胰岛素抵抗小鼠脂肪组织肿瘤坏死因子α和脂联素mRNA表达与有氧运动的影响**★

背景：有研究表明有氧运动可通过调节脂肪组织过氧化物酶体激活物增殖受体γ及其相关脂肪因子进而影响胰岛素敏感性，但其影响结果及作用机制至今少有报道。 目的：观察有氧运动后，胰岛素抵抗C57BL/6小鼠脂肪组织过氧化物酶体激活物增殖受体γ、肿瘤坏死因子α和脂联素 mRNA及蛋白表达水平的变化，分析有氧运动对胰岛素抵抗小鼠影响的作用机制。 方法：C57BL /6 小鼠经高脂饮食喂养10周后建立胰岛素抵抗动物模型，建模后将小鼠随机分为安静组与运动组。运动组进行为期6周，75% VO2max强度跑台运动；安静组同等条件下饲养不运动。使用RT-PCR 和Western blot法检测两组脂肪组织过氧化物酶体激活物增殖受体γ，脂联素、肿瘤坏死因子α mRNA和蛋白表达。 结果与结论：6周有氧跑台运动对小鼠脂肪组织过氧化物酶体激活物增殖受体γ表达差异无显著性意义(P > 0.05)，但可显著增加小鼠脂肪组织脂联素的表达(P < 0.01)，降低肿瘤坏死因子α的表达(P < 0.05)；并且可显著降低血液中三酰甘油、游离脂肪酸水平(P < 0.05, P < 0.01)。结果提示有氧运动可能通过调节过氧化物酶体激活物增殖受体γ相关脂肪因子-脂联素和肿瘤坏死因子α的表达来间接调节脂肪组织对胰岛素的敏感性。有氧运动可以显著增加机体组织对胰岛素的敏感性，从而改善C57BL/6 小鼠胰岛素抵抗的症状。     

神经血管单元及其在脑内胰岛素抵抗中的作用

神经血管单元作为神经活动与脑血流之间的耦合,是构成血脑屏障(BBB)的核心结构,对维持中枢神经系统内环境的稳定具有重要意义。外周胰岛素可经BBB进入脑内发挥多种中枢性作用。脑内胰岛素抵抗表现为脑细胞对胰岛素的敏感性下降,是阿尔茨海默病(AD)的主要发病机制之一。神经血管单元中任一细胞结构的胰岛素受体缺失均可能参与脑内胰岛素抵抗的形成。考虑到神经血管单元的重要性及其与脑内胰岛素的关系,该文综述了神经血管单元的主要细胞构成和功能,包括内皮细胞、周细胞、星形胶质细胞和神经元,以及这些特定细胞的胰岛素信号失调在脑内胰岛素抵抗中的作用。     

胰岛素抵抗、血脂异常与急性脑梗死关系的初步研究

目的探讨胰岛素抵抗、血脂异常与急性脑梗死之间的关系.方法对45例急性脑梗死患者作空腹血糖(FPG)、血清胰岛素(FINS)及血脂测定,并与25例原发性高血压(EH)患者及25例健康体检者比较.采用李光伟提出的方法计算胰岛素敏感性指数(ISI)为空腹血清胰岛素与空腹血糖乘积的倒数,即1/(FINS×FPG),取其自然对数.结果急性脑梗死患者FINS明显高于两对照组(P＜0.01);胰岛素敏感性指数明显低于两健康对照组(P＜0.01);TG、CHOL、apoB明显高于健康对照组(P＜0.01),HDL明显低于对照组(P＜0.01).FPG、LDL及apoA1三组间无明显差异.结论急性脑梗死存在胰岛素抵抗,胰岛素抵抗和血脂异常可能在脑梗死的发生中起重要作用.胰岛素抵抗在脑梗死中的重要作用有待于进一步深入研究.     

颅脑损伤与胰岛素抵抗

胰岛素抵抗是指组织对胰岛素作用不敏感。颅脑损伤患者常可发生一系列代谢紊乱,其中一个显著的特征是胰岛素抵抗。颅脑损伤后胰岛素抵抗的发病机制尚未阐明,主要与血液循环中胰岛素拮抗物的存在及靶组织缺陷有关。颅脑损伤后发生严重的胰岛素抵抗可使机体供能减少,高血糖持续存在,影响颅脑损伤患者的预后。因此胰岛素抵抗的评估对临床医师判断患者的代谢状况、正确地选择有效的治疗方案起重要作用。采取有效措施降低患者胰岛素抵抗将有利于颅脑损伤患者恢复。     

2型糖尿病中国地鼠模型构建与小檗碱对肝脏过氧化物酶体增殖体激活受体及其靶基因表达的影响

背景：研究表明小檗碱可用于治疗2型糖尿病,但小檗碱治疗糖尿病胰岛素抵抗尤其是肝脏脂诱性胰岛素抵抗的分子机制仍不明确。 目的：观察小檗碱对2型糖尿病中国地鼠模型肝脏过氧化物酶体增殖体激活受体及其靶基因表达的影响。 方法：以高脂饮食及结合小剂量链脲菌素的方法建立胰岛素抵抗和2型糖尿病中国地鼠模型。建模后随机分成4组：对照组给予普通饮食,胰岛素抵抗组给予高脂饮食,2型糖尿病组给予高脂饮食+小剂量链脲菌素,2型糖尿病小檗碱治疗组给予高脂饮食+小剂量链脲菌素+小檗碱,治疗9周。 结果与结论：实时定量PCR结果显示与对照组相比,胰岛素抵抗及2型糖尿病组地鼠肝脏过氧化物酶体增殖体激活受体α,β/d,酰基辅酶A氧化酶,肉碱棕榈酰转移酶1和中链酰基辅酶A脱氢酶的表达降低(P < 0.05),而固醇调节元件结合蛋白1c,2,过氧化物酶体增殖体激活受体γ,脂蛋白脂酶,脂肪酸转运者(FAT/CD36)和脂肪酸结合蛋白(ap2)的表达增加(P < 0.05)。结果证实,小檗碱可改善胰岛素抵抗,并逆转了氧化物酶体增殖体激活的受体及其靶基因表达的改变,小檗碱治疗2型糖尿病地鼠脂诱性胰岛素抵抗的分子机制与氧化物酶体增殖体激活的受体及其靶基因表达的改变相关。     

胰岛素及胰岛素抵抗与阿尔茨海默病

胰岛素在中枢神经系统的代谢、调节作用与阿尔茨海默病(AD)发病的关系日益受到重视,胰岛素抵抗(IR)对阿尔茨海默病发病的影响成为研究的热点.其主要机制为胰岛素抵抗促进tau蛋白磷酸化和加重邮Aβ的神经毒性作用,此过程与脑部胰岛素、胰岛素样生长因子所介导的信号系统紊乱有关,胰岛素信号转导在调节和控制神经细胞能量代谢中起着关键作用.随着对胰岛素及胰岛素抵抗与阿尔茨海默病关系的研究深入,希望能对阿尔茨海默病提供更好的预防和治疗措施.     

2型糖尿病增加帕金森病风险相关机制研究进展

2型糖尿病与帕金森病的发生发展密切相关,其中高血糖导致的神经毒性和脑组织胰岛素抵抗发挥重要作用,但具体机制尚不明确。慢性血糖升高可能通过促进氧化应激、神经炎症、晚期糖基化终末产物和内源性神经毒素形成,导致黑质多巴胺能神经元损伤,而胰岛素抵抗通过多种途径参与其中。本文对2型糖尿病增加帕金森病风险的作用机制进行综述,为2型糖尿病患者的帕金森病预防与治疗提供指导。     

脑卒中患者胰岛素抵抗的初步研究

目的 探讨脑梗死、脑出血患者与胰岛素抵抗的相关性。方法 对16例脑梗死、11例脑出血及15例对照组者的空腹血糖、血胰岛素、C-肽和胰岛素敏感性指数的测值进行比较和分析。结果 脑梗死组所测空腹血胰岛素(16.82±8.32μIU/ml)、C-肽(2.44+1.13ng/ml)显著高于对照组(8.89±6.84μIU/ml,1.59±0.96ng/ml)(P<0.05),胰岛素敏感性指数(-4.43±0.57)显著低于对照组(-3.67±0.69)(P<0.01);脑出血组的空腹血胰岛素(21.47±16.27μIU/ml)、C-肽(2.51±0.87ng/ml)和胰岛素敏感性指数(-4.57+0.70)与对照组相比有显著性差异(P<0.05,P<0.01);脑梗死组和脑出血组之间的空腹血糖、血胰岛素、C-肽、胰岛素敏感性指数无显著性差异(P>0.05)。结论 胰岛素抵抗在脑梗死和脑出血的急性期有重要作用,是脑卒中的危险因素。     

人肝癌细胞胰岛素抵抗模型建立及有效中药成分的筛选

背景：目前,复方中药、单味中药在体内降糖作用及其降糖机制研究较多,但体外尤其是中药单体成分对胰岛素抵抗细胞有何影响尚不清楚。 目的：体外建立人肝癌细胞(HepG2)胰岛素抵抗模型,并初步筛选可有效改善胰岛素抵抗的中药有效成分。 方法：用不同浓度的胰岛素对HepG2细胞进行不同时间的诱导,通过MTT法对细胞活性评价及葡萄糖氧化酶法对HepG2细胞葡萄糖消耗量测定,明确建立稳定的HepG2胰岛素抵抗模型的胰岛素诱导浓度及诱导时间。模型建立后,应用不同浓度的齐墩果酸、药根碱、阿魏酸、大黄酸、马钱苷、葛根素、大豆苷分别作用于胰岛素抵抗细胞24 h,用葡萄糖氧化酶法分别观察不同浓度的上述中药成分对胰岛素抵抗模型HepG2细胞葡萄糖消耗的影响,MTT法对各组细胞活性进行评价。 结果与结论：HepG2细胞在10-6 mol/L浓度的胰岛素中作用24 h,葡萄糖消耗量明显减少(P < 0.01),说明实验成功诱导出稳定人肝癌细胞胰岛素抵抗模型。10-5 mol/L浓度胰岛素组的胰岛素抵抗更明显(P < 0.01)。各时间点10-5 mol/L浓度胰岛素作用的细胞成活率逐渐降低,死亡细胞增多(P < 0.05)。齐墩果酸、药根碱、阿魏酸、大黄酸、马钱苷、葛根素、大豆苷均有改善细胞胰岛素抵抗的作用。其中,质量浓度2×10-1 g/L药根碱、大黄酸、葛根素和齐墩果酸,2×10-5 g/L马钱苷和阿魏酸对改善人肝癌细胞胰岛素抵抗效果较好(P < 0.01)。     

干细胞、运动疗法与糖尿病防治的相关性

干细胞是一类具有自我复制能力的多潜能细胞,在一定条件下可以定向分化成为机体内的功能细胞,形成多种类型组织和器官以代替损伤和坏死的相关组织,从而达到治疗疾病的目的。胰岛干细胞和骨髓干细胞对糖尿病的防治具有重要的作用,胰岛干细胞可以通过移植、诱导等识别其特异分子标志,从中筛选胰岛素分泌细胞调整胰岛素的分泌量,但对其研究的机制仍存在较多不足;而骨髓干细胞可以通过直接的转分化和间接分化、移植诱导微嵌合状态,形成免疫耐受、细胞融合以及参与细胞的修复和再生等方式治疗糖尿病患者。运动疗法对于2型糖尿病患者来说,具有药物所不可替代的重要治疗作用,运动疗法能够通过降低血糖、改善肥胖和胰岛素抵抗,调节自身免疫能力,推迟或避免糖尿病并发症的发生,但目前有关运动疗法对影响糖尿病患者干细胞尤其是影响移植效果方面的实验研究仍是一项空白。     

Relationship of muscle sympathetic nerve activity to insulin sensitivity

Purpose

An association between insulin resistance and activation of the sympathetic nervous system has been reported in previous studies. However, potential interactions between insulin sensitivity and sympathetic neural mechanisms in healthy people remain poorly understood. We conducted a study to determine the relationship between sympathetic activity and insulin resistance in young, healthy humans.

Methods

Thirty-seven healthy adults (18–35 years, BMI <28 kg m^?2) were studied. Resting muscle sympathetic nerve activity (MSNA) was measured with microneurography and insulin sensitivity of glucose and free fatty acid metabolism was measured during a hyperinsulinemic-euglycemic clamp with two levels of insulin.

Results

During lower doses of insulin, we found a small association between lower insulin sensitivity and higher MSNA (P < 0.05) but age was a cofactor in this relationship. Overall, we found no difference in insulin sensitivity between groups of low and high MSNA, but when women were analyzed separately, insulin sensitivity was lower in the high MSNA group compared with the low MSNA group of women.

Conclusions

These data suggest that MSNA and insulin sensitivity are only weakly associated with young healthy individuals and that age and sex may be important modifiers of this relationship.     

Long-term central infusion of adiponectin improves energy and glucose homeostasis by decreasing fat storage and suppressing hepatic gluconeogenesis without changing food intake

Adiponectin is known to be an anti-diabetic adipocytokine. However, the action mechanism by which it produces this effect remains controversial. In the present study, we investigated the long-term central effect of adiponectin on energy homeostasis, peripheral insulin resistance, β-cell function and mass in rats and aimed to determine the mechanism by which its effect was achieved. Intracerebroventricular infusion of adiponectin (50 ng/h) and artificial cerebrospinal fluid (CSF) was conducted by means of an osmotic pump for 4 weeks on nondiabetic rats and 90% pancreatectomised diabetic rats that were both fed 45% energy fat diets. After 4-weeks of treatment, i.c.v. adiponectin improved hypothalamic insulin/leptin signalling in nondiabetic and diabetic rats compared to i.c.v. CSF but it did not change the phosphorylation of AMP kinase (AMPK) in the hypothalamus. Adiponectin infusion decreased epididymal fats, representing visceral fat, by increasing energy expenditure and fat oxidation. During the euglycaemic hyperinsulinaemic clamp, i.c.v. adiponectin improved whole body insulin sensitivity and decreased hepatic glucose output in the hyperinsulinaemic state by attenuating hepatic insulin resistance. Central infusion of adiponectin did not modulate glucose-stimulated insulin secretion during the hyperglycaemic clamp compared to i.c.v. CSF infusion but it enhanced insulin sensitivity at a hyperglycaemic state. Although there were no changes in insulin secretion capacity, central adiponectin increased pancreatic β-cell mass in nondiabetic and diabetic rats as a result of decreasing β-cell death. In conclusion, long-term central infusion of adiponectin enhanced energy homeostasis by increasing energy expenditure via activating hypothalamic leptin and insulin signalling pathways but without potentiating AMPK signalling; it also improved glucose homeostasis by attenuating insulin resistance.     

Long-term exercise down-regulates leptin receptor mRNA in the arcuate nucleus

The purpose of this study was to investigate the effects of exercise on blood leptin concentrations and expression of leptin receptor subtype-b (Ob-Rb) mRNA in the arcuate nucleus of hypothalamus (ARC). Male Wistar rats (26 weeks old) underwent regular wheel exercise for 12 weeks. The expression of Ob-Rb mRNA in the ARC decreased at the end of the study period despite reductions of abdominal fat-pad weight and serum leptin concentration. Serum 1,5-anhydroglucitol levels were higher in exercising rats, suggesting lower serum insulin levels in exercising rats. Our results suggested that 12-week wheel exercise reduced the expression of Ob-Rb mRNA in the ARC probably through improvement in insulin resistance.     

Insulin resistance in cognitive impairment: the InCHIANTI study

OBJECTIVE: To test the association between cognitive impairment, with and without subcortical features, and insulin resistance in an elderly community-dwelling population. DESIGN: Cross-sectional wave of an epidemiologic longitudinal study (InCHIANTI). PARTICIPANTS: A total of 523 people, aged 70 to 90 years without diabetes mellitus or hyperglycemia, from the InCHIANTI cohort were included in the study. A total of 119 individuals had cognitive impairment (Mini-Mental State Examination [MMSE] score < 25), 21 of whom had both cognitive impairment and subcortical features (CI/SF+ group). Control groups contained 23 individuals with a history of stroke and 381 individuals with no cognitive impairment (no CI group, MMSE score > or = 25). Indicators of insulin resistance were the fasting plasma insulin level, insulin resistance index (Homeostasis Model Assessment of Insulin Resistance [HOMA-IR]), and insulin sensitivity index (Quantitative Insulin Sensitivity Check Index [QUICKI]). RESULTS: The insulin resistance profile of patients in the CI/SF+ group was similar to that of individuals who had experienced stroke, whereas the profile of individuals with cognitive impairment without subcortical features (CI/SF- group) was similar to that of individuals in the no CI group. Patients in the CI/SF- group showed insulin resistance comparable to individuals in the no CI group (age-adjusted P = .27, .19, and .64, respectively, for difference in fasting blood insulin level, HOMA-IR, and QUICKI in linear regression models) and lower than patients with stroke (age-adjusted P = .01, .02, and .07, respectively). On the contrary, patients in the CI/SF+ group had insulin resistance and sensitivity values similar to those of the stroke group (age-adjusted P = .80, .84, and .75, respectively, for difference in fasting blood insulin level, HOMA-IR, and QUICKI) but significantly different from those in the no CI group (age-adjusted P = .01, .03, and .02, respectively). CONCLUSIONS: Cognitive impairment with but not without subcortical features is associated with biochemical and clinical features of insulin resistance syndrome. In epidemiologic populations, insulin resistance might contribute to cognitive impairment through a vascular mechanism.     

Metabolic risk during antipsychotic treatment in patients with schizophrenia

Compared with the general population, persons with schizophrenia are characterized with an increased prevalence of obesity, type 2 diabetes mellitus, and cardiovascular disease. Weight gain and increased adiposity is associated with decreases in insulin sensitivity, leading to an increased risk of hyperglycaemia and hyperlipidemia. Antipsychotic drugs can increase adiposity and the range of trials suggests that treatment with antipsychotic medications may be associated with an increased risk of acute (ketoacidosis), subacute (weight gain, glucose intolerance, insulin resistance, dyslipidemia), and chronic (diabetes, hypertension, coronary heart disease) metabolic complications. Conclusions regarding the relative effects of various antipsychotic agents on different components of the metabolic syndrome were reviewed, as well as recommendations for monitoring these effects were noted. Selection and management of the antipsychotic agent reflects a balance between optimizing therapeutic effectiveness, modifying diet and exercise, and avoiding excessive weight gain, dyslipidemia, and insulin resistance.     

Tumour necrosis factor α induces neuroinflammation and insulin resistance in immortalised hypothalamic neurones through independent pathways

The links between obesity, inflammation and insulin resistance, which are all key characteristics of type 2 diabetes mellitus, are yet to be delineated in the brain. One of the key neuroinflammatory proteins detected in the hypothalamus with over‐nutrition is tumour necrosis factor (TNF)α. Using immortalised embryonic rat and mouse hypothalamic cell lines (rHypoE‐7 and mHypoE‐46) that express orexigenic neuropeptide Y and agouti‐related peptide, we investigated changes in insulin signalling and inflammatory gene marker mRNA expression after TNFα exposure. A quantitative polymerase chain reaction array of 84 inflammatory markers (cytokines, chemokines and receptors) demonstrated an increase in the expression of multiple genes encoding inflammatory markers upon exposure to 100 ng mL^‐1 TNFα for 4 hours. Furthermore, neurones pre‐exposed to TNFα (50 ng mL^‐1) for 6 or 16 hours exhibited a significant reduction in phosphorylated Akt compared to control after insulin treatment, indicating the attenuation of insulin signalling. mRNA expression of insulin signalling‐related genes was also decreased with exposure to TNFα. TNFα significantly increased mRNA expression of IκBα, Tnfrsf1a and IL6 at 4 and 24 hours, activating a pro‐inflammatory state. An inhibitor study using an inhibitor of nuclear factor kappa B kinase subunit β (IKK‐β) inhibitor, PS1145, demonstrated that TNFα‐induced neuroinflammatory marker expression occurs through the IKK‐β/nuclear factor‐kappa B pathway, whereas oleate, a monounsaturated fatty acid, had no effect on inflammatory markers. To test the efficacy of anti‐inflammatory treatment to reverse insulin resistance, neurones were treated with TNFα and PS1145, which did not significantly restore the TNFα‐induced changes in cellular insulin sensitivity, indicating that an alternative pathway may be involved. In conclusion, exposure to the inflammatory cytokine TNFα causes cellular insulin resistance and inflammation marker expression in the rHypoE‐7 and mHypoE‐46 neurones, consistent with effects seen with TNFα in peripheral tissues. It also mimics insulin‐ and palmitate‐induced insulin resistance in hypothalamic neurones. The present study provides further evidence that altered central energy metabolism may be caused by obesity‐induced cytokine expression.     

Eating attitudes and glucose tolerance in anorexia nervosa patients at 8-year followup compared to control subjects

This study analyzed eating attitudes and plasma glucose, insulin, unesterified fatty acid (FFA), human growth hormone (GH), and cortisol responses to an oral (100 g) glucose load in 26 female anorexia nervosa patients at an 8-year outcome evaluation in comparison to 14 age-matched female control subjects. Recovered patients who were of normal body weight and had cyclical menstruation (n = 19) showed glucose tolerance curves and insulin, cortisol, and GH responses that were indistinguishable from those of normal subjects, although patients tended to be more diet-conscious than controls and showed elevated fasting FFA levels. Two of 19 recovered patients met criteria for impaired glucose tolerance. Nonrecovered patients (n = 7) showed abnormal eating attitudes at an average underweight of 20% with persistent amenorrhea or oligomenorrhea. They had high fasting FFA plasma levels, significantly greater than normal rises in plasma glucose, a significant delay in serum insulin secretion, higher mean glucose levels before and after controlling for amount of exercise, and paradoxical release of GH. One of seven patients met criteria for diabetes mellitus and two of seven had impaired glucose tolerance. The findings suggest that fasting plasma FFA levels may reflect patients' eating and exercise habits more accurately than their verbal or written reports.     

Valproate therapy and nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease was defined recently as another symptom of insulin resistance. Continuous therapy with valproate can result in increased body weight and insulin resistance, but no data are yet available on a possible relationship between valproate and nonalcoholic fatty liver disease. We here demonstrate in abdominal ultrasound investigations that characteristics of fatty liver disease were present in 61% of valproate-treated patients as compared with 23% receiving carbamazepine therapy.     

White adipose tissue: getting nervous

Neuroendocrine research has altered the traditional perspective of white adipose tissue (WAT) as a passive store of triglycerides. In addition to fatty acids, WAT produces many hormones and can therefore be designated as a traditional endocrine gland actively participating in the integrative physiology of fuel and energy metabolism, eating behaviour and the regulation of hormone secretion and sensitivity. WAT is controlled by humoral factors, para- and intracrine factors and by neural regulation. Sympathetic nerve fibres innervate WAT and stimulate lipolysis, leading to the release of glycerol and free fatty acids. In addition, recent research in rats has clearly shown a functional parasympathetic innervation of WAT. There appears to be a distinct somatotopy within the parasympathetic nuclei: separate sets of autonomic neurones in the brain stem innervate either the visceral or the subcutaneous fat compartment. We therefore propose that the central nervous system (CNS) plays a major role in the hitherto unexplained regulation of body fat distribution. Parasympathectomy induces insulin resistance with respect to glucose and fatty acid uptake in the innervated fat depot and has selective effects on local hormone synthesis. Thus, the CNS is involved not only in the regulation of hormone production by WAT, but also in its hormone sensitivity. The developments in this research area are likely to increase our insights in the pathogenesis of metabolic disorders such as hypertriglyceridemia, diabetes mellitus type 2 and lipodystrophy syndromes.