In active acromegaly, IGF1 bioactivity is related to soluble Klotho levels and quality of life

A J Varewijck; A J van der Lely; S J C M M Neggers; S W J Lamberts; L J Hofland; J A M J L Janssen

摘要

The value of measuring IGF1 bioactivity in active acromegaly is unknown. Soluble Klotho (S-Klotho) level is elevated in active acromegaly and it has been suggested that S-Klotho can inhibit activation of the IGF1 receptor (IGF1R). A cross-sectional study was carried out in 15 patients with active acromegaly based on clinical presentation, unsuppressed GH during an oral glucose tolerance test, and elevated total IGF1 levels (>+2 s.d.). Total IGF1 was measured by immunoassay, IGF1 bioactivity by the IGF1R kinase receptor activation assay and S-Klotho by an ELISA. Quality of Life (QoL) was assessed by Acromegaly QoL (AcroQoL) Questionnaire and Short-Form-36 Health Survey Questionnaire (SF-36). Out of 15 patients, nine had IGF1 bioactivity values within the reference range. S-Klotho was higher in active acromegaly compared with controls. Age-adjusted S-Klotho was significantly related to IGF1 bioactivity ( r =0.75, P =0.002) and to total IGF1 ( r =0.62, P =0.02). IGF1 bioactivity and total IGF1 were inversely related to the physical component of the SF-36 ( r =?0.78, P =0.002 vs r =?0.60, P =0.03). Moreover, IGF1 bioactivity, but not total IGF1, was significantly inversely related to the physical dimension of the AcroQoL Questionnaire ( r =?0.60, P =0.02 vs r =?0.37, P =0.19). In contrast to total IGF1, IGF1 bioactivity was within the reference range in a considerable number of subjects with active acromegaly. Elevated S-Klotho levels may have reduced IGF1 bioactivity. Moreover, IGF1 bioactivity was more strongly related to physical measures of QoL than total IGF1, suggesting that IGF1 bioactivity may better reflect physical limitations perceived in active acromegaly. Keywords: IGF1 bioactivity, soluble Klotho, total IGF1, acromegaly, quality of lifeIntroductionAcromegaly is characterized by excess secretion of growth hormone (GH) causing multisystem-associated morbidities and increased mortality. GH is considered as the main regulator of circulating total insulin-like growth factor 1 (IGF1). Total IGF1 is therefore routinely used for diagnosis and monitoring treatment of GH deficiency and acromegaly. Nevertheless, discrepancies between clinical findings, GH, and total IGF1 levels are frequently encountered in clinical practice.Many of the methods used for the measurement of circulating total IGF1 may be hampered by the interferences of insulin-like growth factor (IGF)-binding proteins (IGFBPs) remaining after extraction (1). The most important reason why immunoreactive total IGF1 levels are still used to assess IGF1 bioactivity has been the lack of reliable assays to measure IGF1 bioactivity. An IGF1 receptor (IGF1R)-specific kinase receptor activation (KIRA) assay has been developed as an alternative method to evaluate circulating bioavailable IGF1 (2). The principle of the IGF1R KIRA assay is based on quantification of serum-induced IGF1R phosphorylation in cells transfected with the human IGF1R (2). Compared with current IGF1 immunoassays, this assay theoretically has the advantage of measuring the net effects of serum on IGF1R activation, as it does not ignore the modifying effects of IGFBPs, IGFBP proteases, and other factors that interact between IGFs and the IGF1R (3, 4). One of these factors might be soluble Klotho (S-Klotho). S-Klotho is a protein that has been reported to inhibit IGF1R (and insulin receptor) signaling by inhibiting tyrosine phosphorylation of both receptors and their downstream signaling proteins (i.e. IRS) (5, 6, 7).Acromegaly is characterized by excessively high GH and (immunoreactive) total IGF1 levels. Recent data suggest that S-Klotho level is also elevated in patients with active acromegaly and that S-Klotho level decreases toward normal following removal of the GH-producing pituitary adenoma (8, 9).Previously, we found that determination of IGF1 bioactivity may offer advantages in the evaluation of adult GH deficiency compared with total IGF1 (10). In another study, we found that IGF1 bioactivity reflects different aspects of quality of life (QoL) than total IGF1 in GH-deficient patients during GH treatment (11).The aim of the present study was to investigate the value of IGF1 bioactivity in the evaluation of active acromegaly and in the assessment of QoL in active acromegaly. In addition, we studied whether S-Klotho levels are elevated in active acromegaly and whether a relationship exists between S-Klotho levels and IGF1.Subjects and methodsStudy populationThis was an investigator-initiated cross-sectional study. A total of 15 patients, with active acromegaly, were enrolled. Diagnosis of active acromegaly was based on clinical presentation, unsuppressed GH levels during an oral glucose tolerance test (OGTT), and elevated age-matched total IGF1 levels (and radiological detection of a pituitary tumor). Of them, ten patients had a macroadenoma of the pituitary gland and five had a microadenoma. Body weight, height, blood pressure, and ring size were measured. BMI was calculate

机译：在活跃的肢端肥大症中测量IGF1生物活性的价值尚不清楚。在活跃的肢端肥大症中可溶性Klotho（S-Klotho）水平升高，并且有人提出S-Klotho可以抑制IGF1受体（IGF1R）的激活。根据临床表现，活动性肢端肥大症，口服葡萄糖耐量试验期间未抑制GH和总IGF1水平升高（> +2 s.d.）对15例活动性肢端肥大患者进行了横断面研究。通过免疫测定法测定总的IGF1，通过IGF1R激酶受体活化测定法测定IGF1的生物活性，通过ELISA测定S-Klotho。生活质量（QoL）通过Acromegaly QoL（AcroQoL）问卷和Short-36-36健康调查问卷（SF-36）进行评估。在15位患者中，有9位的IGF1生物活性值在参考范围内。与对照组相比，活动性肢端肥大症的S-Klotho更高。年龄调整后的S-Klotho与IGF1的生物活性（r = 0.75，P = 0.002）和总IGF1显着相关（r = 0.62，P = 0.02）。 IGF1的生物活性和总的IGF1与SF-36的物理成分成反比关系（r =？0.78，P = 0.002 vs r =？0.60，P = 0.03）。此外，IGF1的生物活性而不是总的IGF1与AcroQoL调查问卷的物理尺寸呈显着的负相关（r =？0.60，P = 0.02对r =？0.37，P = 0.19）。与总的IGF1相比，在相当数量的肢端肥大症患者中，IGF1的生物活性在参考范围内。 S-Klotho水平升高可能会降低IGF1的生物活性。此外，IGF1的生物活性与QoL的物理指标比总的IGF1更紧密相关，这表明IGF1的生物活性可能更好地反映了肢端肥大症患者的生理局限性。关键词：IGF1的生物活性，可溶性Klotho，总IGF1，肢端肥大症，生活质量简介肢端肥大症的特征在于生长激素（GH）的过量分泌，导致多系统相关的发病率和死亡率增加。 GH被认为是循环中总胰岛素样生长因子1（IGF1）的主要调节剂。因此，总IGF1通常用于诊断和监测GH缺乏症和肢端肥大症的治疗。然而，临床实践中经常会遇到临床发现，GH和总IGF1水平之间的差异。胰岛素样生长因子（IGF）结合蛋白的干扰可能会阻碍许多用于测量循环总IGF1的方法（IGFBPs）提取后剩余（1）。免疫反应性IGF1总水平仍用于评估IGF1生物活性的最重要原因是缺乏可靠的方法来测量IGF1生物活性。已经开发出一种IGF1受体（IGF1R）特异性激酶受体激活（KIRA）分析法作为评估循环生物利用IGF1的替代方法（2）。 IGF1R KIRA分析的原理基于定量转染人IGF1R的细胞中血清诱导的IGF1R磷酸化（2）。与目前的IGF1免疫测定相比，该测定在理论上具有测量血清对IGF1R活化的净效应的优势，因为它不能忽略IGFBP，IGFBP蛋白酶以及其他在IGF和IGF1R之间相互作用的因素的修饰作用（3， 4）。这些因素之一可能是可溶性Klotho（S-Klotho）。 S-Klotho是一种蛋白质，据报道可通过抑制两种受体及其下游信号蛋白（即IRS）的酪氨酸磷酸化来抑制IGF1R（和胰岛素受体）信号传导。肢端肥大症的特征是GH过高和（免疫反应性）总IGF1水平。最近的数据表明，活动性肢端肥大症患者的S-Klotho水平也升高，并且去除产生GH的垂体腺瘤后S-Klotho水平下降至正常水平（8，9）。以前，我们发现确定IGF1生物活性可能与总IGF1相比，在评估成人GH缺乏症方面具有优势（10）。在另一项研究中，我们发现在GH治疗期间，GH缺乏患者的IGF1生物活性比总IGF1反映了生活质量（QoL）的不同方面（11）。本研究的目的是研究IGF1生物活性在糖尿病治疗中的价值。活动肢端肥大症的评估和活动肢端肥大症的QoL评估。此外，我们研究了活动性肢端肥大症中S-Klotho的水平是否升高以及S-Klotho的水平与IGF1之间是否存在关系。研究对象和方法研究人群这是由研究人员发起的横断面研究。共有15例活动性肢端肥大症患者入组。活动性肢端肥大的诊断基于临床表现，口服葡萄糖耐量试验（OGTT）期间GH水平未降低，年龄匹配的总IGF1水平升高（以及垂体肿瘤的放射学检测）。其中，十名患者患有垂体大腺瘤，五名患有微腺瘤。测量体重，身高，血压和环大小。体重指数被计算

In active acromegaly, IGF1 bioactivity is related to soluble Klotho levels and quality of life

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