Enhanced insulin resistance in diet-induced obese rats exposed to fine particles by instillation

Context: Epidemiological studies indicate that diabetes is a sub-population at risk for particulate matter (PM)-associated cardiovascular disease (CVD). Recent animal studies suggested PM might impair glucose tolerance, which may lead to CVD. However, the mechanism remains unclear.

Objective: To investigate further the PM effect on insulin resistance (IR) in obese and healthy rats.

Materials and methods: Male Sprague–Dawley rats were fed with either a high fat diet (HFD) or normal chow diet (NCD) for 6 weeks. Both groups were then further assigned to receive PM₁₀, PM_2.5 or normal saline (n?=?6 per group) by intratracheal instillation (IT) once per week for 3 weeks. Fasting glucose and insulin were measured and homeostasis model assessment-insulin resistance (HOMA-IR) was used to assess IR. Biochemistry tests and lipids profile were examined at sacrifice. The markers of fibrinogen and [nitrate+nitrite], an indicator of nitric oxide (NO) production, C-reactive protein (CRP) and white blood counts (WBCs) in peripheral blood were also determined.

Results: Body weight, insulin and HOMA-IR of HFD rats were significantly increased compared with a NCD after 6 weeks. In HFD rats, PM_2.5 increased HOMA-IR after first IT and further increased HOMA-IR at the end of exposure. However, this increase was not observed in NCD rats and after PM₁₀ exposure. Increased fibrinogen was also noted after chronic PM_2.5 exposure in both HFD and NCD rats.

Discussion and conclusion: Exposure to PM_2.5 enhanced IR in HFD rats but not in NCD rats. Obese subjects with IR may be a susceptible population to particulate air pollution.     

Adipokines in inflammation, insulin resistance and cardiovascular disease

1. Obesity is a major determinant of cardiovascular disease (CVD). Studies in the past two decades have shown that adipose tissue is not merely an inert energy reserve of triglycerides, but also an active endocrine organ. 2. Adipose tissue can produce and secrete numerous bioactive peptides and/or proteins termed adipokines. These secretory factors are involved in the regulation of local and systemic inflammation and insulin sensitivity in a paracrine and/or endocrine manner. Inflammation and insulin resistance (IR) play critical roles in the obesity-linked development of CVD, such as atherosclerosis, hypertension and restenosis. 3. In the present minireview, we summarize the relationship between inflammation and IR, as well as their contribution to the development of CVD during adipose tissue dysfunction. In particular, we focus on the effects of various adipokines in pathological processes, which may provide an insight into obesity-linked CVD and facilitate the development of new therapeutic strategies.     

海地瓜海参胶对胰岛素抵抗模型小鼠慢性炎症的改善作用

目的 研究海地瓜海参胶对胰岛素抵抗模型小鼠慢性炎症的改善作用。方法 建立高脂高果糖饮食诱导胰岛素抵抗小鼠模型。雄性C57BL/6J小鼠随机分为正常对照组、模型对照组、海地瓜海参胶低剂量组（100 mg · (kg ·bw· d)-1）、海地瓜海参胶高剂量组（200 mg · (kg ·bw· d)-1）。饲喂9周后,检测小鼠空腹血糖、胰岛素、促炎因子游离脂肪酸、肿瘤坏死因子-α、白介素6及抗炎因子脂联素、白介素10水平;qRT-PCR 检测小鼠肝脏炎症因子mRNA表达水平。结果 海地瓜海参胶显著降低胰岛素抵抗模型小鼠空腹血糖、空腹胰岛素水平;显著降低血清促炎因子含量,升高抗炎因子含量;显著下调肝脏肿瘤坏死因子-α、白介素6 mRNA表达,上调脂联素、白介素10 mRNA表达。结论 海地瓜海参胶可显著改善胰岛素抵抗小鼠的慢性炎症。     

2型糖尿病脂肪肝与胰岛素抵抗的关系

目的：探讨2型糖尿病脂肪肝与胰岛素抵抗的关系。方法：对81例糖尿病并脂肪肝患者与80例未合并脂肪肝患者的血糖， 脂，胰岛素进行测定，计算胰岛素敏感指数（IAI），体重指数（BMI）并进行分析比较，结果：2型尿病并脂肪肝时IAI显著降低，而餐后2小时血糖，甘油三酯，空腹胰岛素，体重指数均显著高于对照组。结论：2型糖尿病人脂肪肝的发生与胰岛素抵抗关系密切，提示改善胰岛素抵抗对糖尿病脂肪肝病人具有重要意义。     

非酒精性脂肪性肝病病人血清长链非编码NTF3-5水平与胰岛素抵抗的关系

目的 探讨长链非编码NTF3-5(Lnc-NTF3-5)在非酒精性脂肪性肝病（NAFLD）病人血清中的表达情况,并分析其与胰岛素抵抗的关系。方法 选取2019年12月至2020年12月来武汉市蔡甸区人民医院就诊并确诊为NAFLD病人115例为NAFLD组,根据疾病严重程度分为重度组（33例）,中度组（40例）,轻度组（42例）。同时选取55例健康者为健康对照组。收集一般资料,分别检测两组血清总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、谷氨酰基转移酶（GGT）、碱性磷酸酶（ALP）,空腹血胰岛素（FINS）,血糖（FPG）水平,根据FINS、FPG计算稳态模型胰岛素抵抗指数（HOMA-IR）及胰岛β细胞功能指数（HOMA-β）;采用实时荧光定量PCR法对血清中Lnc-NTF3-5表达水平进行检测,Pearson法分析Lnc-NTF3-5表达水平与上述肝功能指标和糖脂代谢指标的相关性;受试者操作特征（ROC）曲线评价血清Lnc-NTF3-5、HOMA-IR对NAFLD发生的...     

Milk Thistle Extract and Silymarin Inhibit Lipopolysaccharide Induced Lamellar Separation of Hoof Explants in Vitro

The pathogenesis of laminitis is not completely identified and the role of endotoxins (lipopolysaccharides, LPS) in this process remains unclear. Phytogenic substances, like milk thistle (MT) and silymarin, are known for their anti-inflammatory and antioxidant properties and might therefore have the potential to counteract endotoxin induced effects on the hoof lamellar tissue. The aim of our study was to investigate the influence of endotoxins on lamellar tissue integrity and to test if MT and silymarin are capable of inhibiting LPS-induced effects in an in vitro/ex vivo model. In preliminary tests, LPS neutralization efficiency of these phytogenics was determined in an in vitro neutralization assay. Furthermore, tissue explants gained from hooves of slaughter horses were tested for lamellar separation after incubation with different concentrations of LPS. By combined incubation of explants with LPS and either Polymyxin B (PMB; positive control), MT or silymarin, the influence of these substances on LPS-induced effects was assessed. In the in vitro neutralization assay, MT and silymarin reduced LPS concentrations by 64% and 75%, respectively, in comparison PMB reduced 98% of the LPS concentration. In hoof explants, LPS led to a concentration dependent separation. Accordantly, separation force was significantly decreased by 10 µg/mL LPS. PMB, MT and silymarin could significantly improve tissue integrity of explants incubated with 10 µg/mL LPS. This study showed that LPS had a negative influence on the structure of hoof explants in vitro. MT and silymarin reduced endotoxin activity and inhibited LPS-induced effects on the lamellar tissue. Hence, MT and silymarin might be used to support the prevention of laminitis and should be further evaluated for this application.     

非酒精性脂肪肝患者肝损害程度与代谢综合征各组分的关系

目的 探讨非酒精性脂肪肝（NAFLD）患者不同肝损害程度与代谢综合征（MS）各组分之间的关系.方法 1151例NAFLD患者以及年龄、性别相匹配的4113例健康对照人群均来自我院体检中心.所有研究对象均进行身高、体重、血压、血脂、血糖、肝炎系列等指标的检测,空腹行腹部彩超检查.分析并比较检测的各项结果.结果 1151例超声诊断NAFLD患者中轻度767例,中度345例,重度39例,MS检出例数分别为218、144和20例,检出率分别为28.4%、41.7%和51.3%,显著高于健康对照组（7.8%）,且随超声诊断脂肪肝的严重程度逐渐递增（P＜0.01）;ALT正常者905例,升高者246例,其中血脂紊乱、超重或肥胖和MS的检出率分别为54.6%、66.6%、31.9%和71.5%、82.5%、37.8%,均显著高于健康对照组（24.3%、32.4%和7.7%）,且随ALT升高而逐渐递增（P＜0.05）.但NAFLD组高血压、高血糖检出率与健康对照组相比差异无统计学意义（P＞0.05）.结论 NFALD患者肝损害程度与代谢综合征各组分关系密切,尤其与肥胖、血脂紊乱密切相关,因此,应重视NAFLD患者的调脂减肥治疗.     

Lung fibrosis induced by crystalline silica particles is uncoupled from lung inflammation in NMRI mice

Previous studies in rats have suggested a causal relationship between progressive pulmonary inflammation and lung fibrosis induced by crystalline silica particles. We report here that, in NMRI mice, the lung response to silica particles is accompanied by a mild and non progressive pulmonary inflammation which is dispensable for the development of lung fibrosis. We found that glucocorticoid (dexamethasone) dramatically reduced lung injury, cellular inflammation and pro-inflammatory cytokine expression (TNF-α, IL-1β and KC) but had no significant effect on silica-induced lung fibrosis and expression of the fibrogenic and suppressive cytokines TGF-β and IL-10 in mice. Other anti-inflammatory molecules such as the COX inhibitor piroxicam or the phosphodiesterase 5 inhibitor sildenafil also reduced lung inflammation without modifying collagen, TGF-β or IL-10 lung content. Our findings indicate that the development of lung fibrosis in silica-treated NMRI mice is not driven by inflammatory lung responses and suggest that suppressive cytokines may represent critical fibrotic factors and potential therapeutic targets in silicosis.     

2型糖尿病合并非酒精性脂肪肝与胰岛素抵抗及血脂紊乱关系研究

目的探讨2型糖尿病（T2DM）合并非酒精性脂肪肝（NAFLD）与胰岛素抵抗（IR）、血脂紊乱的关系。方法对38例T2DM合并NAFLD患者进行血脂、血糖、血压、空腹及餐后2h血浆胰岛素（Fins、2hlns）的测定，计算胰岛素抵抗指数（HOMA．IR）、体重指数（BMI）、腰臀比（WHR），并与34例非脂肪肝糖尿病患者作比较。结果脂肪肝组甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）、Fins、2hlns、HOMA．IR、BMI、WHR、ALT、γ-谷氨酰转肽酶、尿酸、舒张压的平均水平均较非脂肪肝组明显升高（P〈0．05～0．01），高密度脂蛋白胆固醇水平明显降低（P〈0．05）。两组血糖、糖化血红蛋白水平差异无统计学意义（P〉0．05）。结论T2DM合并NAFLD较未并发脂肪肝患者存在明显的IR、脂质代谢异常及肥胖，提示IR在脂肪肝的发病中具有十分重要的地位；NAFLD可能是代谢综合征的一个组成部分。     

Partial liver resection and inflammation: Role of endogenous glucocorticoids

The early local exudative cellular reaction in an inflammatory lesion (pleurisy) was impaired in partially hepatectomized rats, 5 days postoperatively, whereas splenectomized and sham-operated controls exhibited normal responses. Changes in total plasma protein concentration, prothrombin time and blood glucose levels were not observed in these animals. In contrast, enhanced levels of circulating corticosterone were consistently found in rats undergoing liver resection. This was accompanied by the characteristic eosinopenia evoked by increased concentrations of circulating glucocorticoids. Treatment of hepatectomized animals with metyrapone to block synthesis of glucocorticoids without causing a typical deficiency of mineralocorticoids, resulted in the reversal of previously inhibited inflammatory reactions. Complete recovery of the animals was observed 20 days postoperatively, when 85% of liver tissue was regenerated. It is suggested that liver resection might impair the metabolic capacity of the animals leading to increased levels of circulating glucocorticoids that, in turn, could interfere with the development of inflammatory responses.     

Obese mice are resistant to eosinophilic airway inflammation induced by diesel exhaust particles

Particulate matter can exacerbate respiratory diseases such as asthma. Diesel exhaust particles are the substantial portion of ambient particulate matter with a <2.5 µm diameter in urban areas. Epidemiological data indicate increased respiratory health effects of particulate matter in obese individuals; however, the association between obesity and diesel exhaust particle‐induced airway inflammation remains unclear. We aimed to investigate the differences in susceptibility to airway inflammation induced by exposure to diesel exhaust particles between obese mice (db/db) and lean mice (db/+m). Female db/db and db/+m mice were intratracheally administered diesel exhaust particles or vehicle every 2 weeks for a total of seven times. The cellular profile of bronchoalveolar lavage fluid and histological changes in the lungs were assessed and the lungs and serum were analyzed for the generation of cytokines, chemokines and soluble intercellular adhesion molecule 1. Diesel exhaust particle exposure‐induced eosinophilic infiltration in db/+m mice accompanied by T‐helper 2 cytokine, chemokine and soluble intercellular adhesion molecule 1 expression in the lungs. In contrast, it induced mild neutrophilic airway inflammation accompanied by elevated cytokines and chemokines in db/db mice. The lungs of db/db mice exhibited decreased expression of eosinophil activators/chemoattractants such as interleukin‐5, interleukin‐13 and eotaxin compared with those of db/+m mice. In addition, serum eotaxin and monocyte chemotactic protein‐1 levels were significantly higher in db/db mice than in db/+m mice. In conclusion, obesity can affect susceptibility to diesel exhaust particle‐induced airway inflammation, which is possibly due to differences in local and systemic inflammatory responses between lean and obese individuals. Copyright © 2013 John Wiley & Sons, Ltd.     

Silymarin alleviates bleomycin-induced pulmonary toxicity and lipid peroxidation in mice

Context: The application of bleomycin is limited due to its side effects including lung toxicity. Silymarin is a flavonoid complex isolated from milk thistle [Silybum marianum L. (Asteraceae)] which has been identified as an antioxidant and anti-inflammatory compound.

Objective: This study evaluates the effect of silymarin on oxidative and inflammatory parameters in the lungs of mice exposed to bleomycin.

Materials and methods: BALB/c mice were divided into four groups of control, bleomycin (1.5?U/kg), bleomycin plus silymarin (50 and 100?mg/kg). After bleomycin administration, mice received 10?d intraperitoneal silymarin treatment. On 10th day, blood and lung samples were collected for measurement of oxidative and inflammatory factors.

Results: Silymarin led to a decrease in lung lipid peroxidation (0.19 and 0.17?nmol/mg protein) in bleomycin-injected animals. Glutathione-S-transferase (GST) which was inhibited by bleomycin (32.4?nmol/min/mg protein) induced by higher dose of silymarin (41?nmol/min/mg protein). Silymarin caused an elevation in glutathione (GSH): 2.6 and 3.1?µmol/g lung compare with bleomycin-injected animals 1.8?µmol/g lung. Catalase (CAT) was increased due to high dose of silymarin (65.7?µmol/min/ml protein) compare with bleomycin treated-mice. Myeloperoxidase (MPO) which was induced due to bleomycin (p?p?Conclusions: Silymarin attenuated bleomycin induced-pulmonary toxicity. This protective effect may be due to the ability of silymarin in keeping oxidant–antioxidant balance and regulating of inflammatory mediator release.     

Curcumin decreases oxidative stress in mitochondria isolated from liver and kidneys of high-fat diet-induced obese mice

Oxidative stress plays a key role in obesity and diabetes-related mitochondrial dysfunction. Mitochondrial dysfunction is characterized by increased oxidative damage, nitric oxide (NO) synthesis, and a reduced ratio of adenosine-5'-triphosphate (ATP) production/oxygen consumption. Curcumin represents a potential antioxidant and anti-inflammatory agent. In this study, our objective was to determine the effect of curcumin treatment on oxidative stress and mitochondrial dysfunction in high-fat diet (HFD)-induced obese mice (OM). These results suggest that curcumin treatment increased oxygen consumption and significantly decreased lipid and protein oxidation levels in liver mitochondria isolated from HFD-induced OM compared with those in the untreated OM (UOM). In kidney mitochondria, curcumin treatment significantly increased oxygen consumption and decreased lipid and protein peroxidation levels in HFD-induced OM when compared with those in UOM. Curcumin treatment neither has any effect on body weight gain nor have any effects on mitochondrial NO synthesis. These findings suggest that obesity induces oxidative stress and mitochondrial dysfunction, whereas curcumin may have a protective role against obesity-induced oxidative stress and mitochondrial dysfunction.     

Pioglitazone improves lipid and insulin levels in overweight rats on a high cholesterol and fructose diet by decreasing hepatic inflammation

Background and purpose:

Nutrient overload leads to obesity and insulin resistance. Pioglitazone, a selective peroxisome proliferator-activated receptor (PPAR)γ agonist, is currently used to manage insulin resistance, but the specific molecular mechanisms activated by PPARγ are not yet fully understood. Recent studies suggest the involvement of suppressor of cytokine signalling (SOCS)-3 in the pathogenesis of insulin resistance. This study aimed to investigate the hepatic signalling pathway activated by PPARγ activation in a non-genetic insulin-resistant animal model.

Experimental approach:

Male Wistar rats were maintained on a high-cholesterol fructose (HCF) diet for 15 weeks. Pioglitazone (3 mg·kg⁻¹) was administered orally for the last 4 weeks of this diet. At the end of the treatment, serum was collected for biochemical analysis. Levels of PPARγ, SOCS-3, pro-inflammatory markers, insulin receptor substrate-2 and Akt/glycogen synthase kinase-3β phosphorylation were assesed in rat liver.

Key results:

Rats fed the HCF diet exhibited hyperlipidemia, hyperinsulinemia, impaired glucose tolerance and insulin resistance. Pioglitazone administration evoked a significant improvement in lipid metabolism and insulin responsiveness. This was accompanied by reduced hepatic expression of SOCS-3, interleukin-6, tumour necrosis factor-α and markers of neutrophil infiltration. Diet-induced PPARγ expression was unaffected by the pioglitazone treatment.

Conclusion and implications:

Chronic pioglitazone administration reduced hepatic inflammatory responses in rats fed a HCF diet. These effects were associated with changes in hepatic expression of SOCS-3, which may be a crucial link between the reduced local inflammation and the improved insulin signalling.This article is commented on by Chatterjee, pp. 1889–1891 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00739.x     

脂肪肝患者血清脂联素与胰岛素抵抗的相关性分析

目的探讨脂肪肝患者血清脂联素与胰岛素抵抗的关系。方法选择B超诊断为脂肪肝的患者132例与健康体检者157例,对体重指数(BMI)、腰臀比(WHR)、空腹血糖(FBG)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL)、低密度脂蛋白胆固醇(LDL)、空腹胰岛素(FINS)及血清脂联素水平进行检测,计算胰岛素抵抗指数(HOMA-IR)并进行对照分析。结果与对照组相比,脂肪肝组FBG、TC、LDL水平升高(P<0.05),BMI、WHR、TG、FINS水平及HOMA-IR明显升高(P<0.01),而血清脂联素水平明显下降(P<0.01)。应用Spearman等级相关分析研究显示脂联素与HDL呈正相关(r值为 0.36,P<0.05),与BMI、WHR、TG、HOMA-IR、LDL呈负相关(r值分别为-0.31、-0.27、-0.40、-0.79、-0.57,P<0.05)。结论脂肪肝患者存在胰岛素抵抗,而血清脂联素水平与胰岛素抵抗密切相关。