菠萝蜜低聚肽对db/db小鼠炎症反应、血糖及血脂的影响

目的：研究菠萝蜜低聚肽（JOPs）干预对db/db糖尿病模型小鼠炎症反应、血糖及血脂的影响作用。方法：选择db/db糖尿病小鼠模型,将其随机分为3个JOPs组（0.2、0.4、0.8g/kg·BW）以及糖尿病模型对照组、二甲双胍对照组、乳清蛋白对照组,并选用db/m小鼠作为非糖尿病小鼠空白对照。经过为期6个月的干预,检测小鼠空腹血糖（FPG）、血清胰岛素（INS）、白细胞介素6（IL 6）、白细胞介素8（IL 8）、白细胞介素10（IL 10）和肿瘤坏死因子α（TNF α）、C反应蛋白（CRP）以及脂代谢指标。结果：JOPs可显著降低db/db糖尿病小鼠空腹血糖水平及胰岛素抵抗指数;可使血清IL 6、TNF α、总胆固醇（TC）和甘油三酯（TG）显著降低,并使高密度脂蛋白胆固醇（HDL C）显著升高。结论：JOPs干预可有效降低糖尿病小鼠的血糖水平,改善胰岛素抵抗,同时有效调节炎症反应及血脂代谢。     

非酒精性脂肪肝病大鼠肝脏SOCS-3的表达与吡格列酮干预研究

目的：探讨SOCS-3在非酒精性脂肪肝病（NAFLD）发病中的作用以及吡格列酮的干预作用。方法：29只雄性SD大鼠随机分为正常对照组（8只）,高脂饮食组（21只）。饲养8周后,从高质饮食组随机抽取5只大鼠证实造模成功后,将该组余下的16只大鼠继续以高脂饲料喂养,并随机分为NAFLD对照组（8只）;吡格酮干预组（8只）,予以吡格列酮3mg·kg^-1·d^-1灌胃。16周末,处死所有大鼠,检测血糖、血胰岛素、血脂、肝脏SOCS-3mRNA和SREBP-lcmRNA表达及肝脏病理学。结果：与正常对照组相比,NAFLD组血糖、血胰岛素、血脂、肝脏脂肪变水平及肝组织SOCS-3mRNA、SREBPlCmRNA表达显著上调。吡格列酮干预组sOCS．3mRNA、SREBP-1cmRNA表达较NAFLD组下调,且血糖、血胰岛素、血脂、肝脏脂肪变水平下降。SOCS-3mRNA表达水平与胰岛素抵抗指数、SREBP．1cmRNA表达水平、肝脂肪变成显著正相关。结论：SOCS-3可能通过胰岛素抵抗及上调肝组织SREBP-lcmRNA表达参与NAFLD发病,吡格列酮能抑制肝脏SOCS-3的表达,对NAFLD有一定治疗作用。     

非酒精性脂肪肝病大鼠肝脏SOCS-3 的表达与吡格列酮干预研究

目的:探讨SOCS-3在非酒精性脂肪肝病(NAFLD)发病中的作用以及吡格列酮的干预作用。方法:29只雄性SD大鼠随机分为正常对照组(8只),高脂饮食组(21只)。饲养8周后,从高质饮食组随机抽取5只大鼠证实造模成功后,将该组余下的16只大鼠继续以高脂饲料喂养,并随机分为NAFLD对照组(8只);吡格列酮干预组(8只),予以吡格列酮3mg·kg-·1d-1灌胃。16周末,处死所有大鼠,检测血糖、血胰岛素、血脂、肝脏SOCS-3 mRNA和SREBP-1c mRNA表达及肝脏病理学。结果:与正常对照组相比,NAFLD组血糖、血胰岛素、血脂、肝脏脂肪变水平及肝组织SOCS-3 mRNA、SREBP1c mRNA表达显著上调。吡格列酮干预组SOCS-3 mRNA、SREBP-1c mRNA表达较NAFLD组下调,且血糖、血胰岛素、血脂、肝脏脂肪变水平下降。SOCS-3 mRNA表达水平与胰岛素抵抗指数、SREBP-1c mRNA表达水平、肝脂肪变成显著正相关。结论:SOCS-3可能通过胰岛素抵抗及上调肝组织SREBP-1c mRNA表达参与NAFLD发病,吡格列酮能抑制肝脏SOCS-3的表达,对NAFLD有一定治疗作用。     

松果菊苷对db/db糖尿病小鼠心肌的保护作用

糖尿病心肌病（diabetic cardiomyopathy, DCM）是指发生于糖尿病患者,不能用冠心病、高血压性心脏病及其他心脏病变来解释的心肌疾病。目前,DCM的病因和发病机制尚未完全阐明,且缺乏特异性治疗手段。中药管花肉苁蓉提取物松果菊苷（echinacoside, ECH）对心肌细胞具有保护作用。以db/m小鼠为正常对照组（db/m组）,db/db小鼠分为模型组（db/db组）和ECH干预组（db/db+ECH组）,探讨了ECH对糖尿病db/db小鼠心肌的影响及机制。db/db+ECH组小鼠给予松果菊苷灌胃,db/m组和db/db组小鼠给予0.9%氯化钠溶液灌胃。心脏超声观察心脏功能,Masson染色观察组织胶原纤维含量,逆转录聚合酶链式反应检测Ⅰ型胶原和Ⅲ型胶原mRNA的表达,蛋白质免疫印迹技术检测转化生长因子-β1（transforming growth factor-β1, TGF-β1）、phospho-Smad2（p-Smad2）和phospho-Smad3（p-Smad3）的表达。结果显示,ECH能够改善db/db小鼠左心室肥大和心脏功能,降低胶原沉积（P<0.05）。ECH能够降低Ⅰ型和Ⅲ型胶原mRNA的表达（P<0.01）,下调TGF-β1、p-Smad2和p-Smad3蛋白的表达（P<0.05）。ECH对糖尿病心肌的保护作用可能与负反馈调节TGF-β1/Smads信号通路相关,研究结果为DCM的早期干预提供了新思路。     

十子代平方水煎液对原代骨骼肌细胞胰岛素抵抗模型的影响

本实验观察十子代平方对原代骨骼肌细胞胰岛素抵抗模型的影响,探讨其改善胰岛素抵抗的作用机制。对原代骨骼肌细胞应用5×10-7mol/L胰岛素干预12 h建立胰岛素抵抗模型,应用十子代平方高、中、低浓度(400、100、25μg/m L)(SZDP-H、SZDP-M、SZDP-L)对造模成功的骨骼肌细胞进行干预,同时另设正常组、模型组,吡格列酮组(40μmol/L)作对照,药物干预24 h后用葡萄糖氧化酶法测定骨骼肌细胞上清液葡萄糖剩余量,采用Western-blot方法测定该方药物干预后骨骼肌细胞AKT、GSK-3β蛋白的表达。实验结果表明十子代平方可以改善骨骼肌细胞胰岛素抵抗模型的葡萄糖代谢,增加AKT和磷酸化位点Ser473蛋白表达,降低GSK-3β蛋白表达,增加其磷酸化位点Ser9蛋白表达。十子代平方可能通过调节AKT/GSK3β通路的机制改善胰岛素抵抗模型骨骼肌细胞的葡萄糖代谢。     

乳源性复合益生菌促进db/db糖尿病小鼠白色脂肪棕色化的研究

目的研究乳源性复合益生菌对db/db糖尿病小鼠白色脂肪棕色化细胞因子解偶联蛋白1(UCP1)、过氧化物酶体增殖物激活受体γ共激活因子1α(PGC1α)、R结构域蛋白16(PRDM16)表达的影响。方法将6周龄的SPF级db/db糖尿病雄性小鼠适应性喂养1周,随机分为糖尿病模型组、罗格列酮组及复合益生菌高剂量组和低剂量组,SC57BL/Ks雄性小鼠为正常对照组,每组8只。血糖仪检测不同时段空腹血糖(FBG)水平,ELISA法检测糖化血红蛋(HbA1c)含量,取各组小鼠皮下白色脂肪组织,HE染色观察脂肪组织形态,用Real time-PCR检测各组白色脂肪组织中UCP1、PGC1α、PRDM16 mRNA表达水平以及Western Blot检测各组脂肪组织中UCP1的表达。结果与模型组相比,复合益生菌组FBG、HbA1c水平明显下降,并且复合益生菌能够明显增加脂肪组织多室脂肪细胞数量,具有棕色化的趋向,并能够显著提高UCP1、PGC1α、PRDM16的mRNA表达和UCP1表达量。结论本研究发现乳源性复合益生菌能够促进白色脂肪棕色化从而改善胰岛素抵抗。     

妊娠糖尿病对仔鼠肺成熟的影响及吡格列酮的干预作用

摘要 目的：探究妊娠糖尿病（GDM）对仔鼠肺成熟的影响及吡格列酮对肺发育的干预作用。方法：将30只SD孕鼠分为对照组、GDM组和GDM+吡格列酮组（GDM+P组）,每组10只。GDM组和GDM+P组孕鼠通过腹腔注射链脲霉素（STZ,45 mg/kg）和高脂饮食饲养构建GDM孕鼠模型,GDM+P组大鼠建模后灌胃10 mg/kg的吡格列酮,对照组和GDM组孕鼠每天灌胃等体积生理盐水。分娩后,检测各组仔鼠的血糖和血浆胰岛素水平以及胎肺组织中的总磷脂量。通过苏木精伊红（HE）染色、油红O染色和透射电镜观察胎肺组织结构和形态变化。通过RT-PCR和Western blot检测胎肺组织中SP-A、SP-B、SIRT1和PPARγ的表达。结果：GDM组仔鼠的血糖水平与对照组无显著差异（P>0.05）,胰岛素水平明显高于对照组（P<0.05）。与对照组相比,GDM组仔鼠胎肺组织中的总磷脂含量降低（P<0.05）;胎肺组织中肺泡Ⅱ型上皮细胞(AECⅡ)数量和脂滴明显减少。与对照组相比,GDM组仔鼠胎肺组织中的SP-A、SP-B、SIRT1和PPARγ的mRNA和蛋白相对表达水平均降低（P<0.05）。吡格列酮干预显著逆转了GDM对仔鼠胰岛素、胎肺组织结构和形态变化的影响;GDM+P组仔鼠胎肺组织中的SP-A、SP-B、SIRT1和PPARγ的mRNA和蛋白相对表达水平相较GDM组均升高（P<0.05）。结论：GDM母鼠所生仔鼠存在肺发育延迟,吡格列酮干预可有效促进仔鼠的肺成熟。     

津力达对高脂诱导的胰岛素抵抗ApoE~(-/-)小鼠骨骼肌甘油三酯相关酶的影响

目的探究津力达对高脂诱导的胰岛素抵抗Apo E-/-小鼠骨骼肌甘油三酯相关基因的影响。方法将8只雄性C57BL/6J小鼠设为正常组(A组);40只雄性Apo E-/-小鼠喂养16周后分为模型组(B组)、罗格列酮组(C组)、津力达低剂量组(D组)、津力达中剂量组(E组)、津力达高剂量组(F组),开始灌胃给药,连续8周。采用酶法、BCA蛋白浓度法测定骨骼肌TG含量;OGTT评价小鼠的胰岛素抵抗程度;RT-PCR和Western blot测定小鼠骨骼肌HSL、ATGL、PPARγmRNA和蛋白表达。结果津力达能够不同程度降低小鼠的FBG、TC、TG和LDLC,升高HDL-C;下调FIns水平,提高ISI,明显改善小鼠糖耐量异常;津力达能够不同程度的上调小鼠HSL、ATGL、PPARγmRNA和蛋白表达。结论津力达能够通过调节骨骼肌甘油三酯相关酶的表达,改善高脂诱导的Apo E-/-小鼠的胰岛素抵抗。     

人参低聚肽改善老龄db/db小鼠疾病状态和延长寿命的研究

目的：评价人参低聚肽（GOP）改善老龄db/db小鼠血糖水平和延长寿命的效果。 方法：采用db/db小鼠作为2型糖尿病模型。对老龄db/db（生长至70周龄）小鼠摄食量、体重、饮水量和尿量以及血糖水平进行测定,并且对老龄db/db小鼠存活率进行评价,表征GOP对疾病状态和寿命的改善效果。结果：GOP可以降低小鼠体重、摄食量、饮水量和尿量,改善老龄db/db小鼠的生存状态,同时,相比于模型对照组,GOP可以显著减少老龄db/db小鼠肾周脂肪指数和睾周脂肪指数（P<0.05）。通过GOP干预,可以降低老龄db/db小鼠的血糖水平,GOP干预组AUC为20mmol/（L·h）,显著低于模型对照组小鼠AUC［50 mmol/（L·h）］。当db/db小鼠增长至80周龄时,GOP干预组小鼠存活率为50%,大于模型对照组存活率（20%）。结论：GOP干预小鼠生存质量较高,并且寿命较长,说明GOP可以在一定程度上改善老龄db/db小鼠血糖情况,延长其寿命。本研究为利用GOP开展糖尿病的营养治疗提供了科学依据。     

强化控糖后加用盐酸吡格列酮治疗2型糖尿病的临床疗效观察

目的观察强化控糖后加用盐酸吡格列酮治疗2型糖尿病的临床疗效。方法 60例使用口服降糖药物治疗的血糖控制不佳的2型糖尿病患者,入院后先进行胰岛素泵强化控糖治疗,患者血糖达到目标值后（FPG〈7.0 mmol/L,2 h PG〈10.0 mmol/L）,改为三餐前门冬胰岛素联合睡前甘精胰岛素继续强化治疗,1周后按1：1的比例随机分为两组,一组继续使用三餐前门冬胰岛素联合睡前甘精胰岛素治疗（对照组）,一组在三餐前门冬胰岛素联合睡前甘精胰岛素的基础上加用盐酸吡格列酮30 mg/日（治疗组）。1～4周我院住院治疗,5～12周门诊随访,若出现FPG及2 h PG明显下降或低血糖反应,则减少胰岛素用量。观察加用盐酸吡格列酮治疗前以及治疗12周时FPG、2 h PG、HbAlc、胰岛素用量、甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、体重指数的变化情况。结果 （1）治疗组胰岛素用量明显下降,与加用盐酸吡格列酮治疗前有明显差异（P〈0.05）;对照组的胰岛素用量治疗前后无明显差异（P〉0.05）;（2）治疗组与对照组加用盐酸吡格列酮治疗前后FPG、2hPG均无明显差异（P〉0.05）。（3）治疗组HbAlc有所下降,与加用盐酸吡格列酮治疗前有明显差异（P〈0.05）,对照组HbAlc也有所下降,差异明显（P〈0.05）,但治疗后两组比较无明显差异（P〉0.05）。（4）加用盐酸吡格列酮后,治疗组TG下降,HDL-C升高,与同组治疗前相比,差异明显（P〈0.05）,对照组与治疗前相比差异不明显,组间比较差异有显著性（P〈0.05）。结论在强化控糖血糖达标后,加用盐酸吡格列酮继续治疗,可以明显降低患者胰岛素的使用剂量,提高患者的依从性,并且能改善血脂代谢紊乱,对于减少心血管并发症的发生有一定益处。     

Structural and functional analysis of pancreatic islets preserved by pioglitazone in db/db mice

To evaluate preventive effects of pioglitazone on pancreatic beta-cell damage in C57BL/KsJ db/db mice, an obese diabetic animal model, the pancreatic islets were compared morphologically between pioglitazone-treated (100 mg/kg daily po) and untreated db/db mice (n = 7 for each) after a 12-wk intervention (6-18 wk of age). The fasting blood glucose level was significantly improved by the treatment with pioglitazone (260 +/- 12 vs. 554 +/- 62 mg/dl, P < 0.05). The islet mass in the pancreas was significantly greater in pioglitazone-treated mice than in untreated mice (10.2 +/- 1.1 vs. 4.6 +/- 0.2 mg, P < 0.01). Subsequently, biochemical and physiological analyses of the beta-cell function were employed using pioglitazone-treated and untreated db/db mice (n = 6 for each) and pioglitazone-treated and untreated db/+ mice (n = 6 for each). After 2 wk of treatment (10-12 wk of age), the plasma levels of triglyceride and free fatty acid were significantly decreased, whereas the plasma adiponectin level increased significantly compared with the untreated group (65.2 +/- 18.0 vs. 18.3 +/- 1.3 microg/ml, P < 0.05). Pioglitazone significantly reduced the triglyceride content in the islets (43.3 +/- 3.6 vs. 65.6 +/- 7.6 ng/islet, P < 0.05) with improved glucose-stimulated insulin secretion. Pioglitazone showed no significant effects on the biochemical and physiological parameters in db/+ mice. The present study first demonstrated that pioglitazone prevents beta-cell damage in an early stage of the disease progression in db/db mice morphologically and physiologically. Our results suggest that pioglitazone improves glucolipotoxicity by increasing insulin sensitivity and reducing fat accumulation in the pancreatic islets.     

诱发性2型糖尿病小鼠模型与自发性db/db小鼠特性的比较

目的建立诱发性2型糖尿病小鼠模型,并将其与自发性2型糖尿病小鼠db/db进行比较分析。客观评价两种2型糖尿病小鼠模型,为糖尿病研究中动物模型的选择与实际应用提供实验依据。方法高脂饲料喂养C57BL/6J小鼠4周,腹腔连续3次注射STZ,建立诱发性2型糖尿病小鼠模型。感染后4周,大体肉眼观察小鼠的肝脏、肾脏,测定糖耐量,血清生化指标及血清细胞因子IL-2、IL-4、IL-6、IFN-γ、TNF-α、IL-17、IL-10表达量,将其与同龄的自发性2型糖尿病小鼠db/db进行比较分析。结果肉眼观察发现,两组模型小鼠的肝脏、肾脏与对照组均具有明显差异。糖耐量分析中,两组模型小鼠与对照组小鼠各时间点的血糖值均具有统计学差异（P〈0.05）,耐糖功能低下,两组模型小鼠间血糖值无统计学差异。血液生化指标中,与对照组小鼠相比,两组模型小鼠GLU、CHOL、LDLC明显升高（P〈0.05）;两组模型小鼠相互比较,诱发性2型糖尿病小鼠血脂水平较高（P〈0.05）。免疫指标比较显示：除IL-2外,两组模型小鼠血清中细胞因子水平均较对照组小鼠明显升高（P〈0.05）,而db/db小鼠血清中细胞因子表达较诱发性糖尿病小鼠高,其中IL-6、IFN-γ、TNF-α具有显著性差异（P〈0.05）。结论两组2型糖尿病模型小鼠均在一定程度上模拟了人类糖尿病患者症状,但由于糖尿病产生的原因不同而存在着一定的差异,研究者可根据实际需要参照相关数据进行选择。     

Oxamate Improves Glycemic Control and Insulin Sensitivity via Inhibition of Tissue Lactate Production in db/db Mice

Oxamate (OXA) is a pyruvate analogue that directly inhibits the lactate dehydrogenase (LDH)-catalyzed conversion process of pyruvate into lactate. Earlier and recent studies have shown elevated blood lactate levels among insulin-resistant and type 2 diabetes subjects and that blood lactate levels independently predicted the development of incident diabetes. To explore the potential of OXA in the treatment of diabetes, db/db mice were treated with OXA in vivo. Treatment of OXA (350–750 mg/kg of body weight) for 12 weeks was shown to decrease body weight gain and blood glucose and HbA1c levels and improve insulin secretion, the morphology of pancreatic islets, and insulin sensitivity in db/db mice. Meanwhile, OXA reduced the lactate production of adipose tissue and skeletal muscle and serum lactate levels and decreased serum levels of TG, FFA, CRP, IL-6, and TNF-α in db/db mice. The PCR array showed that OXA downregulated the expression of Tnf, Il6, leptin, Cxcr3, Map2k1, and Ikbkb, and upregulated the expression of Irs2, Nfkbia, and Pde3b in the skeletal muscle of db/db mice. Interestingly, LDH-A expression increased in the islet cells of db/db mice, and both treatment of OXA and pioglitazone decreased LDH-A expression, which might be related to the improvement of insulin secretion. Taken together, increased lactate production of adipose tissue and skeletal muscle may be at least partially responsible for insulin resistance and diabetes in db/db mice. OXA improved glycemic control and insulin sensitivity in db/db mice primarily via inhibition of tissue lactate production. Oxamic acid derivatives may be a potential drug for the treatment of type 2 diabetes.     

Astaxanthin protects beta-cells against glucose toxicity in diabetic db/db mice

Oxidative stress induced by hyperglycemia possibly causes the dysfunction of pancreatic beta-cells and various forms of tissue damage in patients with diabetes mellitus. Astaxanthin, a carotenoid of marine microalgae, is reported as a strong anti-oxidant inhibiting lipid peroxidation and scavenging reactive oxygen species. The aim of the present study was to examine whether astaxanthin can elicit beneficial effects on the progressive destruction of pancreatic beta-cells in db/db mice--a well-known obese model of type 2 diabetes. We used diabetic C57BL/KsJ-db/db mice and db/m for the control. Astaxanthin treatment was started at 6 weeks of age and its effects were evaluated at 10, 14, and 18 weeks of age by non-fasting blood glucose levels, intraperitoneal glucose tolerance test including insulin secretion, and beta-cell histology. The non-fasting blood glucose level in db/db mice was significantly higher than that of db/m mice, and the higher level of blood glucose in db/db mice was significantly decreased after treatment with astaxanthin. The ability of islet cells to secrete insulin, as determined by the intraperitoneal glucose tolerance test, was preserved in the astaxanthin-treated group. Histology of the pancreas revealed no significant differences in the beta-cell mass between astaxanthin-treated and -untreated db/db mice. In conclusion, these results indicate that astaxanthin can exert beneficial effects in diabetes, with preservation of beta-cell function. This finding suggests that anti-oxidants may be potentially useful for reducing glucose toxicity.     

Prevention of diabetic nephropathy by treatment with astaxanthin in diabetic db/db mice

Oxidative stress is implicated as an important mechanism by which diabetes causes nephropathy. Astaxanthin, which is found as a common pigment in algae, fish, and birds, is a carotenoid with significant potential for antioxidative activity. In this study, we examined whether chronic administration of astaxanthin could prevent the progression of diabetic nephropathy induced by oxidative stress in mice. We used female db/db mice, a rodent model of type 2 diabetes, and their non-diabetic db/m littermates. The mice were divided into three groups as follows: non-diabetic db/m, diabetic db/db, and diabetic db/db treated with astaxanthin. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were performed for 12 weeks from the beginning of treatment. After 12 weeks of treatment, the astaxanthin-treated group showed a lower level of blood glucose compared with the non-treated db/db group; however, both groups had a significantly high level compared with the db/m mice. The relative mesangial area calculated by the mesangial area/total glomerular area ratio was significantly ameliorated in the astaxanthin-treated group compared with the non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with astaxanthin. The 8-OHdG immunoreactive cells in glomeruli of non-treated db/db mice were more numerous than in the astaxanthin-treated db/db mice. In this study, treatment with astaxanthin ameliorated the progression and acceleration of diabetic nephropathy in the rodent model of type 2 diabetes. The results suggested that the antioxidative activity of astaxanthin reduced the oxidative stress on the kidneys and prevented renal cell damage. In conclusion, administration of astaxanthin might be a novel approach for the prevention of diabetes nephropathy.     

Chlorogenic Acid Improves Late Diabetes through Adiponectin Receptor Signaling Pathways in db/db Mice

The aim of this study was to examine the effects of chlorogenic acid (CGA) on glucose and lipid metabolism in late diabetic db/db mice, as well as on adiponectin receptors and their signaling molecules, to provide evidence for CGA in the prevention of type 2 diabetes. We randomly divided 16 female db/db mice into db/db-CGA and db/db-control (CON) groups equally; db/m mice were used as control mice. The mice in both the db/db-CGA and db/m-CGA groups were administered 80 mg/kg/d CGA by lavage for 12 weeks, whereas the mice in both CON groups were given equal volumes of phosphate-buffered saline (PBS) by lavage. At the end of the intervention, we assessed body fat and the parameters of glucose and lipid metabolism in the plasma, liver and skeletal muscle tissues as well as the levels of aldose reductase (AR) and transforming growth factor-β1 (TGF-β1) in the kidneys and measured adiponectin receptors and the protein expression of their signaling molecules in liver and muscle tissues. After 12 weeks of intervention, compared with the db/db-CON group, the percentage of body fat, fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) in the db/db-CGA group were all significantly decreased; TGF-β1 protein expression and AR activity in the kidney were both decreased; and the adiponectin level in visceral adipose was increased. The protein expression of adiponectin receptors (ADPNRs), the phosphorylation of AMP-activated protein kinase (AMPK) in the liver and muscle, and the mRNA and protein levels of peroxisome proliferator-activated receptor alpha (PPAR-α) in the liver were all significantly greater. CGA could lower the levels of fasting plasma glucose and HbA1c during late diabetes and improve kidney fibrosis to some extent through the modulation of adiponectin receptor signaling pathways in db/db mice.     

姜黄素对db/db小鼠基因组DNA甲基化的影响

目的:观察姜黄素对2型糖尿病模型db/db小鼠糖尿病症状的改善作用,并从表观遗传角度分析其对小鼠外周血DNA甲基化水平的影响。方法:2型糖尿病模型db/db小鼠随机分为糖尿病组和姜黄素干预组(给予250 mg/kg姜黄素溶液),连续灌胃8周。OGTT检测葡萄糖耐量,ELISA法测定空腹胰岛素并计算HOMA-IR和HOMA-β,RRBS技术检测外周血基因组DNA甲基化水平。结果:与糖尿病组相比,姜黄素干预小鼠的血糖、空腹胰岛素和HOMA-IR显著降低,葡萄糖耐量显著改善(P<0.05);且小鼠外周血基因组启动子区、CGI岸和5’-非编码区CpG甲基化水平显著降低(P<0.05);对两组间差异甲基化基因进行功能富集分析,筛选出前10位显著富集的可能与2型糖尿病相关的差异基因包括Hdac7、Micall1、Vangl2、Dhcr24、Kcnj8、Gnas、Tcf7l2、Dgkh、Dlgap1和Plekhg4。结论:姜黄素能够改善db/db小鼠的葡萄糖耐量及胰岛素抵抗,并且其外周血中存在显著低甲基化改变,提示姜黄素可能是通过抑制糖尿病小鼠中某些基因的异常甲基化修饰而发挥抗糖尿病作用。     

SGK1 抑制剂改善糖代谢紊乱的作用研究

目的:观察血清和糖皮质激素诱导的蛋白激酶1(serum and glucocorticoid-induced protein kinase1,SGK1)抑制剂对db/db小鼠糖代谢紊乱的改善作用,初步探讨该作用是否与改善脂肪组织功能紊乱有关。方法:将db/db小鼠随机分为db/db组、抑制剂组,同时设db/m组,db/db组、db/m组小鼠给予普通饲料喂养,抑制剂组小鼠给予含SGK1抑制剂的饲料喂养,干预8周。观察体重、摄食量、空腹血糖(fasting blood glucose,FBG)、糖化血红蛋白(glycosylated hemoglobin,Hb A1C),干预8周后行腹腔葡萄糖耐量试验(intraperitoneal glucose tolerance test,IPGTT)、腹腔胰岛素耐量试验(intraperitoneal insulin tolerance test,IPITT)。酶联免疫吸附测定(enzyme linked immunosorbent assay,ELISA)法检测血清空腹胰岛素(fasting insulin,FINS)水平,计算胰岛素抵抗指数(homeostasis model assessment of insulin resistance,HOMA-IR)及胰岛素敏感性指数(insulin sensitivity index,ISI)。实时定量荧光PCR(real-time PCR)法检测脂肪组织中SGK1、脂肪细胞因子m RNA表达水平。结果:干预8周后,抑制剂组体重、FBG、Hb A1C、IPGTT、IPITT均低于db/db组(P0.05),摄食量无明显差异。与db/db组相比,抑制剂组血清FINS有下降趋势,HOMA-IR明显降低,ISI明显升高(P0.05)。SGK1抑制剂干预治疗后,脂肪组织中SGK1、单核细胞趋化因子-1(monocyte chemotactic protein-1,MCP-1)、凝血酶元激活因子的抑制因子-1(plasminogen activator inhibitor 1,PAI-1)m RNA表达下降(P0.05),脂联素(adiponectin)m RNA表达无明显变化。结论:SGK1抑制剂干预治疗可一定程度改善db/db小鼠糖代谢紊乱,该作用可能部分与改善脂肪组织功能紊乱有关。     

Metabolic efficacy and safety of once-daily pioglitazone monotherapy in patients with type 2 diabetes: a double-blind, placebo-controlled study.

Pioglitazone is a novel oral anti-diabetic agent belonging to the thiazolidinedione class. Pioglitazone has been shown to be effective and well tolerated in the treatment of patients with type 2 diabetes, as it reduces insulin resistance and improves glycaemic control and abnormal lipid profiles. This double-blind, randomised, placebo-controlled study was conducted for further evaluation of the efficacy and tolerability of once-daily administration of pioglitazone monotherapy alongside dietary measures in patients with type 2 diabetes. Following a 10-week washout period, 251 patients received one of three treatment regimens for 26 weeks: placebo + diet (n = 84), pioglitazone 15 mg once-daily + diet (n = 89), or pioglitazone 30 mg once-daily + diet (n = 78). Pioglitazone, both 15 and 30 mg/day, in addition to dietary control, was associated with significant reductions (vs. placebo) in mean levels of both glycosylated haemoglobin (HbA 1C ) and fasting blood glucose (FBG). HbA 1C was reduced by 0.92 % and 1.05 %, respectively, and FBG was reduced by 34.3 and 36.0 mg/dl, respectively, compared with the control group. Pioglitazone at 15 and 30 mg/day significantly reduced postprandial blood glucose levels at all visits (- 163 and - 165 mg/dl/hour, respectively) compared with an increase of 47.7 mg/dl/hour on placebo. The profile and frequency of adverse events were similar in all treatment groups. These results indicate that pioglitazone monotherapy together with dietary control is both effective and safe in patients with type 2 diabetes.