CN1492766A - 通过施用GnRH拮抗剂预防糖尿病 - Google Patents

通过施用GnRH拮抗剂预防糖尿病 Download PDF

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CN1492766A
CN1492766A CNA018229786A CN01822978A CN1492766A CN 1492766 A CN1492766 A CN 1492766A CN A018229786 A CNA018229786 A CN A018229786A CN 01822978 A CN01822978 A CN 01822978A CN 1492766 A CN1492766 A CN 1492766A
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J��D���Ÿ���ɭ
J·D·雅各布森
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Abstract

提供了一种降低糖尿病易感哺乳动物(如小鼠、大鼠、人)糖尿病发病率或延迟该病发作的方法,其中哺乳动物用促性腺素释放激素(GnRH)拮抗剂处理。优选的拮抗剂是通过皮下注射重复施用的。有用的拮抗剂是乙酰-β-[2-萘基]-D-Ala-D-p-氯代-Phe-β[3-吡啶基]-D-Ala-Ser-Nε-[烟酰]-lys-Nε[烟酰]-D-Lys-Leu-Nε-[异丙基]-Lys-Pro-D-Ala-NH2。其它有用的拮抗剂有Nal-Glu、PPI-149和acryline。

Description

通过施用GnRH拮抗剂预防糖尿病
                         发明背景
发明领域
本发明涉及通过对哺乳动物施用有效量的促性腺素释放激素(GnRH)拮抗剂来降低糖尿病易感的哺乳动物(如小鼠、大鼠、人)中糖尿病发病率或延迟该病发作的方法。此类拮抗剂的施用在统计学上显著降低糖尿病发病率和/或其发作。
现有技术描述
美国有一千五百七十万人(占总人口的5.9%)患有糖尿病。估计有一千零三十万人被诊断患有糖尿病,并有五百四十万人不知道他们患有此病。每天大约有2,200人被诊断出患有糖尿病。在美国糖尿病是第七大致死原因(第六大致死疾病)。糖尿病是一种无法治愈的慢性疾病。糖尿病是美国花费最大的健康问题。直接与糖尿病有关的保健和其它费用以及生产率损失的费用每年多达980亿美元。
糖尿病是人体不能产生或正确使用胰岛素的疾病,胰岛素是一种需要的将糖、淀粉和其它食物转化成日常生活所需能量的激素。糖尿病的原因是一个谜,尽管遗传和环境因素如肥胖和缺乏锻炼似乎与其有关。有两种主要类型的糖尿病。
·I型。一种人体不能产生任何胰岛素的自身免疫性疾病,大多数发生在儿童和青年中。患有I型糖尿病的人必须每天注射胰岛素以维持生命。I型糖尿病占糖尿病总数的5-10%。
·II型。一种导致人体不能产生足够胰岛素或正确使用胰岛素的代谢疾病。它是这种疾病最常见的形式。II型糖尿病占糖尿病总数的90-95%。由于美国老龄人数的增加以及肥胖和久坐的生活方式非常普遍,II型糖尿病的比例正在接近流行病。
I型糖尿病有两种形式。免疫介导的糖尿病由自身免疫过程产生,其中有体的免疫系统攻击并破坏胰腺的胰岛素产生细胞。由于葡萄糖不能进入细胞,它在血液中积累和体细胞被逐渐饿死。第二种特发的I型糖尿病,是指原因不知的稀有类型的疾病。患有I型糖尿病的人必须每天注射胰岛素以维持生命。
与男性相比,女性中某些自身免疫性疾病的发病率上升得非常快,这已被广泛接受。尽管有证据表明雄激素和雌激素在自身免疫性疾病的发病机理中起作用,但性腺甾体在自身免疫性疾病中的确切作用尚不清楚。在实验模型中进行的大量研究表明,性腺切除术会改变自身免疫性疾病包括糖尿病的表现。(Roubinian等,(1978)Effect of Castration and Sex Hormone Treatment on survival,Anti-nucleic Acid Antibodies,and Glomerulonephritis in Nzb/nzw F1 Mice.J.ExpMed,147,1568-83;Hawkins等,(1993)The Effect of Neonatal Sex Hormones onthe Inc idence of Diabetes in Nonobese Diabetic Mice.Proc.Soc.Exper.Biol.Med,202,201-205;Makino等,(1981)The Effect of Castration on the Appearanceof Diabetes in Nod Mouse,Exp Anim,30;和Fitzpatrick等,(1991)Influenceof Castration,along or Combined with Thyrmectomy,on the Development ofDiabetes in the Non-obese Diabetic Mouse.Endocrinology,129,1382-1390)。
然而,在体外进行了许多有关自身免疫中性别差异的研究,这里如性腺切除术或施用性腺甾体等操作必定改变下丘脑和垂体激素的反馈作用,现在已知其中一些与免疫调节有关。一种具有免疫调节特性的下丘脑激素是促性腺素释放激素(GnRH)。已知GnRH通过其对性腺甾体的调节而具有间接的免疫调节特性。已知GnRH在体外和在性腺切除的大鼠体内发挥直接的免疫调节作用。GnRH激动剂可防止胸腺内卷,这通常发生在老龄大鼠中(Marchetti等,(1989)Luteinizing Hormone-releasing Hormone(Lhrh)Agonist Restoration of Age-associated Decline ofThymus Weight,Thymic Lhrh Receptors,and Thymocyte ProliferativeCapacity.Endocrinology,125,1037-45)。GnRH激动剂的施用和大鼠中B和T细胞增殖反应的增加以及表达Il-2受体的T淋巴细胞数目的增加有关(Morale等,(1991)Blockade of Central and Peripheral Lutienizing Hormone-releasingHormone(Lhrh)Receptors in Neonatal Rats with a Potent Lhrh-antagonistInhibits the Morphofunctional Development of the Thymus and Maturation ofthe Cell-mediated and Humoral Immune Responses.Endocrinology,128,1073-85;和Batticane等,(1991)Luteinizing Hormone-releasing Hormone Signaling atthe Lymphocyte Involves Stimulation of Interleukin-2 Receptor Expression.Endocrinology,129,277-86)。此外,脾脏和胸腺制剂显示含有GnRH的mRNA并可产生免疫反应性的GnRH(Emanuele等,(1990)Rat Spleen Lymphocytes Contain anImmunoactive and Bioactive Luteinizing Hormone-releasingHormone.Endocrinology,126,2482-6;和Maier等,(1992)Thymocytes Expressa Mrna That Is Identical to Hypothalamic Luteinizing Hormone-releasingHormone Mrna.Cell Mol Neurobiol,12,447-54)。最近的研究证实,当T细胞在体外被PHA活化时淋巴细胞的GnRH产生会增加(Azad等,(1993)ImmunoactivationEnhances the Concentration of Luteinizing Hormone-releasing HormonePeptide and its Gene Expression in Human Peripheral T-lymphocytes.Endocrinology,133,215-23)。因此,GnRH似乎通常对免疫系统有刺激作用。
发明简述
本发明涉及哺乳类糖尿病的问题,它提供了降低疾病发病率和/或延迟其在对糖尿病有易感性的冒风险的哺乳动物中发作的方法。概括地说,所述方法包括对此类易感哺乳动物施用有效量的GnRH拮抗剂。已发现这样可明显减缓疾病的发展或延迟疾病的发作。GnRH拮抗剂是抑制内分泌系统相关功能、GnRH的生物合成或GnRH体内作用的物质。
实践中,易感哺乳动物如小鼠、大鼠和人可按照本发明治疗。通常,有效的GnRH拮抗剂是反复施用的(通常通过皮下注射)以达到最佳效果。可使用许多已知的GnRH拮抗剂,如乙酰-β-[2-萘基]-D-Ala-D-p-氯代-Phe-β[3-吡啶基]-D-Ala-Ser-Nε-[烟酰]-Lys-Nε[烟酰]-D-Lys-Leu-Nε-[异丙基]Lys-Pro-D-Ala-NH2、Glu-Nal、Abarelix(PPI-149)和acyline(Gamick等,Abarelix(PPI-14)。一种新的和有效的GnRH拮抗剂,它可在近程治疗(BT)和放射治疗(XRT)之前导致迅速且显著的前列腺体积减小(PGYR)和雄激素抑制,Poster Sessions,Endo 98,第265页。另一些此类拮抗剂披露在美国专利6,156,772、5,156,767、6,150,522、6,150,352、6,147,088、6,077,858、6,077,847、6,025,366、6,017,944、6,004,984和5,998,432中。目前认为Abarelix-Depot(Albarelix的一种受控释放形式)将是可供选择的GnRH拮抗剂。
如本文使用的那样,“糖尿病易感哺乳动物”是指与正常的非易感群体相比,对感染I型(自身免疫)糖尿病具有统计学上显著素因的哺乳动物。这种素因可通过大量的遗传和/或抗体筛选或试验确定。例如,糖尿病易感人群通常显示出至少一种,较好的是两种或更多以下列举的危险种类。易感人群的年龄在0-45岁之间,且:
1.是患有I型糖尿病患者的同胞、后代或两代或三代亲属(如侄女、侄子、伯母、伯父、堂兄北、孙);或
2.胰岛细胞自身抗体(ICA)的滴度大于10幼年型糖尿病基础(JDF)单位;或
3.在血清筛选样品中显示有胰岛素自身抗体。
附图简述
图1是说明阉割的NOD小鼠中GnRH、GnRH拮抗剂和GnRH促激动剂对IgG水平作用的图;和
图2是说明GnRH拮抗剂、载体和GnRH激动剂对性腺切除的雄性NOD小鼠中糖尿病的时间控制和发病的作用的图(未患糖尿病的小鼠百分比对一天中时间)。
优选实施例的详细描述
以下实施例列出了用糖尿病易感小鼠进行的一系列试验,这里的小鼠用已知的GnRH拮抗剂处理。应理解提供这些实施例仅是为了阐述,且其中的任何内容都不能作为是对本发明内容的限制。
实施例
在此实施例中,用GnRH激动剂和拮抗剂处理完整的、和切除性腺的非肥胖小鼠模型的糖尿病(NOD)小鼠,以确定其对血清IgG水平、糖尿病发病率和发作的作用。
方法
小鼠。在整个研究中使用良好鉴定的NOD小鼠。雄性和雌性小鼠购自Jackson实验室(Bar Harbor,ME)。这些小鼠是此领域认可的用于糖尿病研究的动物模型。(Makino等,(1980)Breeding of a Non-Obese Diabetic Strain of Mice.Exp anim,29,1-13;Miyazaki,A.T.等,(1985)Predominance of T Lymphocytes in PancreaticIslets and Spleen in Prediabetic Non-obese Diabetic(Nod)Mice:aLongitudinal Study.Clin Exp Immunol,60,622-630)。
实验设计。使用完整的切除性腺的小鼠(GDX)。进行性腺切除术以证实糖尿病发病率的升高,同时也为了排除性激素产生的变化。为比较GnRH激动剂和拮抗剂的作用,性腺切除的动物随机取自14-18天龄的动物,并将它们立即分成以下主要的治疗组:GnRH激动剂;安肽(安肽);载体。用Nal-Glu处理其中一组性腺切除的雄性小鼠,作为附加对照。
将不同几批中获自出生后数周的小鼠的数据和随机处理或对照组小鼠的数据组合。交错收集血清以便所有小鼠以相同的4周间隔采血。将用于抗体测定的血清储存在-20℃,对收集自各个时间点的所有样品进行同样的试验以避免测量间的可变性。
性腺切除要。在戊巴比妥麻醉下通过一个阴囊切口将雄性动物的性腺切除。
在戊巴比妥麻醉下通过阴囊切口对雄性动物进行假手术。
注射。GnRH(天然十肽)购自Bachem(Bubendorf,Switzerland)。GnRH拮抗剂安肽(乙酰-β-[2-萘基]-D-Ala-D-p-氯代-Phe-β[3-吡啶基]-D-Ala-Ser-Nε-[烟酰]-Lys-Nε-[烟酰]-D-Lys-Leu-Nε-[异丙基]-Lys-Pro-D-Ala-NH2)由国立卫生研究的避孕开发分部(NICHHD)和Ares-Serono(Randolph,MA)提供。第二种GnRH拮抗剂,Nal-Glu(乙酰-D2Nal1、D4ClPhe2、D3Pal3、Arg5、Dglu6(AA)、DAla10)由NICHHD提供,并用于小鼠的子集。所有提到的GnRH激动剂都是指天然十肽。用100μg溶于100μl载体的GnRH或GnRH拮抗剂在颈背上皮下注射动物,一周六次,在上午进行,所述载体含有50%丙二醇和50%双蒸水。
血清。血清收集自血液,所述血液在每六周轻微异荧烷麻醉后通过眼眶后穿刺获得。
激素测量。用市售的试剂盒(Coat-A-Count,Diagnostic ProductsCorporation,Los Angeles,CA)通过RIA测量血清睾酮浓度。用前述方法通过放射免疫测定(RIA)测量血清LH和促乳素。(Neill,J.D.等,(1971)Development of aradioimmunoassay for rat prolactin and evaluation of the NIAMD rat prolactinradioimmunoassay.Endocrinology,88,548-55;Niswender等(1968)Radioimmunoassay for Rat Luteinizing Hormone with Antiovine Lh Serum andOvine Lh-131-i.Proc Soc Exp Biol Med,128,807-11。
临床试验用含有IgG单特异性抗血清的免疫扩散平板(ICN Biomedicals,Inc.,Costa Mesa,CA),通过单放射性免疫扩散试验测量总免疫球蛋白G的浓度。用One Touch Fast Take计(Lifescan,Milpitas,CA)每周检测血清葡萄糖。用尿液分析试剂条带(Miles.Inc.,Elkhart IN)检测尿中的葡萄糖。与参考标准进行比较按以下0-4个范围对糖尿进行评分:阴性=0;30mg/dL=1;100mg/dL=2;300mg/dL=3;>1000mg/dL=4。
尸体剖检。对典型的小鼠进行尸体剖检。没有观察到残余的卵巢或睾丸组织。
统计。通过双尾斯图顿特氏成对t-检验比较血清免疫球蛋白的测量。用Mantel-Haenszel法估算仍旧未患糖尿病的小鼠的百分比。(Mantel,N.(1966)Evaluation of Survival Data and Two New Rank Order Statistics Arising inits Consideration.Cancer Chemother Rep,50,163-70)。
结果
血清免疫球蛋白G的浓度。与假装切除性腺相比,在处理8周后,切除性腺明显增加了IgG的水平。与载体相比,用GnRH激动剂处理切除性腺的小鼠进一步增加了IgG的水平。在性腺切除的雄性中,安肽处理将血清IgG浓度降低至第8周时在假手术的小鼠中看到的水平。数据显示在图1中。
糖尿病的发病率。在性腺切除的雄性中,施用GnRH拮抗剂安肽的糖尿病发病率显著降低。与载体相比,第60周时用安肽处理的小鼠无一患有糖尿病(p=0.0025;图2)。
GnRH激动剂处理明显增加了发病率并促进了糖尿病发作的时间安排。
讨论
本研究是要证明GnRH活性的降低是否与易感糖尿病的性腺切除的雄性小鼠的糖尿病的改善有关。我们不试图区分下丘脑和垂体激素的作用;同样,我们不谋略确定性腺激素对下丘脑/垂体激素的相对重要性。然而,该实施例证明GnRH和/或其垂体产物似乎改变鼠糖尿病的表现,并且假设性腺甾体以外的激素可能有助于在自身免疫性表现中熟知的的性别差异。
在该实施例中,研究了性腺切除的小鼠以评估GnRH对性腺甾体产生的作用以及对GnRH释放的性腺反馈作用。这样可以更加直接评估GnRH在调节鼠糖尿病中的作用。发现用GnRH拮抗剂处理的性腺切除的NOD小鼠显示出总IgG明显降低,并延迟了糖尿病的发作。施用GnRH激动剂导致了可逆的效果。
GnRH拮抗剂可能通过对b或T淋巴细胞的直接效应直接作用于免疫系统,或者通过减少促性腺素或减少免疫细胞产生细胞因子而间接作用于免疫系统。现有技术提示,GnRH激动剂可能在体内和体外对B和T细胞的增殖起作用(Marchetti,B.等,(1989)Luteinizing Hormone-releasing Hormone(Lhrh)Agonist Restorationof Age-associated Decline of Thymus Weight,Thymic Lrhr Receptors,andThymocyte Proliferative Capacity.Endocrinology,125,1037-45;Morale等,(1991)Blockade of Central and Peripheral Luteinizing Hormone-releasingHormone(Lhrh)Receptors in Neonatal Rats with a Potent Lhrh-antagonistInhibits the Morphofunctional Development of the Thymus and Maturation ofthe Cell-mediated and Humoral Immune Responses.Endocrinology,128,1073-85;和Batticane等,(1991)Luteinizing Hormone-releasing Hormone Signalingat the Lymphocyte Involves Stimulation of Interleukin-2 ReceptorExpression.Endocrinology,129,277-86)。例如,以前证明用GnRH拮抗剂处理的性腺切除的有狼疮倾向的小鼠中B淋巴细胞比例降低的工作提示,GnRH拮抗剂在一定程度上会影响B淋巴细胞的增殖。B淋巴细胞增殖的减少可以解释观察到血清IgG和自身抗体浓度的降低和减少免疫复合物介导的肾病。
已表明促乳素释放的抑制可减轻疾病的严重程度并延长糖尿病鼠的存活期,而促乳素治疗可加剧疾病。(Mc Murray,R等,(1991)Prolactin InfluencesAutoimmune Disease Activity in the Female B/w Mouse.J Immunol,147,3780-7)。然而,发现无论是激动剂还是拮抗剂处理都改变了血清促乳素的水平。因此,认为所观察到的效果与促乳素无关。
以前报道证明了雌二醇加剧鼠糖尿病的能力。尽管雌二醇对GnRH的反馈作用是复杂的,已知在某些情况下雌二醇对GnRH的产生有正反馈作用。已表明雌二醇在体外可增加从下丘脑细胞释放GnRH(Leadem,C.A.等,(1984)Stimulation withEstrogen and Progesterone of Luteinizing Hormone(Lh)-releasing HormoneRelease from Perifused Adult Female Rat Hypothalami:Correlation with theLh Surge.Endocrinology,114,51-6。增加的雌二醇被认为有助于中间循环GuRh骤增。(Roselli,C.E.等,(1990)Regulation of Hypothalamic LuteinizingHormone-releasing Hormone Levels by Testosterone and Estradiol in MaleRhesus Monkeys.Brain Res,509,343-6)。已在GnRH基因的5’侧鉴定了具有正调节作用的雌激素响应元件。(Radovick,S.等(1991)Evidence for Direct EstrogenRegulation of the Human Gonadotropin releasing Hormone Gene.J ClinInvest.88,1649-55)。基于这些观察结果,雌二醇的一些免疫刺激作用可导致其对GnRH的正反馈。
已表明雄激素对GnRH和促性腺素的产生和释放有负调节作用。(Finkelstein,J.S.等(1991),Sex Steroid Control of Gonadotropin Secretionin the Human Male.I.Effects of Testosterone Administration in Normal andGonadotropin releasing Hormone-deficient Men.Clin Endocrinol Metab,73,609-20;Veldhuis,J.D.等,(1992)Evidence That androgen Negative FeedbackRegulates Hypothalamic Gonadotropin-releasing Hormone Impulse Strength andthe Burst-like Secretion of Biologically Active Luteinizing Hormone in Men.J Clin Endocrinol Metab,74,1227-35;和Kalra,P.S.等(1982)DiscriminativeEffects of Testosterone on Hypothalamic Luteinizing Hormone-releasingHormone Levels and Luteinizing Hormone Secretion in Castrated MaleRats:Analysis of Dose and Duration Characteristics.Endocrinology,111,24-9)。它们还显现出对自身免疫性的抑制作用:雄激素处理可改善鼠糖尿病,而切除性腺的雄性则糖尿病加剧。(Hawkins,T.等,(1993)The Effect of NeonatalSex Hormones on the Incidence of Diabetes in Nonobese DiabeticMice.Proc.Soc.Exper.Biol.Med,202,201-205;Makino等,(1981)The Effectof Castration on the Appearance of Diabetes in NOD Mouse.Exp Anim,30;和Fitzpatrick等,(1991)Influence of Castration,along or Combined withThyrmectomy,on the Development of Diabetes in the Non-obese Diabetic Mouse.Endocrinology,129,1382-1390)。各种雄激素制剂已被成功地用于人自身免疫性疾病如狼疮和特发性凝血细胞减少性紫殿(ITP).(Bizzarro,A.等,(1987)Influence of Testosterone Therapy on Clinical and ImmunologicalFeatures of Autoimmune Diseases Associated with Klinefelter’s Syndrome.JClin Endocrinob Metal,64,32-6;和Weinblatt,M.E.等,(1988)Danazol forChildren with Immune Thrombocytopenic Purpura.Am J Dis Child,143,1317-9)。
该实施例证明,GnRH拮抗剂对糖尿病具有免疫调节作用。如图2所示,GnRH拮抗剂可显著增加整个试验期间未患糖尿病的小鼠的数目。总之,这些研究证实GnRH拮抗剂对鼠糖尿病表现的调节不依赖于它们对性腺的作用。因此,证实GnRH激动剂和拮抗剂具有免疫作用,这种作用与雄激素和雌激素的作用不同。
在此说明书中并入本文引用的所有专利和文献以供参考。

Claims (6)

1.一种降低糖尿病易感哺乳动物的糖尿病发病率或延迟糖尿病发作的方法,其特征在于,所述方法包括对哺乳动物施用有效量的促性腺素释放激素拮抗剂的步骤。
2.如权利要求1所述的方法,其特征在于,它包括通过皮下注射施用所述拮抗剂的步骤。
3.如权利要求1所述的方法,其特征在于,它包括在一段时间内重复施用所述拮抗剂的步骤。
4.如权利要求1所述的方法,其特征在于,所述拮抗剂选自乙酰-β-[2-萘基]-D-Ala-D-p-氯代-Phe-β[3-吡啶基]-D-Ala-Ser-Nε-[烟酰]-Lys-Nε-[烟酰]-D-Lys-Leu-Nε-[异丙基]-Lys-Pro-D-Ala-NH2,Glu-Nal和乙酰-D2Nal-D4CIPhe-D3Pal-Ser-Aph(Ac)-D-Aph(Ac)-Leu-Lys(Ipr)-Pro-D-Ala-NH2。
5.如权利要求1所述的方法,其特征在于,所述哺乳动物是小鼠。
6.如权利要求1所述的方法,其特征在于,所述糖尿病是IA型自身免疫性糖尿病。
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