimental evidence suggests that the higher breast cancer risk associated with greater abdominal visceral obesity may be related to aberrant insulin signalling through the insulin receptor substrate 1 pathway, leading to insulin resistance, hyperinsulinaemia and increased concentrations of endogenous oestrogen and androgen. The putative role of aberrant insulin signalling in the promotion of mammary carcinogenesis may help to explain clinical relationships between breast cancer risk and age at menarche, pregnancies and onset of obesity. CONCLUSION: Overall adiposity in women adversely affects breast cancer risk mainly by greater exposure of mammary epithelial tissue to endogenous oestrogen. Upper abdominal adiposity appears to involve an additional effect related to the presence of insulin resistance. Aetiological factors in the development of hyperinsulinaemic insulin resistance are still uncertain but may involve aberrant susceptibility genes in adipocyte insulin receptors or in the insulin receptor substrate 1 pathway. Epigenetic factors are also likely to contribute, including high free fatty acid levels and obesity. Dietary fatty acids, particularly polyunsaturated fatty acids, are known to regulate adipocyte differentiation through the nuclear peroxisome proliferator-activated receptor gamma, and may also have a role in insulin resistance. These aetiological factors are likely to be relevant to the high risk of postmenopausal breast cancer in industrialised Western populations.     

Vascular dysfunction in obesity and insulin resistance

With the growing prevalence of obesity and impaired glycemic control, and the correlation between these conditions and an elevated predisposition for the development of vascular disease, research emphases are increasingly being targeted to the mechanistic bases and functional outcomes of these relationships. Given this, the current issue of Microcirculation, presents a series of reviews that summarize knowledge on an array of topics relevant to obesity, insulin resistance, and vascular dysfunction. The first chapters discuss altered patterns of blood flow regulation, vascular reactivity, microvascular density, and vascular wall mechanics. The second grouping details alterations to coronary, renal, and hepatic circulations and the implications of these effects for organ function. Additionally, one article presents knowledge and outlines future research directions for the study of endothelial permeability and barrier function within insulin resistance. The last group of articles discusses the effects of inflammation with obesity and insulin resistance on vascular function, and also details the role of perivascular adipose tissue in contributing to vascular dysfunction. The final review extends this general topic to the effects of the metabolic syndrome on microvascular dysfunction, wherein obesity and impaired glycemic control are contributing elements to a larger constellation of systemic pathologies. The authors hope that this Special Topics Issue will be informative for its readers and will provide a basis for future investigation into microvasculopathy in obesity and insulin-resistance.     

Inflammation, insulin resistance, and cardiovascular disease: Cause or correlate?

There is considerable interest in novel risk pathways for vascular disease. In the last decade, substantial attention has focused on inflammatory parameters, particularly C-reactive protein, but data on other inflammatory factors have also emerged. Similarly, insulin resistance has attracted considerable recent interest as a vascular risk factor pathway. This review critically appraises the evidence to support the apparent causal involvement of both pathways in vascular disease. Key recent findings are summarized and, more importantly, critical weaknesses in the arguments are highlighted. Also examined is the distinction between low-grade inflammation commonly seen in the general population and high-grade inflammation related to chronic inflammatory conditions. Finally, areas for further research are suggested to enhance the evidence base. Presently, however, the current focus in clinical practice should remain on established risk factors (eg, smoking, lipids, blood pressure) to determine and reduce coronary heart disease risk.     

Visceral obesity without insulin resistance in late-onset obesity rats

We describe a line of transgenic rats in which the males develop a unique autosomal dominant, late-onset obesity (LOB) phenotype. LOB males gradually accumulate fat specifically in visceral, but not peripheral, fat depots despite a normal intake of a low fat diet. LOB females normally develop only mild obesity with advanced age. However, the phenotype can be induced rapidly in young females by ovariectomy and prevented by estrogen replacement. LOB males are highly sensitive to dietary fat. Young, nonobese LOB males gain more weight on a 30% fat diet and lose more weight when treated with the lipase inhibitor, Orlistat, than their nontransgenic littermates. Remarkably, despite severe visceral obesity, LOB rats have normal fasting blood glucose, insulin, and corticosterone; show normal or increased insulin sensitivity in glucose and insulin tolerance tests; have increased plasma adiponectin levels; and display a heightened response to treatment with rosiglitazone. Their visceral adiposity reflects a specific increase in visceral adipocyte number, not size. Analysis of the transgene in LOB rats revealed a deletion in the gene encoding the S26 subunit of the mitochondrial ribosome that results in the production of a truncated protein, which we show to be imported into mitochondria. However, the transgene integrant is complex, so whether this is the sole molecular disruption underlying this phenotype remains to be established. Nevertheless, LOB rats provide a valuable new model of late-onset, male-preponderant, visceral-specific obesity, clearly dissociated from insulin resistance.