CN1078479C - 诊断代谢综合症和包括该综合症疾病的试剂 - Google Patents

诊断代谢综合症和包括该综合症疾病的试剂 Download PDF

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CN1078479C
CN1078479C CN96194229A CN96194229A CN1078479C CN 1078479 C CN1078479 C CN 1078479C CN 96194229 A CN96194229 A CN 96194229A CN 96194229 A CN96194229 A CN 96194229A CN 1078479 C CN1078479 C CN 1078479C
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Abstract

利用皮质醇激动剂以制备用于诊断代谢综合症和相关疾病，如腹部肥胖、包括出现老年型糖尿病(即Ⅱ型糖尿病)危险的胰岛素抵抗、高血脂和高血压的诊断系统，在该系统中皮质醇激动剂的剂量是不同的；它对患有代谢综合症的个体的皮质醇的自主生成的抑制作用与正常值相比是有差异的。

Description

诊断代谢综合症和包括该综合症疾病的试剂
背景
代谢综合症的特征在于腹腔内脂肪组织量增加(通常称为腹部肥胖症)，具有出现老年性糖尿病，即II型糖尿病(＝NIDDM，非胰岛素依赖性的糖尿病)危险的胰岛素抵抗，高血脂和高血压。与之并行出现的是冠心病危险增加、中风、猝死和其它动脉硬化疾病。
对代谢综合症的一个假定解释是可能皮质醇产生过多，它是导致脂肪在腹腔内积聚和胰岛素抵抗的一种应激反应激素。这在理论上可通过继发性代谢效应来解释与代谢综合症相关的其它疾病。
在“代谢(Metabolism)杂志”，第41卷，第8号，1992，882-886页中显示：有腹部肥胖症的妇女分泌的皮质醇比“不胖的(evenly fat)”妇女分泌的皮质醇多。同一著作揭示了急性心理性应激反应对皮质醇生成的影响。它显示腹部肥胖型妇女在给定的应激信号下产生的皮质醇比“不胖的”妇女的多。这表明，但不是证明，压力和腹部肥胖之间有关联。用1毫克地塞米松进行地塞米松抑制剂试验，接着测量血清中皮质醇含量。在腹部肥胖妇女和不胖的妇女和标准值之间对皮质醇生成的抑制作用没有差异。
多年来皮质醇类似物，如地塞米松被用来追踪人体所谓的内源性抑郁(常为遗传的)。但其试验机理至今未知。
发明目的和最重要的特征
本发明的目的是找到一种诊断试验，通过该试验可早期鉴定具有患上述代谢综合症特征的一种或多种综合症和/或疾病危险的个体。在本发明中这种鉴定是通过诊断系统来实现，所述的诊断系统作为活性物质是具有一定剂量范围的皮质醇激动剂，其中可得到对在患有代谢综合症或一种或多种相关危险/疾病的个体的皮质醇自主生成的抑制作用和正常值之间的差异。优选的皮质醇激动剂是具有糖皮质激素作用和/或盐皮质激素作用的合成皮质醇类似物，如地塞米松。本发明也涉及用于诊断代谢综合症的诊断系统，包括上述剂量的皮质醇激动剂和测量唾液或血清中皮质醇含量的试剂。
附图说明
图1显示了沿着大脑-下丘脑-垂体-肾上腺的激素信号轴。
图2显示了对根据其身体脂肪分布划分的两组个体给予不同剂量地塞米松后产生的血清皮质醇读数。
发明详述
本发明的目的是皮质醇激动剂，这里是指具有糖皮质激素作用和/或盐皮质激素作用的所有合成的皮质醇的新颖的药用。新颖的药用是作为用来诊断代谢综合症和相关疾病，如腹部肥胖、胰岛素抵抗、高血脂和高血压的诊断制剂。
本发明基于这样的假设：在慢性消极应激压力下，沿着大脑-下丘脑-垂体-肾上腺的激素信号轴得以加强，它可能继发地导致GR(糖皮质激素)和/或MR(盐皮质激素)-受体的下调(参见附图)，接着导致恶性循环，其中GR和/或MR对CRF(cartocotropin释放因子，来自下丘脑的信号物质，它刺激下丘脑释放ACTH)-分泌变少。结果通过GR-和/或MR受体对皮质醇的抑制变弱，这样每个给定的应激压力会导致皮质醇分泌增高(参见附图)。
为了试验上述假设，我们进行了科学试验测量了皮质醇基础浓度，然后给予各种剂量地塞米松(一种合成的皮质醇类似物，具有皮质醇作用的合成激素物质)。其指导思想是：与原始值比较，GR和/或MR受体已下调的病人在使用低剂量地塞米松时(合成的皮质醇类似物的一个例子)对皮质醇成生的抑制应较少，特别是与初始值比较时，这在健康人体中稍高。这不良的抑制作用因此与未抑制的皮质醇的生成有关。对正常体重、一般超重和腹部肥胖人体进行试验时，我们发现假设与事实一致。与一般肥胖相对比腹部肥胖是在腹腔内的肥胖症。与对照组的血清皮质醇相比，这些腹部肥胖的个体在8：00时其基础皮质醇值也明显地较低。此处等于或超过400毫微摩尔/升的值被认为是正常值。
试验组是22名40到60岁之间的男性。其中的8名根据BMI(体质指数)定义＜25kg/m2，不属肥胖，14名BMI＞25，属于肥胖，12名男性WHR(腰臀比)＜1.0，10名男性WHR＞1.0。
以1周的间隔，按任意的次序给予0.05、0.125、0.25和0.5剂量的地塞米松。
在22：00时摄入地塞米松，在第二天的早晨8：00时测量皮质醇含量。为了建立抑制效应，在摄入皮质醇拮抗剂和测量皮质醇含量之间须经过至少3小时，最多24小时。
图2显示了使用了不同剂量地塞米松后测量的皮质醇含量和基础值(未抑制)之间的差值(δ值)。在WHR＜1.0的男性(空心方块)和WHR＞1.0的男性(实心方块)之间进行比较。
结果显示腹部肥胖的个体由低剂量地塞米松(合成的皮质醇类似物)产生的抑制明显较差。这样的效应在0.05毫克和0.5毫克剂量之间产生。这应与上述的试验进行比较，所述的试验给予1毫克地塞米松，但没有作用。这出人意外地表示腹部肥胖个体使用低剂量地塞米松后对自体产生皮质醇的抑制作用明显较差。
对于正常体重个体和一般超重但没有腹部肥胖的个体，在0.05毫克剂量下已经得到对自体产生皮质醇的抑制，并持续直至在1毫克达到最大的抑制(对于一些个体在0.5毫克下也达到最大)。
对于“危险的”腹部肥胖个体，我们发现在剂量增加到0.25毫克时才能测到抑制。其后最大的抑制剂量与健康个体的相同，即最大的抑制在0.5-1毫克范围里。
这表明对于腹部肥胖的个体，其抑制曲线右移。我们在材料中发现有明显差异的临界剂量(约20人)为0.125毫克，特别是0.5毫克(该剂量的差异最明显)。
人们首次可在地塞米松试验中找到所谓的剂量-反应曲线，并通过该曲线，在与健康个体比较时对有形成代谢综合症危险的个体和/或有一种或数种严重危险因素/与代谢综合症相关的疾病的个体中监测到存在的差异。
上述的剂量是对试验物质为地塞米松而言。对于不同的皮质醇拮抗剂有不同的有效剂量。在文献，如在FASS中可找到不同皮质醇激动剂的有效剂量的大致的转换。
皮质醇激动剂，在本发明中是地塞米松，以片剂给药。血清中皮质醇含量测量两次。
在同一研究中，对于少数个体也同时测量唾液中皮质醇的含量。这通过标准化的咀嚼物(Salivette)来进行，病人将所述的咀嚼物放在嘴中达45秒，此后以简单和标准化的方法密封。然后分析咀嚼物的皮质醇含量。在试验中我们发现血清和唾液中的皮质醇含量的相关性很好。
本发明也涉及一诊断系统，包括如上所述的皮质醇激动剂，和测量唾液或血清中皮质醇含量的工具，其目的是测量对皮质醇生成的抑制作用。这类测量皮质醇含量的工具已有标准化设备。诊断系统也涉及测量基础皮质醇含量的工具，因为如上所示，与常人相比腹部肥胖的个体的基础皮质醇值明显地低(低于400毫微摩尔/升血清)。通过测量皮质醇激动剂至少两个不同的剂量(对于地塞米松其剂量可为0.125和0.5毫克)，并同时考虑测得的抑制作用和测得的基础皮质醇浓度来构筑抑制曲线，这样便得到了相当特异性的诊断试验。

Claims (12)

1.皮质醇激动剂在制备用于诊断代谢综合症和相关疾病的诊断系统中的应用，所述的代谢综合症和相关疾病选自腹部肥胖、胰岛素抵抗、II型老年型糖尿病、高血脂和高血压，所述的诊断系统的使用包括：
(a)对个体给予一定剂量的皮质醇激动剂；然后
(b)测定所述的激动剂对所述个体生成皮质醇的抑制作用。
2.根据权利要求l所述的应用，其中诊断系统的使用包括
(a)对个体给予皮质醇激动剂；然后
(b)测定所述个体的皮质醇含量。
3.根据权利要求2所述的应用，其中测量了血清或唾液中的皮质醇含量。
4.根据权利要求1或2所述的应用，其中诊断系统的使用进一步包括在给予皮质醇激动剂前测量基础皮质醇含量。
5.根据权利要求2所述的应用，其中步骤(a)和(b)之间的间隔为3-24小时。
6.根据权利要求l所述的应用，其中诊断系统用于识别有患代谢综合症危险的个体和/或有被一种或多种与代谢综合症相关的疾病侵袭危险的个体。
7.根据权利要求1所述的应用，其中所述的皮质醇激动剂是合成的皮质醇类似物，它具有具有(i)糖皮质激素作用，或(ii)盐皮质激素作用，或(iii)同时具有糖皮质激素和盐皮质激素作用。
8.根据权利要求7所述的应用，其中皮质醇激动剂是地塞米松。
9.根据权利要求8所述的应用，其中地塞米松的剂量在0.05-0.5毫克范围里。
10.根据权利要求9所述的应用，其中地塞米松的剂量在0.125-0.5毫克范围里。
11.根据权利要求1所述的应用，其中对个体给予至少两个不同剂量的所述皮质醇激动剂。
12.根据权利要求11所述的应用，其中所述的皮质醇激动剂是地塞米松，所述的至少两个不同的剂量是0.125毫克和0.5毫克。
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NO319829B1 (no) 2005-09-19
ATE235258T1 (de) 2003-04-15
SE505391C2 (sv) 1997-08-18
CA2222215A1 (en) 1996-12-05
CN1185743A (zh) 1998-06-24
PT835138E (pt) 2003-08-29
JPH11505850A (ja) 1999-05-25
NO975492L (no) 1998-01-27
MX9709234A (es) 1998-10-31
US6410339B1 (en) 2002-06-25
SE9501991L (sv) 1996-12-01
DK0835138T3 (da) 2003-07-21
BR9608683A (pt) 1999-12-07
SE9501991D0 (sv) 1995-05-30

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