嘌呤P2受体的分子生物学研究进展

嘌呤P2受体家族是目前发现的最复杂的受体家族之一,在体内分布广泛,功能复杂,目前已有7种P2X受体和8种P2Y受体被克隆。P2受体的分类和研究历史非常复杂,随着分子生物技术的发展,P2受体的研究取得了明显的进展,特别是新克隆出的P2Y_(12),P2Y_(13)和P2Y_(14)受体,丰富了P2受体家族,使其结构特征、药理学特性不断被揭示。本文对P2受体的研究历史、分类方法、分子结构特征和药理学特性做一概述,并对最新报道的P2受体的相互作用以及关于P2Y_(15)受体的争论进行综述。     

胰腺-十二指肠同源框-1与糖尿病的研究新进展

糖尿病是以胰岛素绝对或相对不足为主要特征的临床综合征,而胰岛素是由胰岛β细胞分泌的体内唯一降血糖激素。胰腺-十二指肠同源框-1(PDX-1)在胰腺的早期发育和晚期分化、胰岛β细胞正常功能的维持及胰岛素的分泌等方面均有重要作用。此外,PDX-1可诱导非胰岛细胞如肝细胞、成肌细胞等向胰岛素分泌细胞分化,提示PDX-1在糖尿病的治疗领域有重要作用。     

胰腺内分泌肿瘤的诊治探讨

胰腺内分泌肿瘤是一种少见的肿瘤,它可发生于胰岛,也可以起源于腺泡和胰管之间的内分泌细胞。在临床上表现多有与某一激素过量分泌相关的症候群,多被误诊或漏诊,多数医院与医师对此缺乏足够认识,极有必要提高胰腺内分泌肿瘤的认识和诊疗水平。     

胰腺内分泌肿瘤诊治的探讨

目的探讨胰腺内分泌肿瘤(PET)的最新诊治方法,提高对胰腺内分泌肿瘤的认识和诊疗水平。胰腺内分泌肿瘤是一种胰腺内部少见的肿瘤,发病率较低,但具有恶变行,常发生于胰岛,也可以起源于腺泡和胰管之间的内分泌细胞。方法对临床的资料进行总结和分析。结论只有早期明确诊断、提高有效治疗才是提高胰腺内分泌肿瘤患者生存率和术后恢复率的关键。     

P_2嘌呤受体的研究进展

P2 嘌呤受体最初被分为P2X和P2Y两种亚型 ,其后扩展到P2T、P2Z 和P2D亚型。 90年代发现 ,一些组织标本对UTP、ATP和ATPγS反应良好 ,而对α ,β MeATP和 2 MeSATP不敏感 ,此类受体被称为“P2U受体”。晚近又证明 ,存在一种对UTP敏感而对ATP不敏感的“嘧啶受体”。据此IUPHAR(Internationalunionofpharmacology)规定 ,任何被核苷酸激活的离子通道型和G蛋白偶联型受体的亚型均分别命名为P2Xn和P2Yn受体。随着分子生物学技术的发展以及上述受体的克隆和表达 ,此分类系统得到了有力的支持。     

嘌呤受体在神经元和神经胶质细胞间信息传递中的作用

神经系统的功能在很大程度上取决于神经元-神经胶质细胞间的信息交流。而神经元与神经胶质细胞间复杂的信号通路间的相互作用涉及多种信号分子,嘌呤和嘌呤受体在此过程中起着重要作用。长久以来,关于中枢神经系统的研究主要集中在神经元,相比之下神经胶质细胞主要被作为支持细胞或在应对脑损伤时提供导向作用。最新研究表明,神经胶质细胞在神经系统疾病的发生发展中也扮演着重要角色。该文主要阐述嘌呤受体在神经元和神经胶质细胞之间的相互作用及其在神经系统疾病中的作用。     

功能性胰腺神经内分泌肿瘤的药物治疗进展

胰腺神经内分泌肿瘤(pancreatic neuroendocrine tumor,pNET)可来源于多种神经内分泌细胞,不同类型其临床表现、进展与预后各有不同。针对其中能够产生过量激素的功能性pNET,治疗时需兼顾抑制肿瘤生长与激素分泌。除了传统的手术治疗与化疗,近年来在生长抑素类似物(somatostatin analogue,SSA)、靶向药物、免疫检查点抑制剂、肽受体放射性核素疗法以及多种疗法联合使用方面取得了新的进展,为不同肿瘤类型和分期的患者提供了更多干预手段。本文对近年来功能性pNET的治疗进展进行综述,并对不同激素类型的pNET的药物治疗进行逐一总结。     

胰腺内分泌肿瘤的诊断和外科治疗

目的：探讨胰腺内分泌肿瘤（pancreatic endocrine tumours, PET）的临床特点,藉以提高临床诊治水平。方法：对我院1973年1月至2006年12月收治的77例PET患者的临床、病理资料进行回顾性分析。结果：本组女性46例（59.7%）;功能性PET占72.7%;良性为81.8%。术前B超和CT检查发现65例（84.4%）有胰腺占位病变;单发肿瘤位于胰头、体、尾部,分别为18.2%、28.6%和45.5%;多发肿瘤6例。肿瘤最大径8 cm。所有病例均得到病理检查,显示胰岛素瘤43例（55.8%）,胃泌素瘤7例,胰高血糖素瘤5例,血管活性肠肽瘤1例,余21例为无功能PET。2例胃泌素瘤合并甲状旁腺瘤,为Ⅰ型多发性內分泌瘤。胰高血糖素瘤表现为游走性坏死性红斑、大泡性皮损和糖尿病。血管活性肠肽瘤表现为腹泻和低钾血症;无功能PET主要症状为反复中上腹隐痛。手术治疗PET的主要术式为肿瘤局部切除术（53例,68.8%）。手术后43例胰岛素瘤患者中,39例血糖恢复正常;胃泌素瘤、胰高血糖素瘤和血管活性肠肽瘤患者的术后症状均有缓解或完全消失。胰漏是主要的术后并发症。结论：PET发病隐匿,根据B超和CT检查可明确肿瘤的位置。最终诊断根据病理检查。本病预后明显好于胰腺癌,因此一旦明确诊断,应争取彻底切除肿瘤。恶性PET伴转移者的术后病死率较高。     

胰腺β细胞的移植来源

1型糖尿病由分泌胰岛素的胰腺β细胞自身免疫破坏引起,其治疗目前主要是补充外源性胰岛素。与传统的胰岛素治疗相比,胰岛移植能获得稳定的正常血糖状态、避免低血糖发作、防止或延缓糖尿病慢性并发症,且手术安全、简便及可反复多次移植。     

新型餐后血糖调节剂——格列奈类药物的研究进展

早期相胰岛素分泌能力的损害是引起2型糖尿病及其并发症的重要因素，格列奈类药物作为一种新型促胰岛素分泌的药物，起效快，作用时间短，较磺酰脲类能更好地控制餐时血糖的增高，降低餐后血糖高峰，与双胍类合用可以发挥协同效应。其安全性良好，极少发生餐后低血糖，并能预防糖尿病的心血管并发症等。本文就早期相胰岛素分泌与糖尿病的关系、格列奈类药物的药理特性及临床应用等作一概述。     

Beneficial effect of T-1095, a selective inhibitor of renal Na+-glucose cotransporters,on metabolic index and insulin secretion in spontaneously diabetic GK rats

1. To investigate the pharmacological effects of T-1095, this novel derivative of phlorizin was administered to GK rats for 8 weeks. T-1095 treatment significantly lowered plasma glucose and glycosylated haemoglobin (HbA1c) levels, but did not significantly affect bodyweight. 2. T-1095 treatment did not affect 3.3 mmol/L glucose-induced insulin secretion in the isolated perfused pancreas of GK rats. 3. The peak insulin release in T-1095-treated GK rats was significantly higher during the first phase than in untreated GK rats (3-4 min after beginning 16.7 mmol/L glucose perfusion). The total amount of insulin secreted during the first phase in T-1095-treated GK rats was significantly higher than in untreated GK rats (35.3 +/- 1.4 vs. 27.3 +/- 2.5 ng in T-1095-treated compared with untreated rats, respectively). 4. During the second phase, insulin release in T-1095-treated GK rats was somewhat higher than in untreated GK rats (7-30 min after beginning 16.7 mmol/L glucose perfusion). The total amount of insulin secreted during the second phase in T-1095-treated GK rats was significantly higher than in untreated GK rats (88.2 +/- 6.1 vs. 68.1 +/- 5.7 ng, respectively). 5. The total amount of insulin secreted during perfusion in T-1095-treated GK rats was significantly higher than in untreated GK rats (123.5 +/- 7.3 vs. 95.4 +/- 7.7 ng, respectively). 6. These data show that the metabolic indices, plasma glucose and HbA1c levels and insulin secretion are significantly improved by T-1095 treatment in GK rats, which are spontaneously diabetic rats, suggesting its usefulness as a novel oral therapeutic antidiabetic agent.     

高胰岛素-正葡萄糖钳夹技术的研究进展*

高胰岛素-正葡萄糖钳夹技术（简称正糖钳技术）已被公认为测定胰岛素敏感性的金标准,并在糖尿病及其治疗药物的研究中得到日益广泛且深入的应用。该技术通过同时输注外源性胰岛素与葡萄糖,升高血浆胰岛素水平,同时维持血糖在基础稳态水平。该技术减少了内源性因素对实验的影响,具有准确可靠、重复性好、避免低血糖发生等优点。现介绍该技术的原理、方法、应用等,以促进该技术在我国的进一步完善、发展及应用。     

甲壳低聚糖硒对2型糖尿病大鼠胰岛素指标及胰腺组织的影响

目的观察甲壳低聚糖硒(COS-Se)对2型糖尿病大鼠的胰岛素含量、胰岛素敏感性及胰腺组织的影响。方法制备2型糖尿病大鼠模型,分别给予COS-Se、Se、甲壳低聚糖(COS)对其进行干预,观察20周,期间检测血糖、胰岛素的含量、胰岛素敏感指数及胰腺组织HE染色观察。结果 COS-Se、Se、COS对糖尿病模型的高胰岛素血症都有一定改善作用,随着时间的延长,COS-Se的改善作用更明显。结论 COS-Se可保护胰岛细胞,改善2型糖尿病大鼠的胰岛素敏感性。     

促泌剂对胰岛素强化治疗后的初诊2型糖尿病患者胰岛β细胞分泌胰岛素的影响

目的:观察瑞格列奈或格列美脲对短期胰岛素强化治疗后血糖达标的初诊2型糖尿病(T2DM)患者胰岛β细胞分泌胰岛素的影响。方法:对60例经为期约2周的胰岛素强化治疗后血糖达标的初诊T2DM患者,进行75 g葡萄糖耐量试验(OGTT),测定血糖和胰岛素值,计算早相胰岛β细胞分泌指数(△I30/△G30,糖负荷30 min净增胰岛素与净增葡萄糖的比值),以30～120 min的胰岛素分泌曲线下面积和葡萄糖曲线下面积比值(△AUCI 30-120/△AUCG 30-120)表示晚相胰岛素分泌能力。然后按照1∶1比例,随机分成瑞格列奈组和格列美脲组,分别接受瑞格列奈和格列美脲治疗,维持6个月后重复行OGTT,检测上述指标。对口服药物治疗前后胰岛β细胞功能进行自身比较。结果:瑞格列奈组△I30/△G30差异有显著性(P<0.01),而△AUCI 30-120/△AUCG 30-120无统计学意义(P>0.05)。格列美脲组△AUCI 30-120/△AUCG 30-120显著上升(P<0.05),而△I30/△G30无统计学意义(P>0.05)。结论:瑞格列奈以促进早相分泌为主,格列美脲以促进晚相分泌为主。     

老年2型糖尿病患者骨钙素与胰岛β细胞功能及hs-CRP的相关性研究

目的分析老年2型糖尿病患者血清骨钙素(OC)与胰岛β细胞功能、胰岛素抵抗、血脂及hs-CRP之间的关系。方法随机选取临床资料完善的住院老年糖尿病患者119名,测定其OC、糖脂代谢指标及hsCRP,并计算体重指数(BMI)、胰岛素抵抗指数(HOMA-IR)、胰岛β细胞分泌指数(HOMA-β),采用Person偏相关分析,比较OC与其他糖脂代谢指标的相关性。并与不同水平Hb A1c组的糖脂代谢、OC等指标行t检验。结果老年糖尿病患者的血清OC水平与空腹血糖、糖化血红蛋白、hs-CRP呈负相关(P<0.05),与空腹胰岛素、HOMA-β呈正相关;与HOMA-IR、TG、TC、LDL、HDL无相关性。低Hb A1c组的HOMA-β和OC水平显著高于高Hb A1c组(P<0.01),差异具有统计学意义。但2组hs-CRP和HOMA-IR无明显差别。结论老年2型糖尿病患者OC水平与胰岛β细胞功能和全身性炎症反应密切相关。     

P633H,a novel dual agonist at peroxisome proliferator-activated receptors α and γ, with different anti-diabetic effects in db/db and KK-Ay mice

Background and purpose:

Peroxisome proliferator-activated receptors (PPARs) are attractive targets for the treatment of type 2 diabetes and the metabolic syndrome. P633H (2-[4-(2-Fluoro-benzenesulphonyl)-piperazin-1-yl]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid), a novel PPARα/γ dual agonist, was investigated for its very different effects on insulin resistance and dyslipidemia in db/db and KK-A^y mice.

Experimental approach:

The action of P633H at PPARα/γ was characterized by using transactivation assays. Functional activation of PPARα/γin vitro was confirmed by pre-adipocyte differentiation and regulation of target gene expression. Anti-diabetic studies were performed in two different diabetic mice models in vivo.

Key results:

P633H activated both PPARα and PPAR γ, (with EC₅₀ values of 0.012 µmol and 0.032 µmol respectively). Additionally, P633H promoted pre-adipocyte differentiation, up-regulated expression of adipose specific transport protein (aP2) mRNA (3T3-Ll cells) and acyl-CoA oxidase mRNA (LO2 cells). In db/db mice, P633H reduced serum glucose, insulin, triglycerides, non-esterified fatty acids and liver triglycerides. It also improved glucose intolerance without affecting food intake and body weight after 15 days of treatment. However in KK-A^y mice, hyperglycaemia, dyslipidemia and impaired glucose tolerance were not relieved even after a 25 day treatment with P633H. Further studies with real-time PCR and electron microscopy revealed that P633H promoted progression of diabetes in KK-A^y mice by increasing hepatic gluconeogenesis and exacerbating pancreatic pathology.

Conclusion and implications:

Although P633H was a high-potency PPARα/γ dual agonist, with good functional activity in vitro, it produced opposing anti-diabetic effects in db/db and KK-A^y mice.     

Effect of chlorpromazine on blood glucose and plasma insulin in man

Summary In three groups of normal subjects and in one group of patients with latent diabetes mellitus a study has been made of the effects of chlorpromazine (CPZ) on blood glucose and plasma insulin. CPZ 75 mg/day for 7 days did not alter the plasma insulin response after oral glucose; nor did CPZ 50 mg/day for 7 days affect the glucose assimilation rate or insulin response to glucose injection. Infusion of CPZ 50 mg in 60 min slightly increased the basal blood glucose level but had no significant effect on basal plasma insulin. The insulin/glucose ratio after the end of the infusion was significantly higher than during the period of infusion of the drug. In latent diabetic patients CPZ infusion significantly diminished the insulin/glucose ratio during an intravenous glucose tolerance test. These results suggest that, whereas prolonged treatment with low doses of CPZ did not modify glucose tolerance and glucose-stimulated pancreatic response, higher acute doses of the drug may induce hyperglycaemia and can inhibit insulin secretion both in normal man and in patients with latent diabetes mellitus.