地特胰岛素导致外源性胰岛素抵抗综合征二例报道

部分DM患者使用胰岛素后会导致外源性胰岛素抵抗综合征（EIAS）,常表现为对大剂量胰岛素不敏感的血糖波动。本文报道了2例使用地特胰岛素引起EIAS的患者,在更换胰岛素并使用口服药治疗后病情好转。     

胰岛素自身免疫综合征三例

自身免疫性低血糖症（AIH）是低血糖的一种少见原因,其临床特点为自发性低血糖发作、高胰岛素血症及胰岛素抗体或胰岛素受体抗体阳性.根据自身抗体的不同可以分为两种类型：（1）在无外源性胰岛素应用时出现针对内源性胰岛素的抗体（IAA）阳性,称为胰岛素自身免疫综合征（IAS）,1970年由日本Hirata等首次报道,又称Hirata病[1];（2）是针对靶细胞表面的胰岛素受体的抗体（IRA）阳性,称为B型胰岛素抵抗综合征（TBIRS）,较罕见[2],部分可出现低血糖.我院自2009年报道1例IAS后[3],陆续出现数例,现再报告3例IAS患者,以提高临床认识.     

胰岛素自身免疫综合征

胰岛素自身免疫综合征是由血中非外源性胰岛素诱导的胰岛素自身抗体及高浓度免疫活性胰岛素所致的自发性低血糖症。其与伴发自身免疫性疾病及应用含巯基药物有关,并与人白细胞抗原高度相关,DRB1*0406可能是主要易感基因;不同人群的发病机制存在异质性。临床上主要特征为未使用外源性胰岛素情况下,出现反复发作性严重低血糖、胰岛素自身抗体滴度明显升高及游离胰岛素升高;主要应与胰岛素瘤鉴别。治疗以停用诱发药物为主,辅以少量多餐、低糖和高纤维饮食,多数患者可自行缓解。必要时应用小剂量泼尼松。     

老年外源性胰岛素抗体综合征一例并文献复习

对于糖尿病特别是老年糖尿病患者, 胰岛素作为控制高血糖的重要治疗手段被广泛应用。然而因老年糖尿病患者大剂量胰岛素使用率高、更易合并胰岛素抵抗及治疗不规范等问题, 使用外源性胰岛素时诱导产生的胰岛素自身抗体与严重胰岛素抵抗、顽固性高血糖和低血糖相关, 称为外源性胰岛素抗体综合征。低血糖时可存在与C肽不匹配的高胰岛素水平, 为控制血糖增加胰岛素剂量可能适得其反, 需要及时明确诊断并对降糖方案做出个体化调整, 以免造成严重后果。     

胰岛素抗体致自身免疫综合征

别名免疫性低血糖症;自身免疫性低血糖症;自体免疫性胰岛素低血糖症;自体免疫性低血糖综合征;Hiram病自平田幸正于1970年报告第1例以来,平田幸正在日本先后报告了15例,在欧美仅在奥斯陆Flling报告1例,国内杜建玲等于2001年报告1例[3]。据2006年文献介绍全世界已有400多例报告,单日本1970~1997年就报告了244例[4],当时日本以外的东亚地区仅报告10例,其中华人占9例[5],截至2004年欧美共报道40例。     

外源性人胰岛素所致自身免疫性低血糖三例

20世纪70年代,Hirata等[1]首先报告了从未使用过胰岛素的Graves病患者在使用甲巯咪唑时出现自发性低血糖,体内检测到高滴度的胰岛素抗体。其后随着此类病例报道不断增多,胰岛素自身免疫综合征（IAS）的概念被提出,即在某些特定人群,外源性因素,如含巯基药物,可诱导机体产生胰岛素抗体,这些抗体与内源性胰岛素结合使胰岛素生物学效应无法发挥,当这些抗体一胰岛素复合物短期内大量解离可导致一过性游离胰岛素水平增高,发生低血糖反应。     

胰岛素自身抗体影响胰岛素测定及作用的临床及试验分析二例报道

目的 分析IAA(+)、FIns＞300μU/ml的2例T2DM患者,明确IAA对胰岛素测定及作用的影响. 方法 以零胰岛素标准品稀释血清测定直接胰岛素,聚乙二醇沉淀法检测游离胰岛素,酸解法检测总胰岛素,采用相同方法同步处理IAA(一)的高胰岛素血症患者血清并作为对照,比较试验组和对照组血清直接胰岛素、游离胰岛素和总胰岛素水平. 结果 两患者直接胰岛素水平分别为15144.0、4563.2 μU/ml,去除IAA干扰后,两患者游离胰岛素、总胰岛素水平均降低,且游离胰岛素低于总胰岛素水平.同法检测IAA(一)的高胰岛素血症患者,其直接胰岛素、游离胰岛素、总胰岛素水平基本一致. 结论 T2DM患者应用外源胰岛素后可诱导机体产生IAA,导致血胰岛素测定值假性增高,并干扰胰岛素作用,引起重度IR或自发性低血糖.     

胰岛素受体抗体致自身免疫综合征

别名自身免疫低血糖症;B型胰岛素抵抗综合征(TBIR);胰岛素抵抗性糖尿病B型Kahn等~[1]于1976年首先报导了6例伴有黑棘皮病的高胰岛素血症患者,存在明显的胰岛素抵抗,后查证体内存在胰岛素受体抗体,后Kahn将伴免疫性疾病、血中存在胰岛素受体抗体的病人命名为胰岛素抵抗性糖尿病B型。2002年Arioglu等~[13]总结了24例B型胰岛素抵抗综合     

外源性胰岛素自身免疫综合征1例

外源性胰岛素自身免疫综合征(EIAS)是糖尿病患者使用外源性胰岛素后出现胰岛素抗体相关的血糖异常临床综合征, 包括胰岛素抵抗相关的严重高血糖及自发性低血糖等。该文报道1例临床表现不典型的高龄EIAS患者的诊治经过。患者为90岁男性, 糖尿病病史30余年, 在使用同一剂型预混胰岛素近20年后出现自发性低血糖及餐后高血糖交替, 血清胰岛素水平轻中度升高, 与C肽呈分离现象, 同时合并胰岛素自身抗体阳性。更换胰岛素剂型2周后, 患者血糖较前明显改善, 复查空腹胰岛素水平明显下降, C肽水平较前升高。结合国内外相关文献对该病进行系统回顾, 旨在提高对EIAS的认识和理解, 减少漏诊、误诊, 并为临床诊疗提供可借鉴经验。     

心血管X综合征和胰岛素抵抗

目的 探讨Ｘ综合征患者是否存在胰岛素抵抗现象。方法 观察１１例Ｘ综合征患者（Ｘ综合征组）和１０例正常人（对照组）糖耐量试验时空腹和服糖后３０、６０、１２０和１８０分钟时血糖、血胰岛素水平和胰岛素敏感性指数的变化。结果 Ｘ综合征相对照组空腹血糖,服糖后１２０及１８０分钟时的血糖无变化;服糖后３０、６０分钟时的血糖Ｘ综合征组较对照级组高;Ｘ综合征且空腹胰岛素水平和胰岛素敏感性指数比正常对照组高;服糖后     

Recurrent Hypoglycemia Due to a High Titer of Insulin Antibody in Response to Exogenous Insulin Administration in Two Cases of Type 1 Diabetes

In the first case, a 60-year-old man who was using continuous subcutaneous insulin infusion (CSII), developed recurrent hypoglycemia due to insulin antibodies. This is the first report of such a case using CSII. In the second case, a 70-year-old man was follow-up case who developed hypoglycemia while using human insulin. In both cases, the hypoglycemia subsided after switching to multiple daily insulin injection and/or insulin preparation. The results of Scatchard analyses of the two cases were similar to those of cases of insulin autoimmune syndrome (IAS) that improved after recovery from hypoglycemia. The clinical characteristics and Scatchard analysis data were essentially the same as those for IAS, except for the presence of insulin administration.     

胰岛素抵抗机制的探研——阻断型胰岛素抗体是导致胰岛素抵抗的原因之一

目的　探讨胰岛素抗体导致胰岛素抵抗发生的机制。方法　利用单抗制备技术和酶联免疫方法获得１７ 株抗人胰岛素单克隆抗体（ＭＡｂｓ） ,测定这些抗体阻断胰岛素与其受体结合、抑制ＣＨＯ 细胞（Ｃｈｉｎｅｓｅｈａｍｓｔｅｒｏｖａｒｙｃｅｌｌｓ）上胰岛素受体自身磷酸化、以及免疫结合共价交联的胰岛素胰岛素受体的能力。结果　在这组ＭＡｂｓ 中,多数ＭＡｂｓ（１６／１７）阻断胰岛素与其受体结合或抑制ＣＨＯ细胞上胰岛素受体自身磷酸化,其识别胰岛素上的位点与胰岛素的受体结合区域相重叠。有１ 株ＭＡｂ 具有免疫结合已与受体交联的胰岛素的能力,但不阻断胰岛素的作用。结论　在胰岛素抗体阳性的糖尿病患者中,其胰岛素抗体的识别位点对胰岛素抵抗的发生有重大作用。     

2型糖尿病合并胰岛素自身免疫综合征106例临床特点分析

目的分析2型糖尿病应用外源性胰岛素治疗后合并胰岛素自身免疫综合征患者的临床特点。方法纳入复旦大学附属中山医院内分泌科2017年9月至2019年3月符合外源性胰岛素相关胰岛素自身免疫综合征(EIAS)诊断的2型糖尿病住院患者106例,收集患者临床资料、体格检查和实验室结果。结果106例患者中84例(79.24%)使用预混人胰岛素或预混胰岛素类似物,18例患者(16.98%)近期反复发生低血糖。精氨酸刺激试验显示胰岛素0 min基线值中位数73.40(23.07~146.75)μU/ml,胰岛素4 min/0 min比值中位数1.27(1.03~1.85),平均值1.72±1.47,胰岛素0 min(μU/ml)/C肽0 min(ng/ml)比值44.60(14.92~87.93),平均值81.92±130.93。以本院空腹胰岛素检测参考值2倍上限(49.8μU/ml)为切点,将患者分为胰岛素蓄积组(胰岛素0 min基线值≥49.8μU/ml)和胰岛素非蓄积组(胰岛素0 min基线值<49.8μU/ml)。胰岛素蓄积组66例患者中14例(21.21%)发生低血糖,胰岛素非蓄积组40例患者中4例(10%)发生低血糖,胰岛素蓄积组的胰岛素4 min/0 min比值、胰岛素0 min/C肽0 min比值、血糖水平标准差(SDBG)及最大血糖波动幅度(LAGE)均显著高于胰岛素非蓄积组(P<0.05)。在胰岛素蓄积组66例患者中,36例予更换胰岛素剂型(胰岛素治疗组),30例停用胰岛素改为口服降糖药(口服药治疗组)的方案治疗后,2组治疗后的SDBG和LAGE均较治疗前明显下降(均P<0.05)。结论随着外源性胰岛素蓄积的加重,患者血糖波动明显增加,低血糖比例显著升高。胰岛素自身免疫综合征患者胰岛功能出现特征性改变,精氨酸刺激后,胰岛素分泌无明显峰值,呈现"高平"曲线,基线胰岛素/C肽比值水平显著升高。及时诊断和调整治疗方案后,EIAS患者预后良好。     

干燥综合征合并获得性Gitelman综合征二例并文献复习

目的 提高对干燥综合征(SS)合并获得性Gitelman综合征的认识,了解其特点及治疗.方法 报告2例SS合并获得性Gitelman综合征病例的临床资料,并结合相关文献进行分析.结果 2例患者均为首次就诊的老年女性,临床以低钾血症及相关肌炎症状、肌酶学改变为特点入院.虽口干、眼干症状不典型,但查体及实验室等相关检查诊断SS明确,伴低血镁、代谢性碱中毒、高肾素-血管紧张素-醛固酮,且无高血压,符合Gitelman综合征改变,因此考虑为SS合并获得性Gitelman综合征.结论 在符合Gitelman综合征临床特点基础上,诊断应完善肾活检.SS患者合并的Gitelman综合征少见,其发生机制与SS的关系有待进一步探讨.     

成人自身免疫性肠病三例及文献复习

目的明确成人自身免疫性肠病（AIE）临床诊断标准，探讨相关治疗方法。方法对我院过去3年中3例持续性严重腹泻且对禁食无效患者的病史进行回顾性分析。结果3名患者符合AIE描述的典型腹部症状并伴有严重低白蛋白血症，并排除其他自身免疫性疾病。病变部位限于十二指肠至回肠，病理检查示肠黏膜重姨慢性活动性炎症，绒毛结构消失。1例尝试性使用大剂量皮质激素后症状迅速改善，另2例在激素减量后出现腹泻症状反复，予甲氨蝶呤后好转。结论据此认为3名患者罹患罕见的成人自身免疫性肠病，建议有上述病症且禁食无效的患者应行肠黏膜活检，检测上皮细胞自身抗体及进行胶囊胃镜检查。     

胰岛素受体基因突变与遗传性胰岛素抵抗综合征

遗传性胰岛素抵抗综合征是指一类与胰岛素、胰岛素受体及受体后基因突变有关的疾病,其中以胰岛素受体基因突变最为常见,主要包括矮妖综合征、Rabson-Mendenhall综合征及A型胰岛素抵抗.矮妖综合征是遗传性胰岛素抵抗综合征中最严重的一种表型,多在2岁前由于胰岛β细胞功能衰竭,导致酮症酸中毒和各种并发症而死亡.A型胰岛素抵抗多见于青年女性,糖尿病一般不重.可存活至成年后.Rabson-Mendenhall综合征临床表型的严重程度常介于矮妖综合征和A型胰岛素抵抗之间.此三者临床表现的异质性可能与突变的类型、突变位点的差异以及是否合并其他基因缺陷有关.     

Purification of insulin-binding antibody by affinity chromatography using monocomponent insulin as ligand

Insulin-binding antibody (IBA) was purified by affinity chromatography using porcine monocomponent (MC) insulin as the ligand. The purity of the antibody was compared with that of the antibody extracted using porcine crystalline (Cr) insulin. Comparing the antibody solutions obtained with MC insulin (MC-lig-sol) or Cr insulin (Cr-lig-sol), the content of IBA in Cr-lig-sol was higher than in MC-lig-sol, but the content of proinsulin-binding antibody (PBA) in MC-lig-sol was very small and statistically lower than that in Cr-lig-sol (P less than 0.01). Adding native MC insulin to a competitive radioimmunoassay suppressed the IBA titer obtained with MC insulin more than that obtained with Cr insulin. By adding native proinsulin in a similar assay system, the PBA titer obtained with Cr insulin was suppressed more than that extracted with MC insulin. Scatchard analysis of the 2 solutions showed that the affinity constants of high affinity antibodies were almost identical, but that of low affinity antibody in MC-lig-sol was larger than in Cr-lig-sol. The binding capacity of low affinity antibody in Cr-lig-sol was 15 times as much as that in MC-lig-sol. Using MC insulin, instead of Cr insulin, as the ligand in affinity chromatography increased the purity of recovered IBA. chromatography increased the purity of recovered IBA.     

A型胰岛素抵抗综合征胰岛素分泌变化的七年随访

目的 对1例A型胰岛素抵抗综合征患者随访7年,观察血糖及胰岛素分泌变化.方法 患者初诊年龄16岁,分别于基线、第3、6、7年进行临床随访,观察患者延长口服葡萄糖耐量试验(OGTT)及同步胰岛素、C肽的分泌,比较各随访年血糖、胰岛素、C肽曲线下面积(AUC);比较基线与第7年静脉葡萄糖耐量试验急性胰岛素分泌反应(AIR)的变化;将延长OGTT各时间点胰岛素分泌速率用体表面积标化后,与相应血浆葡萄糖作出剂量反应曲线,比较各随访年胰岛β细胞对葡萄糖的分泌反应.结果 患者7年间糖化血红蛋白均维持正常(4.6%～5.5%),葡萄糖AUC无增加,胰岛素及C肽AUC呈下降趋势;第7年胰岛素AIR较基线时减少56%;胰岛β细胞对葡萄糖的分泌反应随时间推移而呈下降趋势.结论 随着青春期结束,该患者总体胰岛素分泌水平呈下降趋势,因不伴血糖的进行性恶化,考虑为青春期过后生理性胰岛素敏感性恢复,而非真正意义的胰岛β细胞分泌功能衰退.

Abstract：

Objective A previously reported female diagnosed with type A insulin resistance syndrome bearing a heterozygous missense mutation of R1174W in the insulin receptor gene was followed for 7 years since the age of 16 years. Methods Five-hour oral glucose tolerance tests (OGTT) were done on baseline, the 3rd, 6th and 7th year respectively, with serum insulin and C-peptide measured at the same time points. Areas under of curve (AUC) of glucose, insulin and C-peptide were compared between the years.Acute insulin response (AIR) was determined at baseline and the 7th year. The dose response were insulin secretion rates at each time point during OGTT being plotted over the corresponding glucose levels, and the slopes of which quantified the insulin secretion responding to glucose. Results The follow up data showed that the glucose metabolism of the subject did not deteriorate over time with yearly glycosylated hemoglobin A1c (HbAlc) being normal (4.6%-5.5%), and hyperinsulinemic hypoglycemia was a persistent phenomenon observed at 4-5 hours post-load. The fasting and AUCs of serum insulin and C-peptide tended to decline without simultaneously increase of those of plasma glucose. The AIR decreased by 56% as compared to baseline. The dose response curves shifted downward as years went by. Conclusions It supports that with the alleviation of physiological insulin resistance after puberty, the gross hyperinsulinemia tends to ameliorate, and β-cell secretion does not deteriorate over time as glucose homeostasis maintains.     

The effect of insulin antibodies on insulin dose and diabetic control

Summary In a single blind randomised cross-over study, 40 patients were changed from ordinary bovine to highly purified porcine insulins for a period of 6 months. Half were later rechallenged with bovine insulin. Sequential determinations of IgG insulin binding capacity for bovine insulin were correlated with insulin dose and diabetic control. After changing to highly purified insulins the following correlations were observed between percentage change in insulin dose and change in insulin binding capacity: at 2 months r = 0.35 (p < 0.05), at 4 months r = 0.38 (p < 0.02) and at 6 months r=0.37 (p < 0.02). When the patients who showed substantial changes in HbA₁ were removed from the analysis, the remaining 29 demonstrated a clearer relationship between these two variables (r = 0.56, p < 0.01). Removal of patients with a low initial insulin binding capacity left 18 patients with stable diabetes, and changes in insulin binding capacity and insulin dose showed an even closer correlation for this group (r = 0.77, p < 0.001). A similar degree of positive correlation was observed after rechallenge with bovine insulin. We conclude that the level of circulating insulin antibody affects the dose of insulin required to maintain stable diabetic control.     

Insulin antibody determination: Theoretical and practical considerations

Conclusion The immunogenicity of insulin preparations is of both academic and clinical interest. The links between insulin antibodies and insulin allergy, some forms of insulin resistance and injection site lipoatrophy are well-established, but other more subtle metabolic effects require further examination. Contamination with impurities (e.g. proinsulin) has been a major factor in the immunogenicity of conventional bovine insulin preparations but the less frequent, although still detectable, immunogenicity of highly purified porcine and human preparations remains enigmatic. Further work is required to analyse the physico-chemical factors involved, while the genetic control of the immune response to insulin is of fundamental interest.In order to facilitate comparative studies of different insulin preparations and data translation between different laboratories, it is essential that efforts be made to introduce some elements of standardisation in assay techniques, reporting of results and assessment of precision, accuracy and sensitivity. International collaborative laboratory studies have been successful in various other areas of clinical research relevant to diabetes, notably the series of HLA workshops [53] and comparisons of the radioimmunoassay and bioassay of insulin [54, 55] and the radioimmunoassay of C-peptide [56]. It is hoped that present efforts to achieve successful collaboration for insulin antibody determination will harmonise the diverse approaches to the problems which continue to surround the immunogenicity of insulin.