PPAR及其激动剂与脂肪酸代谢及胰岛素抵抗

过氧化物酶体增殖物激活受体(PPAR)在脂肪细胞分化、脂肪酸代谢中起重要作用,PPAR及其所调控基因的激活可促进脂肪细胞分化、减少脂质产生、增加脂肪酸氧化,从而减少脂质的异位沉积,进一步改善损伤的胰岛素信号转导通路,逆转胰岛素抵抗。针对脂肪酸合成及氧化的关键调控点的药物可能是今后治疗胰岛素抵抗引发的一系列代谢异常的新的靶点。     

黄连素抑制FSP27基因表达改善2型糖尿病地鼠内脏白色脂肪组织胰岛素抵抗的研究

摘要：目的 研究黄连素（BBR）对2型糖尿病（T2DM）中国地鼠内脏白色脂肪组织（VWAT）中脂肪特异蛋白27（FSP27）和PR结构域蛋白16 （PRDM16）信号通路基因mRNA表达的影响并探讨相关机制。方法 以高脂饮食诱导肥胖胰岛素抵抗（OIR）地鼠模型,然后给予小剂量链脲菌素建立T2DM地鼠模型,对照组喂以普通饲料。造模完成后随机分成对照组、OIR组、肥胖T2DM组和T2DM BBR组。BBR治疗9周后,应用实时定量PCR方法检测各组地鼠VWAT中FSP27和PRDM16信号通路及其靶基因的mRNA表达改变。结果 与对照组相比,OIR组和肥胖T2DM组地鼠VWAT中PRDM16、CtBP-1、CtBP-2、C/EBPβ、PPARγ、PGC1α、PGC-1β及棕脂组织特异基因UCP-1、Cidea、Elovl3、PPARα及Acox、Cpt1和Acadm的mRNA表达降低,而FSP27和白脂组织特异基因Resistin、MEST和Serpina3k的mRNA表达增加。BBR治疗降低肥胖T2DM组地鼠VWAT中FSP27的表达而增强PRDM16信号通路效应,诱导棕脂组织特异基因mRNA的表达,诱导VWAT棕色化基因表型,改善脂诱性胰岛素抵抗。结论 BBR降低FSP27表达而增加PRDM16的表达与其诱导VWAT棕色化的分子机制相关,有助于增强产热耗能, 改善VWAT的异常脂代谢,改善FIVWATIR,恢复VWAT的功能。     

Visceral adipose tissue is more strongly associated with insulin resistance than subcutaneous adipose tissue in Chinese subjects with pre-diabetes

Aims: To investigate the value of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in a cohort of a community’s residents who were diagnosed as pre-diabetes, and to evaluate the association of VAT and SAT with insulin resistance.

Methods: This study was based on cross-sectional analysis of data from 107 adults. VAT and SAT were assessed by computed tomography. Insulin resistance was defined by homeostasis model assessment of insulin resistance >2.69. The relationship of VAT and SAT with insulin resistance were examined by linear regression. Logistic regression was used to analyze the association of VAT and SAT with insulin resistance.

Results: A total of 87 subjects had VAT ≥100?cm². Thirty-six out of 107 (33.6%) subjects were detected to have insulin resistance, 71 were normal (66.4%), and all had insulin resistance with VAT ≥100?cm². VAT (r?=?0.378, p?r?=?0.357, p?p?=?.003), but that of SAT was lost.

Conclusion: Pre-diabetic subjects with insulin resistance had elevated levels of VAT. VAT was more strongly associated with insulin resistance than SAT in Chinese subjects with pre-diabetes.     

高脂饮食致脂肪肝胰岛素抵抗大鼠模型中PPARs的表达及作用

目的研究PPARα、PPARγ在SD大鼠NAFLD/NASH的形成中的作用,并初步从胰岛素抵抗(IR)方面探讨其机制。方法将SD大鼠60只随机分为正常对照组(NC组,n=20)、高脂对照组(FC组,n=20),高脂加罗格列酮组(FR组,n=10)、高脂加非诺贝特组(FF组,n=10)。饲养12周末时随机取NC组与FC组各10只一并做高胰岛素正葡萄糖钳夹实验及肝组织的HE染色,确定造模成功。然后给予罗格列酮、非诺贝特及继续高脂饮食干预,共4周。氨基转移酶、三酰甘油等以生物化学方法测定,并以逆转录-聚合酶链反应(RT-PCR)技术分析PPARα、PPARγ基因的mRNA表达水平。结果 FC组大鼠呈高脂血症,与NC组比较,PPARα的mRNA表达下调,而PPARγmRNA表达上调(P<0.05),IR和肝细胞脂肪变及炎性程度加重(P<0.05);与FC组比较,FF及FR组PPARα的mRNA表达上调,PPARγmRNA表达下调,IR明显改善(P<0.05)。结论在高脂饮食诱导的NASH、IR模型中,PPARα、PPARγ的mRNA表达水平与IR密切相关,可以共同促进NASH的进展,而使用PPARs激动剂后对大鼠NASH及IR起到了有效治疗作用。     

2型糖尿病合并非酒精性脂肪肝患者血清铁蛋白水平与氧化应激、胰岛素抵抗的关系

目的 探讨合并非酒精性脂肪肝(NAFLD)的2型糖尿病(T2DM)患者血清铁蛋白(SF)水平与氧化应激、胰岛素抵抗的关系.方法 对44例T2DM患者(A组,22例,无NAFLD;B组,22例,合并NAFLD)和健康体检者(C组,22例)检测了血总胆固醇(TC)、甘油三酯(TG)、空腹血糖(FPG)、空腹胰岛素(FINS)、糖化血红蛋白(HbA1c)、SF和丙二醛(MDA)水平,并采用稳态模型评估胰岛素抵抗指数(HOMA-IR).结果 A组和B组的SF、MDA水平高于C组(P＜0.01),B组SF、MDA水平显著高于A组(P＜0.01).SF水平与病程、体重指数、TC、TG、HbA1c、FPG、FINS、HOMA-IR、MDA水平呈正相关.结论 T2DM合并NAFLD患者体内铁超负荷;氧化应激、胰岛素抵抗可能参与了NAFLD的发生发展.     

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。     

藻酸双酯钠改善模型大鼠的胰岛素抵抗和血脂异常

藻酸双酯钠具有抗凝、抗血栓以及调节血脂等作用，是一种新型的抗动脉粥样硬化药物。但它对糖尿病伴脂代谢异常血症的治疗作用还没有明确。本研究建立糖尿病伴脂代谢异常血症大鼠模型，初步探讨藻酸双酯钠对其血糖和血脂的调节作用。Wistar大鼠高脂饲料喂养1.5个月后尾静脉注射链脲佐菌素。建模成功后，灌胃给予藻酸双酯钠1个月，检测血中血糖、胰岛素和脂质浓度。结果显示，藻酸双酯钠治疗组与糖尿病对照组相比，血中甘油三酯、总胆固醇和低密度脂蛋白明显降低，高密度脂蛋白显著升高，藻酸双酯钠治疗后血糖和胰岛素浓度有所下降，而胰岛素敏感指数比糖尿病对照组明显提高。本研究提示，藻酸双酯钠可以改善糖尿病伴脂代谢异常血症大鼠血脂异常，并提高胰岛素敏感性。     

The impact of insulin resistance, serum adipocytokines and visceral obesity on steatosis and fibrosis in patients with chronic hepatitis C

Aims To assess whether host metabolic factors influence the degree of hepatic steatosis and fibrosis in patients infected with hepatitis C virus, and to evaluate the impact of anti‐viral therapy on insulin resistance and serum levels of adipocytokines. Methods Clinical and biochemical features, anthropometrical characteristics, and levels of fasting insulin, leptin, adiponectin and resistin were measured in ‘naïve’ patients with chronic hepatitis C, before, during and after therapy with Peg‐Interferon‐alpha 2a plus Ribavirin. Results Forty‐eight patients were included (M/F 28/20; mean age 50.0 ± 12.6 years; 62.5% genotype‐1). Body mass index was 26.4 ± 4.0 kg/m², and visceral obesity was present in 24 patients. At multivariate analysis (RR; 95% CI), steatosis was associated to older age (1.08; 1–1.18), necroinflammatory activity (17.67; 1.6–194.46), and raised insulin levels (1.39; 1.1–1.77). Fibrosis was related to necroinflammatory activity (25.73; 2.54–261.11), and steatosis (6.47; 1.09–38.29). Sustained viral response was achieved by 62.5% of patients and was associated with younger age (0.92; 0.85–0.99), genotype non‐1 (10.61; 1.52–73.76) and absence of visceral obesity (13.78; 2.36–80.29). At the end of follow‐up, insulin and the homeostasis model assesment for insulin resistance were reduced and adiponectin increased when compared with baseline, all unrelated to the outcome of treatment. Conclusions Visceral obesity correlates with the degree of steatosis and fibrosis, and it negatively affects treatment response. Significant changes of insulin resistance and adipocytokines occur under treatment, irrespective of virological outcome.     

Modulation of liver function,antioxidant responses,insulin resistance and glucose transport by Oroxylum indicum stem bark in STZ induced diabetic rats

A decoction of stem bark of Oroxylum indicum Vent. (OI) is taken (2–3times/day) by the tribal people of Sikkim, India to treat diabetes but scientific validation of its overall potential is lacking. Present study was aimed to assess in vitro antihyperglycemic activity of standardized OI extract using inhibition of α-glucosidase, BSA glycation and enhancement of insulin sensitivity. Antidiabetic and antioxidant modulatory effects of OI extract along with the blood biomarkers of toxic response were studied in streptozotocin (STZ) induced diabetic rats. In vitro analysis showed strong antioxidant capacity of OI -and potential to inhibit BSA glycation and α-glucosidase activity which was comparable to standard counterparts. Extract also improved insulin sensitivity in mature 3T3-L1 adipocytes. In vivo effects of OI extract (oral 250 mg/kg b.wt.) on STZ induced type II diabetic rats normalized the antioxidant status (p ⩽ 0.01). Analysis of blood biomarkers of toxic response indicated its safety. Lowering of total cholesterol and HDL levels (p ⩽ 0.05) and restoration of glycated Hb (p ⩽ 0.01) were also found in OI treated diabetic rats. HOMA-IR, QUICKI analysis along with area under the curve analysis showed the capacity of OI extract to enhance the insulin sensitivity significantly (p ⩽ 0.01) which was confirmed by increased GLUT-4 translocation in skeletal muscles.     

Combination therapy with statin and fibrate in patients with dyslipidemia associated with insulin resistance,metabolic syndrome and type 2 diabetes mellitus

Introduction: People with insulin resistance/metabolic syndrome (IR/MS) and/or type 2 diabetes mellitus (T2DM) have increased rates of cardiovascular disease (CVD) even when low-density lipoprotein cholesterol levels are at or near target levels. Contributors to this problem are the high triglyceride (TG) levels and low levels of high-density lipoprotein cholesterol (HDLC) that are commonly present in this population, even with statin therapy.

Areas covered: This review focuses on the use of a combination of statins with fibrates, which lower TG and raise HDLC concentrations and, therefore, have the potential to further lower rates of CVD more in people with IR/MS and/or T2DM. Treatment with this combination is uncommon because doctors and patients are fearful of muscle, liver and renal complications and because the evidence that the combination will actually reduce risk has been lacking. In this review, the authors examine the efficacy and safety of the statin–fibrate combination, particularly fenofibrate and simvastatin, the combination used in the ACCORD trial.

Expert opinion: The authors' opinion is that this combination of fenofibrate and statin is as safe as either drug alone and, in patients with significant dyslipidemia, is likely to reduce CVD. Concerns remain concerning fenofibrate-associated increases in serum creatinine levels and the significant heterogeneity in the reduction in CVD by the combination in women. A trial of statin + fenofibrate in people with IR/MS and/or T2DM who also have significant dyslipidemia is needed.     

红花黄色素联合二甲双胍对早期糖尿病肾病患者氧化应激、胰岛素抵抗及肾功能的影响

目的 观察红花黄色素联合二甲双胍对早期糖尿病肾病(DN)患者氧化应激、胰岛素抵抗及肾功能的影响.方法 选取2015年10月至2016年10月诊治的DN患者80例,随机分为对照组和观察组,每组40例.2组均接受常规治疗,对照组在常规治疗基础上口服盐酸二甲双胍治疗,观察组在对照组基础上静脉滴注红花黄色素,疗程均为2周.观察2组血清空腹血糖(FBG)、餐后2 h血糖(2 hPG)、胰岛素(FINS)、谷胱甘肽过氧化物酶(GSH-Px)、丙二醛(MDA)、超氧化物歧化酶(SOD)、8异前列腺素F2α(8-iso-PGF2α)、胱抑素C(Cys C)、同型半胱氨酸(Hcy)、24 h尿蛋白量、尿白蛋白排泄率(UAER)变化,计算胰岛素抵抗指数(HOMA-IR).结果 与治疗前比较,2组治疗后FBG、2 hPG、FINS、HOMA-IR、MDA、Cys C、Hcy水平均较治疗前显著降低(P<0.05),GSH-Px、SOD水平均较治疗前显著升高(P<0.05),且观察组上述指标改善程度优于对照组(P<0.05).结论 红花黄色素联合二甲双胍治疗早期糖尿病肾病能够显著降低氧化应激水平,改善胰岛素抵抗,从而发挥肾脏保护作用.     

Cholinergic, dopaminergic and insulin receptors gene expression in the cerebellum of streptozotocin-induced diabetic rats: Functional regulation with Vitamin D3 supplementation

The study was to find out the effect of Vitamin D₃ supplementation on preventing the altered gene expression of cholinergic, dopaminergic, insulin receptors and GLUT3 gene expression in cerebellum of diabetic rats. Radioreceptor binding assays and gene expression were done in the cerebellum of male Wistar rats. Rota rod has been used to evaluate motor coordination. Our results showed a significantly increased gene expression of dopamine D2, muscarinic M1, M3, α7 nicotinic acetylcholine, insulin receptors, acetylcholine esterase, GLUT3 and Vitamin D receptor in the cerebellum of diabetic rats. There was a down-regulation of dopamine D1 receptor. Total dopamine receptor showed a decreased and total muscarinic, muscarinic M1 and M3 receptors showed an increased binding parameter, B_max. Rota rod experiment showed a significant decrease in the retention time on the rotating rod in diabetic while treatment improved retention time near to control. Vitamin D₃ and insulin treatment markedly recovered the altered gene expression and binding parameters to near control. Our study showed Vitamin D₃ functional regulation through dopaminergic, cholinergic and insulin receptors and glucose transport mechanism through GLUT3 in the cerebellum of diabetic rats which play a major role in neuroprotection in diabetes which has clinical application.     

Occurrence of autoimmune antibodies to liver microsomal proteins associated with lethal hepatitis in LEC rats: effects of TJN-101 ((+)-(6S,7S,R-biar)-5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy-6,7-dimethyl-10,11-methylenedioxy-6-dibenzo[a,c]cyclooctenol) on the development of hepatitis and the autoantibodies

Long Evans Cinnamon (LEC) rats, that spontaneously develop hepatitis, were found to possess autoantibodies to liver microsomal proteins (anti-LM) before the development of hepatitis. Anti-LM antibody was assumed to appear in association with the lethal hepatitis in the LEC rats. Thus, the purpose of this study was to investigate the effects of an anti-hepatitis drug on the development of hepatitis and the occurrence of the antibody in LEC rats. Mortality, blood biochemical parameters and the titer of serum anti-LM antibody were measured. In control LEC rats, 4 of 8 rats died before 20 weeks of age. In rats treated with TJN-101 ((+)-(6S,7S,R-biar)-5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy-6,7-dimethyl-10,11-methylenedioxy-6-dibenzo[a,c]cyclooctenol), 4 of 7 rats died of hepatitis, but the time of death was delayed by 7–10 weeks compared for the control rats. The titer of the anti-LM antibody increased 3–7 weeks before death in the non-survivors in control and TJN-101-treated rats, supporting the idea that anti-LM antibody occurs in association with acute lethal hepatitis.