Latent autoimmune diabetes in adults (LADA) should be less latent

Latent autoimmune diabetes in adults (LADA) is the term coined to describe adults who have a slowly progressive form of autoimmune or type 1 diabetes that can be treated initially without insulin injections. The diagnosis of LADA is currently based on three clinical criteria: (1) adult age at onset of diabetes; (2) the presence of circulating islet autoantibodies, which distinguishes LADA from type 2 diabetes; and (3) insulin independence at diagnosis, which distinguishes LADA from classic type 1 diabetes. The prevalence of LADA in adults presenting with non-insulin-requiring diabetes is approximately 10%. Recognition of LADA expands the concept and prevalence of autoimmune diabetes, but LADA remains poorly understood at both a clinical and research level. In this perspective, we review the nomenclature, diagnostic criteria, genetics, pathology and therapy of LADA, to arrive at recommendations that might advance knowledge and management of this form of diabetes.A perspective commissioned by the Immunology of Diabetes Society and dedicated to the memory of Umberto di Mario.     

糖尿病的连续疾病谱学说

糖尿病连续疾病谱学说认为,从1型糖尿病、高滴度成人隐匿性自身免疫糖尿病（LADA）、低滴度LADA到2型 糖尿病,糖尿病表现为连续的疾病谱,中间存在多个过渡类型。该学说最早于2003年提出,随后经典遗传背景、胰岛 功能及衰退速度、胰岛自身免疫反应、其他自身免疫病、其他代谢特征、炎症细胞及因子等研究均证实这一学说。该学 说有助于深入理解糖尿病异质性的病因学机制,强调多维度、多指标指导临床分型与诊疗,进而推动精准分型的发展。     

成人隐匿性自身免疫性糖尿病研究进展

成人隐匿性自身免疫性糖尿病(LADA)属于1型糖尿病的一种亚型,临床上与2型糖尿病不易区分.目前对LADA的研究进展主要集中在流行病学、胰岛自身抗体、遗传学及治疗学等方面,其中对胰岛自身抗体的研究为当前热点.本文就近几年来国内外对LADA的发病机制、遗传学、自身抗体及治疗方面的新进展作一综述.     

Latent (slowly progressing) autoimmune diabetes in adults

About 10% of patients with the clinical presentation of type 2 diabetes suffer from an autoimmune form of diabetes associated with a rapid decline of residual β-cell mass and subsequent development of insulin dependency. In this condition, called latent autoimmune diabetes in adults (LADA), there are clinical and metabolic features intermediate between type 1 and type 2 diabetes. Recent studies provide novel information on the immune markers associated with progressive β-cell loss in LADA patients. However, LADA pathogenesis is still poorly understood; further studies are needed to establish general recommendation for preventing and treating this subtype of autoimmune diabetes.     

成人隐匿性自身免疫糖尿病的诊断

成人隐匿性自身免疫糖尿病(LADA)属于自身免疫性缓慢起病的1型糖尿病,因其早期临床表现貌似2型糖尿病而易误诊。LADA的诊断目前国际上尚无统一标准,应从临床特征、体液和细胞免疫标志、组织病理学、遗传易感基因等方面综合考虑,其中胰岛自身抗体是诊断LADA的重要指标。     

Latent autoimmune diabetes of the adult: current knowledge and uncertainty

Patients with adult‐onset autoimmune diabetes have less Human Leucocyte Antigen (HLA)‐associated genetic risk and fewer diabetes‐associated autoantibodies compared with patients with childhood‐onset Type 1 diabetes. Metabolic changes at diagnosis reflect a broad clinical phenotype ranging from diabetic ketoacidosis to mild non‐insulin‐requiring diabetes, also known as latent autoimmune diabetes of the adult (LADA). This latter phenotype is the most prevalent form of adult‐onset autoimmune diabetes and probably the most prevalent form of autoimmune diabetes in general. Although LADA is associated with the same genetic and immunological features as childhood‐onset Type 1 diabetes, it also shares some genetic features with Type 2 diabetes, which raises the question of genetic heterogeneity predisposing to this form of the disease. The potential value of screening patients with adult‐onset diabetes for diabetes‐associated autoantibodies to identify those with LADA is emphasized by their lack of clinically distinct features, their different natural history compared with Type 2 diabetes and their potential need for a dedicated management strategy. The fact that, in some studies, patients with LADA show worse glucose control than patients with Type 2 diabetes, highlights the need for further therapeutic studies. Challenges regarding classification, epidemiology, genetics, metabolism, immunology, clinical presentation and treatment of LADA were discussed at a 2014 workshop arranged by the Danish Diabetes Academy. The presentations and discussions are summarized in this review, which sets out the current ideas and controversies surrounding this form of diabetes.     

Clinical review: Type 1 diabetes and latent autoimmune diabetes in adults: one end of the rainbow

CONTEXT: The aim of this review was to explore the pathogenic and clinical spectrum of type 1 diabetes, which includes a form of adult onset autoimmune diabetes usually referred to as latent autoimmune diabetes in adults (LADA). We looked at this entire range of forms of autoimmune diabetes as a spectrum of genetic and nongenetic environmental influences, diabetes-associated immune responses, and metabolic changes. EVIDENCE ACQUISITION: We assessed epidemiological, genetic, immunological, and clinical data from major articles on autoimmune diabetes, including LADA and type 1 diabetes, published since 1992. EVIDENCE SYNTHESIS: Data analysis of autoimmune diabetes indi-cates that type 1 diabetes and LADA occupy different poles of the same spectrum. CONCLUSION: Evidence is presented that LADA represents one end of a rainbow encompassing type 1 diabetes. The clinical nature and management of autoimmune diabetes poses important therapeutic questions regarding conventional therapy for hyperglycemia as well as therapy aiming to protect residual beta-cell function. Limiting loss of endogenous insulin secretion using immunomodulation could be valuable, not only for LADA but also for type 1 diabetes.     

Clinical heterogeneity of type 1 diabetes (T1D) found in Asia

Diabetes mellitus among young patients in Asia is caused by a complex set of factors. Although type 1 diabetes (T1D) remains the most common form of diabetes in children, the recent unabated increase in obesity has resulted in the emergence of type 2 diabetes (T2D) as a new type of diabetes among adolescents and young adults. In addition to the typical autoimmune type 1 diabetes (T1aD) and T2D patients, there is a variable incidence of cases of non‐autoimmune types of T1D associated with insulin deficiency (T1bD). Additional forms have been described, including fulminant T1D (FT1D). Although most diagnoses of T1D are classified as T1aD, fulminant T1D exists as a hyper‐acute subtype of T1D that affects older children, without associated autoimmunity. Patient with this rare aetiology of diabetes showed a complete loss of β‐cell secretory capacity without evidence of recovery, necessitating long‐term treatment with insulin. In addition, latent autoimmune diabetes in adults is a form of autoimmune‐mediated diabetes, usually diagnosed during the insulin‐dependent stage that follows a non‐insulin requiring phase, which can be diagnosed earlier based on anti‐islet autoantibody positivity. Some reports discuss T1bD. Others are elaborating on the presence of “atypical T1b diabetes,” such as Flatbush diabetes. The prevalence of diabetes mellitus in young adults continues to rise in Asian populations as T2D increases. With improved characterization of patients with diabetes, the range of diabetic subgroups will become even more diverse in the future. Distinguishing T1D, T2D, and other forms of diabetes in young patients is challenging in Asian populations, as the correct diagnosis is clinically important and has implications for prognosis and management. Despite aetiological heterogeneity in the usual clinical setting, early diagnosis and classification of patients with diabetes relying on clinical grounds as well as measuring islet autoantibodies and fasting plasma C‐peptide could provide a possible viable method to minimize complications.     

Der latent autoimmune Diabetes im Erwachsenenalter (LADA): Eine Sonderform des Diabetes?

Latent autoimmune diabetes in adults (LADA) is often clinically diagnosed as a type 2 diabetes that leads however more quickly to insulin deficiency. Immunologically it is characterized by diabetes type 1-associated autoantibodies against glutamic decarboxylase (GADA) or islet cells (ICA). In Europe about 10% of type 2 diabetes patients are positive for GADA/ICA and classified therefore with LADA. This means in Germany about two times more patients with LADA exist than with type 1 diabetes. Several observations suggest interpreting LADA as a separate form of diabetes, linking both ends of the type 1 and type 2 spectrum. According the guidelines of the German Diabetes Association, LADA is allocated to type 1 diabetes, though it differs in that the insulin requirement is mostly not necessary at diagnosis, in contrast to type 1 diabetes. At the moment no evidence-based recommendations regarding therapy are available, since very few clinical studies address this point. The current therapeutic recommendation is optimization of blood glucose and concomitant risk factors, though many prefer insulin therapy due to the similarities with type 1 diabetes.     

Diabetes classification: grey zones, sound and smoke: Action LADA 1

Diseases gain identity from clinical phenotype as well as genetic and environmental aetiology. The definition of type 1 diabetes is clinically exclusive, comprising patients who are considered insulin dependent at diagnosis, whilst the definition of type 2 diabetes is inclusive, only excluding those who are initially insulin dependent. Ketosis-prone diabetes (KPD) and latent autoimmune diabetes in adults (LADA) are each exclusive forms of diabetes which are, at least initially, clinically distinct from type 2 diabetes and type 1 diabetes, and each have a different natural history from these major types of diabetes.KPD can be diagnosed unequivocally as diabetes presenting with the categorical clinical feature, ketoacidosis. In contrast, LADA can be diagnosed by the co-occurrence of three traits, not one of which is categorical or exclusive to the condition: adult-onset non-insulin-requiring diabetes, an islet autoantibody such as glutamic acid decarboxylase autoantibodies (GADA) or cytoplasmic islet cell autoantibodies (ICA), and no need for insulin treatment for several months post-diagnosis. But while some would split diabetes into distinct subtypes, there is a strong case that these subtypes form a continuum of varying severity of immune and metabolic dysfunction modified by genetic and non-genetic factors. This article discusses the nature of disease classification in general, and KPD and LADA in particular, emphasizing the potential value and pitfalls in classifying diabetes and suggesting a need for more research in this area.     

The islet autoantibody titres: their clinical relevance in latent autoimmune diabetes in adults (LADA) and the classification of diabetes mellitus

Latent autoimmune diabetes in the adult (LADA) is a slowly progressive form of autoimmune diabetes, characterized by diabetes‐associated autoantibody positivity. A recent hypothesis proposes that LADA consists of a heterogeneous population, wherein several subgroups can be identified based on their autoimmune status. A systematic review of the literature was carried out to appraise whether the clinical characteristics of LADA patients correlate with the titre and numbers of diabetes‐associated autoantibodies. We found that the simultaneous presence of multiple autoantibodies and/or a high‐titre anti‐glutamic acid decarboxylase (GAD)—compared with single and low‐titre autoantibody—is associated with an early age of onset, low fasting C‐peptide values as a marker of reduced pancreatic B‐cell function, a high predictive value for future insulin requirement, the presence of other autoimmune disorders, a low prevalence of markers of the metabolic syndrome including high body mass index, hypertension and dyslipidaemia, and a high prevalence of the genotype known to increase the risk of Type 1 diabetes. We propose a more continuous classification of diabetes mellitus, based on the finding that the clinical characteristics gradually change from classic Type 1 diabetes to LADA and finally to Type 2 diabetes. Future studies should focus on determining optimal cut‐off points of anti‐GAD for differentiating clinically relevant diabetes mellitus subgroups.     

胰岛自身抗体在糖尿病精准诊断和预测中的价值及进展

胰岛自身抗体是自身免疫糖尿病的体液免疫标志物,联合多个自身抗体检测不但有助于经典1型糖尿病的诊 断和发病风险预测,而且能从初诊2型糖尿病中甄别出成人隐匿性自身免疫糖尿病（LADA）,并预测其将来对胰岛素 治疗的需要。胰岛自身抗体检测方法目前的“金标准”为放射配体法,采用生物素-链酶亲和素的桥联酶联免疫法, 以及MSD电化学发光法具有很好的检测效果。新型胰岛自身抗体的发现、多抗体筛查方法的改进以及胰岛自身抗 体的异质性研究等,将为临床上筛查自身免疫糖尿病以及预测胰岛功能的衰竭提供更好的手段。     

LADA研究之路何在?

本文对成人隐匿性自身免疫糖尿病(LADA)的诊断标准、并发症、合并症、发病机制及治疗措施等问题以及未来研究的方向试予介绍和评论;开展协作研究可能是加速我国LADA研究进展之路。     

谷氨酸脱羧酶抗体诊断成人隐匿性自身免疫性糖尿病探讨

采用放射配体法检测谷氨酸脱羧酶（ＧＡＤ６５）抗体，对１９５例≥３５岁非酮症Ⅱ型糖尿病起病半年以上者和４５例正常对照者的观察表明：本组Ⅱ型糖尿病者ＧＡＤ６５抗体阳性率为１４．８％，高于正常对照者的２．２％；发病年龄〈４０岁、有酮症史、体重指数（ＢＭＩ）〈２１ｋｇ／ｍ＾２、空腹血清Ｃ肽〈０．３ｎｍｏｌ／Ｌ和（或）胰升糖素刺激后６分钟血清Ｃ肽〈０．６ｎｍｏｌ／Ｌ者，ＧＡＤ６５抗体阳性率均高于相应对照组（     

Latent autoimmune diabetes in adults (LADA) in Asian and European populations

Diabetes mellitus is a chronic disorder caused by relative or absolute insulin deficiency and characterized by chronic hyperglycaemia. It is expected that by year 2025, 80% of all type 2 diabetic patients will be living in developing or low‐ and middle‐income countries. Among Asians, there has been an overall increase in abdominal obesity; however, the risk of diabetes in these populations starts at much lower body mass index as compared to Caucasians. A significant proportion of diabetic patients with adult‐onset, initially nonrequiring insulin treatment, have diabetes‐associated autoantibodies in their sera. A new subclass of diabetes with the designation of latent autoimmune diabetes of adult‐onset (LADA) has been proposed for this category of subjects. Studies have demonstrated that patients with autoimmune diabetes, characterized by the presence of glutamic decarboxylase autoantibodies display a different clinical phenotype from classical type 2 diabetes without glutamic decarboxylase autoantibodies. This subset of phenotypic type 2 diabetes subjects with islet autoantibodies tend to have sulphonylurea failure and need insulin treatment earlier in the disease process. Diagnosing LADA at an initial stage will be important so that insulin can be initiated earlier, facilitating improved glycemic control sooner as well as the preservation of residual beta‐cell function in adult‐onset autoimmune diabetes. Because of differences in dietary habits, environmental factors, and phenotypic characteristics between European and Asian populations, there may be heterogeneity in the prevalence and other characteristics of LADA in these two populations.     

两种成人隐匿性自身免疫糖尿病亚型的谷氨酸脱羧酶抗体界值的探讨

目的　探讨判别两种成人隐匿性自身免疫糖尿病(LADA)亚型的最佳谷氨酸脱羧酶抗体(GAD-Ab)界值及其诊断价值。　方法　绘制LADA患者GAD-Ab指数的频数分布图,进行曲线拟合。比较130例经典1型糖尿病、145例2型糖尿病和145例LADA患者的临床特点,利用受试者运筹特征(ROC)曲线比较不同GAD-Ab滴度对LADA患者中反映 LADA 1 型特征的胰岛素缺乏和反映LADA 2型特征的代谢综合征(MS)的诊断价值,确定诊断两种 LADA亚型的最佳 GAD-Ab界值。用放射配体法测定 GAD-Ab。　结果　(1) GAD-Ab 频数在 LADA患者中呈双峰分布模式。(2)以GAD Ab指数0.3为切点所区分的两组LADA患者具有差异的临床特征最多。(3)ROC曲线显示GAD Ab指数0.3是区分两种LADA亚型的最佳界值,其对胰岛素缺乏和MS诊断的敏感性和特异性分别为54 5%和92 1%,ROC曲线下面积为 0.79(与 0.5 相比,P<0.01)。　结论　GAD Ab指数0 3是区分LADA-1型和LADA-2型的最佳界值。     

Autoimmune thyropathies in diabetics

Autoimmune thyropathies are frequent in patients with type 1 diabetes mellitus. Some recently published papers confirm similarly high prevalence of autoimmune thyropathies also in patients with type 2 diabetes mellitus. Chronic autoimmune thyroiditis is the most frequent form of autoimmune thyropathies. Authors examined 79 accidentally selected diabetics (38 women and 41 men, x = 55.4 +/- 2.8). Diabetic patients were divided into three groups. 20 patients with type 1 diabetes mellitus - classical form were the first group, 12 patients with LADA were the second group and 47 patients with type 2 diabetes mellitus constituted the third group. Authors diagnosed chronic autoimmune thyroiditis in 8 (40 %) patients in the group of patients with type 1 diabetes mellitus, in 6 (50%) in the group of patients with LADA and in 20 (43%) of patients with type 2 diabetes mellitus. They didn't find out statistically more frequent prevalence of chronic autoimmune thyroiditis in all groups of patients with diabetes (patients with type 1 diabetes mellitus, patients with LADA, patients with type 2 diabetes mellitus) in comparison with control group of non-diabetic subjects. They found out statistically significant more frequent prevalence of chronic autoimmune thyroiditis in diabetics of woman gender and in diabetics with positive family history of thyropathies. Results of paper confirm recommendation of examining once or twice a year autoantibodies against thyroid gland and level of thyrotropin (TSH) with the aim of early finding of laboratory manifestation of thyroidal autoimmunity or developing functional disorder.     

成人隐匿性自身免疫性糖尿病患者T细胞亚群变化与胰岛β细胞功能相关性研究

目的观察成人隐匿性自身免疫性糖尿病（LADA）患者T细胞亚群的变化,及其与胰岛β细胞功能的相关性。方法LADA组24例,经典1型糖尿病（T1DM）18例,健康对照（NC）组20例,应用流式细胞技术测定三组入选者T细胞表面分子CD4、CD8,以百分比表示各表面分子阳性T细胞占外周血淋巴细胞的比例。测空腹C肽（FC-P）和糖负荷后2h C肽（2hC-P）。测空腹血糖、空腹胰岛素、应用HOMA公式计算胰岛素敏感指数（HOMA-IS）。结果LADA与T1DM组CD4^＋T细胞、CD4^＋／CD8^＋比值明显高于NC组（P〈0．01）,LADA与TIDM对比无统计学差异。CD4^＋T细胞与反映胰岛功能2hC-P呈明显的负相关。结论T淋巴细胞亚群失衡参与并介导了胰岛β细胞的损伤和LADA的发生。     

Should There be Concern About Autoimmune Diabetes in Adults? Current Evidence and Controversies

Autoimmune diabetes has a heterogeneous phenotype. Although often considered a condition starting in childhood, a substantial proportion of type 1 diabetes presents in adult life. This holds important implications for our understanding of the factors that modify the rate of progression through the disease prodrome to clinical diabetes and for our management of the disease. When autoimmune diabetes develops in adulthood, insulin treatment is often not required at the time of diagnosis, and this autoimmune non-insulin requiring diabetes is generally termed latent autoimmune diabetes in adults (LADA). Patients with LADA are generally leaner, younger at diabetes onset; have a greater reduction in C-peptide; and have a greater likelihood of insulin treatment as compared with patients with type 2 diabetes. The LADA subset of patients with adult-onset autoimmune diabetes has highlighted many shortcomings in the classification of diabetes and invokes the case for more personalized data analysis in line with the move towards precision medicine. Perhaps most importantly, the issues highlight our persistent failure to engage with the heterogeneity within the most common form of autoimmune diabetes, that is adult-onset type 1 diabetes, both insulin-dependent and initially non-insulin requiring (LADA). This review discusses characteristics of autoimmune diabetes and specifically aims to illustrate the heterogeneity of the disease.     

蛋白酪氨酸磷酸酶抗体对成人隐匿性自身免疫性糖尿病的诊断价值

目的探讨蛋白酪氨酸磷酸酶抗体（IA-2A）对成人隐匿性自身免疫性糖尿病（LADA）的诊断价值。方法采用放射配体法检测2027例初诊2型糖尿病（T2DM）患者的IA．2A和谷氨酸脱羧酶抗体（GAD-Ab）,分析IA-2A在初诊T2DM患者中的分布及其与临床特征的关系。结果初诊T2DM患者中IA-2A阳性检出率低于GAD-Ab阳性检出率（2．2％7）S10．6％,P〈0．01）。联合GAD-Ab和IA-2A检测,可使LADA阳性检出率达11．5％。IAm2A在低体重、低c肽水平患者中阳性检出率高;随着起病年龄增大,IA-2A阳性检出率下降（P〈0．05）。与T2DM组比较,单独IA-2A阳性患者使用胰岛素治疗的比例高（P〈0．05）。高滴度IA-2A阳性LADA患者具有起病年龄小（P〈0．01）、体重轻、高血压比例低、空腹C肽低、合并GAD-Ab阳性和使用胰岛素比例高（P〈0．05）等特点。结论IA-2A检测对LA—DA具有辅助诊断价值,与GAnAb联合检测可提高LADA诊断的敏感性。