青少年的成人起病型糖尿病的发病机制及防治研究进展

本文在总结国内外关于青少年的成人起病型糖尿病(MODY)的理论成果上,对MODY的发病机制与防治方法进行研究,希望为患者防治MODY提供借鉴与参考。MODY1型糖尿病的发病机制是由HNF-4α基因突变形成的,MODY2型糖尿病的发病机制是由葡萄糖激酶(glucokinase,GCK),GCK突变导致胰腺细胞GCK活性降低而引发的,MODY3型糖尿病的发病机制是由肝细胞核因子1α基因突变所致,MODY4型糖尿病的发病机制是由胰岛素启动因子IPF-1基因突变所致。MODY患者选择高纤维清淡的食物保证患者营业均衡,通过跑步等运动消耗糖量,合理使用胰岛素、二甲双胍药物进行治疗。     

胃旁路术对非肥胖2型糖尿病大鼠肝脏葡萄糖激酶表达的影响

目的:探讨胃旁路术对非肥胖2型糖尿病GK大鼠肝脏葡萄糖激酶(glucokinase,GCK)表达的影响?方法:雄性GK和Wistar大鼠各20只,随机分为GK手术组(GO组)?GK假手术组(GS组)?Wistar手术组(WO组)和Wistar假手术组(WS组),每组10只?检测术前及术后第1?4?8周各组空腹血糖和血清胰岛素水平,术后8周取大鼠肝脏组织,采用RT－PCR检测肝脏GCK mRNA表达水平?结果:GO组术后第1周空腹血糖已开始下降,术后第1?4?8周分别由术前(8.73 ± 1.30)mmol/L下降到(6.84 ± 0.89)?(6.27 ± 0.93)?(5.86 ± 0.57)mmol/L(P < 0.05);随访过程中,GO组空腹血清胰岛素较术前和相应时间点GS组均有所升高,尚未达统计学差异(P > 0.05);GO组术后第8周肝脏GCK mRNA表达水平明显高于GS组(P < 0.05)?结论:胃旁路术能显著改善非肥胖2型糖尿病大鼠的糖代谢,手术的降糖作用可能与肝脏葡萄糖激酶表达增加有关?     

化痰活血法改善2型糖尿病胰岛素抵抗的作用机制研究

目的:研究化痰活血法对2型糖尿病胰岛素抵抗大鼠的葡萄糖激酶(GK)和磷酸烯丙醇羧激酶(PEPCK)的影响与作用机制。方法:将健康的SD大鼠随机分为正常对照空白组和造模组,采用文献法建立2型糖尿病胰岛素抵抗大鼠模型;模型鼠又随机分成三组,即胰苏灵组、罗格列酮组、模型组,分别于给药后测定血糖、血脂、胰岛素、胰岛素受体数目与结合力,4周后禁食处死大鼠,留取血清并剪取肝组织以检测GK、PEPCK。结果:胰苏灵在改善胰岛素敏感指数,降糖、降脂、降低FFA等指标方面与罗格列酮无显著性差异(P>0.05),且胰苏灵可减轻大鼠体质量,胰苏灵组大鼠GK、PEPCK活性与罗格列酮组无显著性差异(P>0.05)。结论:胰苏灵可通过增加肝脏细胞葡萄糖激酶的mRNA及其蛋白质的表达达到改善胰岛素抵抗,发挥治疗糖尿病的作用。     

表没食子儿茶素没食子酸酯对大鼠胰岛素抵抗的影响

目的 研究表没食子儿茶素没食子酸酯(EGCG)对自发性2型糖尿病GK大鼠的胰岛素抵抗的影响及作用机制.方法 自发性2型糖尿病GK大鼠40只,同系健康对照Wistar大鼠10只,大鼠随机分为:正常对照组、2型糖尿病对照组、2型糖尿病低剂量EGCG( 50 mg/kg)治疗组、中剂量(100 mg/kg)组、高剂量EGCG( 300 mg/kg)组.干预6周后,分别检测葡萄糖耐量试验、胰岛素耐受试验、肝脏GcK、G6P以及PEPCKmRNA表达情况,以及骨骼肌细胞膜GLUT4含量的变化.结果 各剂量治疗组的糖耐量均得到明显改善(P＜0.05),胰岛素耐量在240 min时较模型对照组有明显差异(P＜0.05).与模型组比较,低剂量和中剂量治疗组均能提高肝脏葡萄糖激酶(GcK) mRNA的表达(P＜0.05),同时抑制葡萄糖-6-磷酸酶(G6P)和磷酸烯醇式丙酮酸激酶(PEPCK) mRNA的表达(P＜0.05);高剂量治疗组肝脏三类酶mRNA的表达与模型对照组相比无明显差异.各剂量治疗组GK大鼠的骨骼肌细胞膜GLUT4的含量较模型对照组均具有明显上调(P＜0.05).结论 中低剂量EGCG可以改善GK大鼠胰岛素抵抗,其作用机制可能与抑制肝脏糖异生作用以及骨骼肌GLUT4的转位水平有关,并且EGCG具有代偿胰岛素的作用.     

二甲氨基偶氮苯(DAB)诱发大白鼠肝癌形成过程中葡萄糖激酶、肝糖原和血糖之间关系的研究

葡萄糖激酶(GK)是葡萄糖:ATP-磷酸转移酶的Ⅳ型同工酶,仅存在于第肝脏。其活性对宿主营养因素和激素水平的变化反应敏感,禁食48小时和四氧嘧啶糖尿病大鼠肝中GK活性下降,但重饲葡萄糖和给予胰岛素可诱导GK再现。已经证明这是新合成的酶蛋白,不是由于存在抑制剂或激活剂的缘故。     

小檗碱对胰岛素分泌缺陷型糖尿病大鼠葡萄糖激酶相关糖代谢的影响

目的探讨小檗碱对胰岛素分泌缺陷型糖尿病大鼠肝脏葡萄糖激酶(GK)相关糖代谢的影响。方法观察小檗碱对实验性胰岛素分泌缺陷型糖尿病大鼠空腹血糖、血清胰岛素(INS)、糖原、肝脏乳酸(LA)、GK活性及其蛋白表达的影响。结果与模型组比较,小檗碱组大鼠血清空腹血糖水平明显降低,而INS、肝脏LA无明显变化,肝糖原合成增多、GK活性及其蛋白表达明显增高。结论小檗碱能调节胰岛素分泌缺陷型糖尿病大鼠糖代谢,这可能与其促进GK活性及其蛋白表达有关。     

葡萄糖激酶基因启动子区-30位点多态性与2型糖尿病的相关性研究

目的 探讨葡萄糖激酶(glucokinase,GCK)基因启动子区-30位点多态性与2型糖尿病及其各项指标之间的关系.方法 运用PCR-RFLP分析方法在389例无亲缘关系的个体中对GCK基因多态性进行检测.结果 在2型糖尿病患者组中GG、GA和AA基因型频率分别为63.1%、31.9%和5.0%;健康对照者组中分别为66.4%、31.8%和1.8%.结论 GCK基因启动子区-30位点多态性对2型糖尿病的发生不起主要作用,但两个变异等位基因同时存在时,发生2型糖尿病的年龄有所提前,而且可不伴有肥胖.     

以葡萄糖激酶为靶点治疗2型糖尿病的实验研究进展

目的探讨以葡萄糖激酶为靶点治疗2型糖尿病药物的研究现状。方法参阅国内外发表的相关文献,综述葡萄糖激酶激活剂、葡萄糖激酶调节蛋白以及突变的葡萄糖激酶基因对2型糖尿病治疗的效果及影响。结果3种方法均能不同程度地调节2型糖尿病动物的血糖水平,但其具体作用机制及其副作用有待进一步研究。结论以葡萄糖激酶为靶点来调控血糖水平可能是一种安全有效的措施。     

葡萄糖激酶基因逆转录病毒表达载体及包装细胞系的构建及鉴定

目的构建葡萄糖激酶(glucokinase,GK)基因逆转录病毒表达载体及稳定的产毒细胞系,为将GK基因应用于糖尿病的基因治疗打下基础.方法质粒pCMV4-GKZ1经EcoRⅠ/BamHⅠ双酶切后亚克隆至逆转录病毒载体PLXSN,构建成重组逆转录病毒表达载体PLX-GK,采用酶切及测序对重组体进行鉴定.而后脂质体转染PLX-GK至包装细胞PA317,检测培养上清病毒滴度,挑选滴度较高的稳定产毒细胞系并对其行PCR及免疫组化鉴定.结果构建了GK基因逆转录病毒表达载体PLX-GK,经酶切及序列分析证实目的基因插入位点和读码框架正确、无突变;建立了稳定产毒细胞系PA317/GK,其培养上清平均病毒滴度为6.8×105cfu/ml,最高为1.8×106cfu/ml,PCR及免疫组化证实GK基因整合入PA317/GK细胞基因组并有GK的表达.结论成功构建了携GK基因的逆转录病毒表达载体及高滴度的稳定产毒细胞系.     

桦褐孔菌水提取物对糖尿病豚鼠血糖、血脂水平及糖、脂代谢关键酶表达的影响

[目的]探讨桦褐孔菌水提取物对血糖、血脂水平及糖、脂代谢关键酶表达的影响,并探讨其作用机理.[方法]采用链脲佐菌素腹腔注射方法制作豚鼠糖尿病模型,灌胃给予不同剂量的桦褐孔菌水提取物,给药前及给药8周后分别检测豚鼠空腹血糖(FBG)、总胆固醇(TC)、葡萄糖激酶(GK)及羟甲基戊二酸单酰(HMG)CoA还原酶水平.[结果]桦褐孔菌水提取物降低糖尿病豚鼠FBG,TC水平,增高GK表达,降低HMGCoA还原酶表达.[结论]桦褐孔菌水提取物具有降低糖尿病豚鼠FBG,TC水平的作用,其机制可能与增强GK表达及降低HMGCoA还原酶表达相关.     

Type II diabetes of early onset: a distinct clinical and genetic syndrome?

The inheritance of non-insulin-dependent (type II) diabetes was studied by a continuous infusion of glucose test in all available first degree relatives of 48 diabetic probands of various ages and with differing severity of disease. In an initial study of 38 type II diabetic subjects and their first degree relatives six islet cell antibody negative patients with early onset disease (aged 25-40 at diagnosis) were found to have a particularly high familial prevalence of diabetes or glucose intolerance. Nine of 10 parents available for study either had type II diabetes or were glucose intolerant. A high prevalence of diabetes or glucose intolerance was also found in their siblings (11/16;69%). In a second study of the families of a further 10 young diabetic probands (presenting age 25-40) whose islet cell antibody state was unknown a similar high prevalence of diabetes or glucose intolerance was found among parents of the five islet cell antibody negative probands (8/9; 89%) but not among parents of the five islet cell antibody positive probands (3/8;38%). Islet cell antibody negative diabetics with early onset type II disease may have inherited a diabetogenic gene or genes from both parents. They commonly need insulin to maintain adequate glycaemic control and may develop severe diabetic complications. Early onset type II diabetes may represent a syndrome in which characteristic pedigrees, clinical severity, and absence of islet autoimmunity make it distinct from either type I diabetes, maturity onset diabetes of the young, or late onset type II diabetes.     

Serum lipid profile in hypertensive and normotensive type II diabetes mellitus patients--a comparative study

A comparative prospective study was done in 10 patients suffering from hypertension with type II diabetes mellitus and 10 patients suffering from type II diabetes without hypertension. The serum Lipid profile was studied on 10 healthy normotensive nondiabetic subject, on 10 patients suffering from hypertension with type II diabetes mellitus and on 10 patients suffering from type II diabetes mellitus without hypertension. In present study a significantly higher level of serum total cholesterol, triglyceride and LDL-Cholesterol concentration were observed in hypertensive type II diabetes mellitus and normotensive type II diabetes mellitus subjects in comparison to control group and serum HDL-cholesterol concentration was significantly lower in both the groups in comparison to healthy control. There was significantly increased level of serum total cholesterol (P < 0.001) and LDL-cholesterol (P < 0.001) in hypertensive type II diabetes mellitus in comparison to normotensive type II diabetes mellitus. Though serum triglyceride level was increased in hypertensive type II diabetes mellitus in comparison to normotensive type II diabetes mellitus, but it was not statistically significant. Serum HDL-cholesterol level was more in normotensive type II diabetes mellitus in comparison to hypertensive type II diabetes mellitus group but it was not statistically significant.     

Serum levels of copper and zinc in newly diagnosed type-2 diabetic subjects

Diabetes mellitus is a chronic metabolic disorder which affects carbohydrate, lipid and protein metabolism. There is a strong relation between some specific oligoelements and diabetes mellitus. The study was undertaken to determine serum levels of copper and zinc in 60 type 2 diabetic (Group I) and 60 healthy non-diabetic subjects (Group II). Diabetic patients studied were without any complications. Serum copper and zinc were estimated by Atomic Absorption Spectrophotometer (AAS). The serum copper levels (144.00±12.87μg/dl) significantly increased in Group I compared to Group II (138.50±11.00μg/dl). On the other hand, the Plasma zinc (72.70±8.43μg/dl) levels significantly decreased in type 2 diabetic patients compared to control group (75.92±8.20μg/dl). It is concluded that type 2 diabetes mellitus can result in changes in copper and zinc levels. However, it is difficult to draw any definite conclusion from this small study sample but may be suggested that estimation of both copper and zinc is better to be considered in those cases.     

Fournier's gangrene and diabetic ketoacidosis with lower-than-anticipated glucose levels associated with SGLT-2 inhibitor: A double trouble

Empagliflozin has a demonstrated cardiovascular benefit. It is co-prescribed as a glucose-lowering medication in patients with type II diabetes mellitus. Herein, we discuss dual-emergency side-effects, Fournier's gangrene (FG) and diabetic ketoacidosis with lower-than-anticipated glucose levels in a patient on Empagliflozin, a sodium-glucose transport protein 2 inhibitor (SGLT-2i). The pathophysiologic mechanism of FG in correlation with SGLT-2i is not yet elucidated. SGLT-2i increase predisposition to genital mycotic and urinary infections, a mechanism favouring FG. A patient with type II diabetes mellitus on SGLT-2i presented with acute necrotic infection of the scrotum and simultaneous diabetic ketoacidosis with lower-than-anticipated glucose levels. This dual emergency was managed with debridement and medical treatment on lines of diabetes ketoacidosis, respectively. A re-look at this group of glucose-lowering medications from bedside towards benchtop research may help to prod into any other mechanistic basis of these life-threatening clinical occurrences.     

慢白激酶Cζ亚型基因及Urotensin Ⅱ基因中各有一个单核苷酸位点与中国北方汉族人群2型糖尿病相关

目的 采用单核苷酸多态性（single mucleotide polymorphism,SNP)标记,在以往中国北方汉族人群2型糖尿病相关基因定位区域（1p36.33-p36.23)内寻找疾病易感基因位点。方法 通过生物信息学方法在公共SNP数据库中查找定位区域内10个候选基因中的23个SNP位点,用单碱基延伸反应（single base extension,SBE)法对北方汉族人群散发2型糖尿病患者（192例）及对照组（172例）进行分型及病例－对照关联分析。结果 23个SNP位点中有8个为中国北方人群常见SNP位点;对病例组和对照组分型分析显示,位于蛋白激酶Cζ亚型（PRKCZ）基因中的一个位点（rs436045)及urotensin Ⅱ（UTS2）基因中的一个位点（rs228648),其等位基因频率在两组的差异具有统计学意义9P＜0．05）。结论 上述两个SNP位点可能和中国北方汉族人群2型糖尿病相关,以上结果为进一步研究上述两个位点所在的基因与2型糖尿病的关系提供了理论依据。     

A型性格与非胰岛素依赖型糖尿病关系的病例对照研究

目的 探讨A型性格与非胰岛素依赖型（II型）糖尿病的关系。方法 采用频数匹配病例对照研究设计，随机选择徐州市II型糖尿病新发病例185例，医院对照201例和人群对照197例，使用“A型性格问卷”和统一的调查表开展现场调查，并对结果进行单因素和多因素非条件Logistic回归分析。结果病例组行为特征计分TH，CH及TH＋CH计分与对照组相比，差异有非常显著意义（P＜0．01），与B型性格相比，A型性格者患II型糖尿病的OR值为2．59（95％CI为1．62－4．13），结论 A型性格可能是II型糖尿病独立的危险因素。     

栽培甘草的黄酮提取物对糖尿病大鼠血糖、尿糖及抗氧化作用的影响

目的观察宁夏地区栽培甘草(Glycyrrhiza uralensis Fisch.)提取物甘草黄酮(licorice flavonoids,LF)对2型糖尿病(T2DM)模型大鼠的降糖作用及抗氧化作用的研究。方法采用高脂高糖饮食喂养后(12周)注射链脲佐菌素(streptozotocin,STZ,35mg.kg-1,ip)制备大鼠2型糖尿病模型,实施腹腔注射300mg.kg-1和100mg.kg-1剂量的LF干预40d后,测定空腹血糖、血浆糖化血红蛋白(HbA1C)、尿糖值、24h尿蛋白值和酮体值,以及血清超氧化物歧化酶(SOD)、丙二醛(MDA)、谷胱甘肽过氧化物酶(GSH-PX)和总抗氧化能力(T-AOC)。结果 LF降低空腹血糖、HbA1C水平、尿糖值,升高血清SOD和GSH-PX水平的同时,降低血清MDA含量。LF对血浆T-AOC、24h尿蛋白值和酮体值,改善不明显。结论宁夏地区栽培甘草中甘草黄酮具有改善实验性2型糖尿病大鼠糖代谢的作用,其抗氧化活性可能与其作用有关。     

The abnormal changes of apolipoprotein(s) in patients with type 2 diabetes mellitus]

OBJECTIVE: To investigate the changes of the apolipoproteins(apoA I, A II, B100, C II, C III, E) in patients with type 2 diabetes mellitus. METHODS: The levels of fasting plasma glucose(FBG), insulin, TG, TC, apoA I, A II, B100, C II, C III, E were all measured in 127 non-diabetic subjects and 143 type 2 diabetic patients (20 associated with coronary heart disease (CHD) and 66 associated with hypertriglyceridemia(HTG), 55 associated with hypercholesterolemia). RESULTS: In male type 2 diabetic patients, the levels of FBG, WHR and apoC II were significantly higher (P < 0.05) and apoA I, A II levels were significantly lower (P < 0.05) than those in male non-diabetic subjects. In female type 2 diabetic patients, the levels of FBG, BMI, WHR, TG significantly elevated while HDL-C, apoA I, A II levels significantly decreased as compared with those in female non-diabetic subjects. In type 2 diabetic group, the levels of WHR, FBG and TG in HTG patients were elevated significantly as compared with those without HTG, and the levels of HDL-C, apoA I and apoA II were decreased; the levels of WHR, TG, TC, apoB100, C II, C III, E in patients with HTC were significantly higher than those whose cholesterol levels were normal. In patients with CHD, the levels of fasting insulin, apoB100, apoC II and apoE were significantly higher than those in patients without CHD, and the levels of HDL-C and apoA II were decreased significantly. CONCLUSION: Abnormal changes of apo(s) in type 2 diabetes mellitus may be a cause of type 2 diabetes associated with HTG and CHD.     

高血压病合并糖尿病患者尿微量蛋白与左室重量指数的关系和意义

目的探讨高血压病合并糖尿病患者尿微量蛋白、左室重量指数(LVMI)的变化及其相互关系.方法采用免疫发光法测定36例高血压病患者(EH组)、35例糖尿病患者(DM组)和34例高血压病合并糖尿病患者(EM DM组)的尿微量蛋白,并对3组患者作超声心动图检查,根据有关数据计算出LVMI,并对结果进行比较分析.结果3组尿微量蛋白各项指标均高于正常范围,EH DM组尿微量白蛋白(ALB)、LVMI较EH组、DM组显著升高(均P＜0.05).LVMI与ALB、尿转铁蛋白、免疫球蛋白均呈显著正相关(均P＜0.05).结论高血压病和糖尿病可引起尿微量蛋白的增高,并且与LVMI相关,两者并存可以加重心、肾等脏器的损害.     

腺苷酸活化蛋白激酶与消化道肿瘤的分子靶向治疗

哺乳动物的腺苷活化蛋白激酶(AMPK)是一类丝氨酸-苏氨酸蛋白激酶,属于蛋白激酶级联系统的中心元件。作为细胞的能量感受器,AMPK调节多条代谢途径,AMPK异常导致多种代谢异常综合征,且活化状态的AMPK可通过多条途径抑制细胞生长并诱导凋亡,包括抑制在人类绝大多数肿瘤细胞中激活的mTORC1激酶。因此,它已经成为治疗2型糖尿病、肥胖症甚至肿瘤的良好药物靶。