Family history of type 1 and type 2 diabetes and risk of latent autoimmune diabetes in adults (LADA)

BackgroundA family history of diabetes (FHD) is a strong predictor of diabetes risk, yet has rarely been investigated in latent autoimmune diabetes in adults (LADA). This study therefore investigated the risk of LADA and type 2 diabetes (T2D) in relation to FHD, taking into account the type of diabetes in relatives.MethodsData from a population-based study were used, including incident cases of LADA [glutamic acid decarboxylase antibody (GADA)-positive, n = 378] and T2D (GADA-negative, n = 1199), and their matched controls (n = 1484). First-degree relatives with disease onset at age < 40 years and taking insulin treatment were classified as type 1 diabetes (T1D) or, if otherwise, as T2D. Odds ratios (ORs) were adjusted for age, gender, BMI, education and smoking. Cases were genotyped for high- and low-risk HLA genotypes.ResultsBoth FHD–T1D (OR: 5.8; 95% CI: 3.2–10.3) and FHD–T2D (OR: 1.9; 95% CI: 1.5–2.5) were associated with an increased risk of LADA, whereas the risk of T2D was associated with FHD–T2D (OR: 2.7; 95% CI: 2.2–3.3), but not FHD–T1D. In LADA patients, FHD–T1D vs FHD–T2D was associated with higher GADA but lower C-peptide levels, lower prevalence of low-risk HLA genotypes (5.0% vs 28.6%, respectively; P = 0.038) and a tendency for higher prevalence of high-risk genotypes (90.0% vs 69.1%, respectively; P = 0.0576).ConclusionThe risk of LADA is substantially increased with FHD–T1D but also, albeit significantly less so, with FHD–T2D. This supports the idea of LADA as a mix of both T1D and T2D, but suggests that the genes related to T1D have greater impact. LADA patients with FHD–T1D had more T1D-like features, emphasizing the heterogeneity of LADA.     

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.     

Pro- and anti-inflammatory cytokines in latent autoimmune diabetes in adults, type 1 and type 2 diabetes patients: Action LADA 4

Aims/hypothesis

Systemic pro- and anti-inflammatory cytokines are associated with both type 1 and type 2 diabetes, while their role in latent autoimmune diabetes in adults (LADA) is unclear. Therefore, we compared cytokine concentrations in patients with LADA, type 1 or type 2 diabetes and healthy individuals to test the hypothesis that differences of cytokine concentrations between all groups are attributable to diabetes type and BMI.

Methods

The pro-inflammatory cytokines IL-6 and TNF-??, and the anti-inflammatory cytokines IL-1 receptor antagonist (IL-1RA) and IL-10 were measured in 90 participants with type 1 diabetes, 61 with LADA, 465 with type 2 diabetes and 41 control participants using multiple regression models adjusted for BMI, sex, age, blood pressure and diabetes duration.

Results

Patients with type 2 diabetes had higher concentrations of systemic IL-1RA, IL-6 and TNF-?? cytokines than patients with either LADA or type 1 diabetes (p?<?0.0001 for all differences). Cytokine concentrations in controls were lower than those in all diabetes types (p?<?0.04). Increased BMI was positively associated with higher systemic cytokine concentrations in all diabetes types (p?<?0.0001). Despite the association of cytokines with anthropometric data, differences between diabetes forms persisted also after adjusting analysis for the confounders BMI, age, sex, disease duration and blood pressure (p?<?0.04).

Conclusions/interpretation

Although body mass associates positively with pro- and anti-inflammatory cytokine levels, patients with type 2 diabetes have higher cytokine levels independent of the prevailing BMI. LADA and type 1 diabetes could not be distinguished by systemic cytokines.     

Prevalence of latent autoimmune diabetes of adults (LADA) in Southern Spain

OBJECTIVE: To study the prevalence of diabetes mellitus and islet autoantibodies in an adult population from Southern Spain. RESEARCH AND METHODS: A cross-sectional study in Southern Spain of 1226 people, age 18-65 years. Clinical data were obtained and a blood sample taken to measure autoantibodies (glutamic acid decarboxylase antibodies (GADAb), tyrosine phosphatase antibodies (IA2Ab), and insulin antibodies (IAA)). An oral glucose tolerance test (OGTT) was also given to 982 of the subjects. RESULTS: The overall prevalence of diabetes mellitus according to the WHO 1979 criteria was 10.9% and according to the ADA 1997 criteria it was 14.7% (8.8% were unaware of their diabetes). The prevalence of impaired fasting glucose (IFG) was 12.4% and of impaired glucose tolerance (IGT) 11.5%. The prevalence of GADAb+ in the general population was 0.9% and in the diabetic population 3.7%. There were no significant differences between groups in the prevalence of IA2Ab or IAA (both were 0.8% in the general population). Of the three autoantibodies studied, only GADAb were significantly different in the diabetic population (P=0.0006). CONCLUSIONS: The prevalence of Type 2 diabetes and LADA are high in the south of Spain.     

成人隐匿性自身免疫性糖尿病患者胰岛β细胞功能的6年前瞻性研究

目的探讨谷氨酸脱羧酶抗体(GAD-Ab)阳性的成人隐匿性自身免疫性糖尿病(LADA)患者胰岛β细胞功能变化的特点及其影响因素.方法GAD-Ab阳性的LADA患者45例(LADA 1组16例,LADA2组29例),年龄28～68岁;GAD-Ab阴性的2型糖尿病(T2DM)患者45例(T2DM 1组16例,T2DM 2组29例),年龄26～68岁.每半年随访一次,LADA 1组和T2DM1组随访至第6年,LADA 2组和T2DM 2组随访至第1.5年.测定空腹C肽(FC-P)和100 g馒头餐后2 h C肽(2 hC-P)及糖代谢控制指标.采用放射配体法测定GAD-Ab,放免法测定C-P.结果LADA 1组的FC-P较入组时下降50%以上,随访第1.5年时为25%,随访第2.5年平均水平呈显著性下降[(396±189)pmol/L对(573±289)pmol/L,P＜0.05]直至第6年,而T2DM 1组的FC-P在随访期间则无显著变化(P＞0.05);LADA患者平均每年FC-P下降15.8%(4.0%～91.0%),而T2DM平均为5.2%(-3.5%～35.5%,P=0.000).LADA患者的FC-P与GAD-Ab滴度呈负相关(r=-0.483,P=0.000)FC-P平均每年下降百分数的相关因素为GAD-Ab滴度、体质指数(BMI)和发病年龄(r分别为0.408、-0.301和-0.523,P＜0.05).结论LADA患者胰岛β细胞功能减退的速率是T2DM的3倍,但其个体间异质性较大;GAD-Ab滴度是其重要预测因子,且发病年龄和BMI亦有一定预测作用.     

Rosiglitazone combined with insulin preserves islet beta cell function in adult-onset latent autoimmune diabetes (LADA)

BACKGROUND: LADA is thought to result from the chronic autoimmune destruction of the insulin-producing pancreatic beta cells. In addition to antidiabetic effects, the newly developed insulin sensitizer-thiazolidinediones have the potential to increase the insulin content of islet cells by downregulating local inflammation and autoimmune response. Therefore, we hypothesized that LADA patients might benefit from thiazolidinediones treatment. METHODS: LADA patients, with a fasting C-peptide (FCP) of 0.3 nmol/L or more, were enrolled and randomly assigned to receive subcutaneous insulin alone (insulin group, n = 12) or rosiglitazone plus insulin (insulin + RSG group, n = 11) to compare the impacts on islet beta cell function. Plasma glucose, HbA 1c, fasting C-peptide (FCP) and C-peptide after 2 h 75-g glucose load (PCP) were determined every 6 months. GAD-Ab and C-peptide were measured with radioimmune assays. Islet beta cell function was evaluated by PCP and DeltaCP(DeltaCP = PCP-FCP). RESULTS: All of the 23 patients have been followed up for 6 months, 17 cases for 12 months and 14 for 18 months. (1) During 6 months' follow-up, there were no significant changes for DeltaCP and PCP levels in both groups. (2) PCP and DeltaCP levels in insulin + RSG group patients stayed steady during the 12 months' observation (P = 0.161 for both PCP and DeltaCP), while in the insulin alone group, both FCP (P = 0.021) and PCP (P = 0.028) levels decreased significantly. Furthermore, PCP (P = 0.004) and DeltaCP(P = 0.015) differences between 12th month and baseline were higher in insulin + RSG group than those in the insulin group. (3) When observed up to 18 months, PCP and DeltaCP levels in insulin + RSG group patients still stayed steady, while PCP and DeltaCP levels decreased more in the insulin alone group. CONCLUSIONS: This pilot study suggests that rosiglitazone combined with insulin may preserve islet beta cell function in LADA patients.     

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.     

成人迟发自身免疫性糖尿病与1、2型糖尿病临床表现的比较

目的：探讨成人迟发自身免疫性糖尿病（LADA）的临床特征，方法：评价谷氨酸脱羧酶抗体（GADA）、胰岛细胞抗体（ICA）阳性LADA患者各种急性和慢性并发症的患病率，并与速发型1和2型糖尿病（DM）相比较。结果：LADA患者的年龄，BMI，空腹及餐后C肽水平介于1和2型DM之间，LADA组29％患者有酮症，再次酮症的频率与1型相似，但至首次酮症的时间较长。视网膜病变患病率为19．5％，与1型DM相似；白内障患病率为48．8％，与2型DM相似；冠心病患病率与2型DM相似，高血压患病率介于1、2型DM之间。LADA组有微量白蛋白尿者较少，3组间显性肾病变。周围神经病变和高脂血症的患病率相似。结论：LADA的临床特征及急性和慢性并发症的患病率与1和2型DM有所不同。     

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.     

成人隐匿性自身免疫性糖尿病与HLA-DQ、DR基因的关联性

探讨成人隐匿性自身免疫性糖尿病（LADA）与HLA-DQ、DR基因的关联性. 方法用聚合酶链反应序列特异性引物（PCR-SSP）检测60例正常人、41例1型糖尿病人（TlDM）和39例LADA患者的HLA-DR、DQ基因频率. 结果HLA-DR3、DR4、HLA-DQA1＊0301、HLA-DQB1＊0201与TlDM的易感性相关;HLA-DR15、HLA-DQB1＊0601与T1DM的保护性相关.HLA-DR4、HLA-DQA1＊0301、HLA-DQB1＊0201与LADA的易感性相关,HLA-DQB1＊0601的基因频率在LADA组中显著高于TlDM组（P＜0.05）. 结论不同的遗传背景可能是影响LADA和TlDM起病方式及病情进展的重要因素之一.     

Latent autoimmune diabetes in adults (LADA) in South Wales: incidence and characterization

Aim To define the incidence and characteristics of latent autoimmune diabetes in adults (LADA). Methods We estimated the incidence of LADA by examining the incidence of Type 2 diabetes and calculating the proportion that were antibody positive. The incidence of Type 2 diabetes was calculated by analysis of computer records of 35 out of 36 general practices in Swansea. In addition, thirty‐two practices participated in recruiting people with Type 2 diabetes to have glutamic acid decarboxylase (GAD) antibody testing. Results The crude proportion of Type 2 patients testing positive for GAD antibodies (GADA) was 4.0% (28/683). This figure did not change when we analysed only the practices that tested more than 60% of all eligible patients. In these practices, 79% (387/487) of all eligible patients were GADA tested and 14/387 [3.6% (95% confidence interval: 2.1–6.1%)] were classified as having LADA. This gives an incidence of LADA of 9 per 100 000 (95% confidence interval: 4.4–17.8 per 100 000) people per year registered with a general practitioner. Patients testing positive for GADA were more likely to have a lower body mass index, other antibodies, to present with acute symptoms and to have higher glycated haemoglobin. Conclusions This is the first study of the incidence of LADA in primary care. People with LADA make up a significant proportion of people with apparent Type 2 diabetes. Patients with LADA are likely to be symptomatic, have poorer glycaemic control and have other autoimmune antibodies.     

胰岛素自身抗体对成人隐匿性自身免疫糖尿病的诊断价值

目的 探讨胰岛素自身抗体(IAA)对成人隐匿性自身免疫糖尿病(LADA)的诊断价值.方法 选取2003年10月至2007年3月连续在中南大学湘雅二医院就诊的1003例初诊2型糖尿病、110例1型糖尿病患者,并选取同期米院体格检杏的317名健康对照者,采用微量平板放射免疫法和放射配体法检测IAA及谷氨酸脱羧酶抗体(GADA)和蛋门酪氨酸磷酸酶抗体(IA-2A)水平,了解IAA阳性率及与其他抗体重叠情况.对4例IAA单独阳性的LADA患者进行了4年随访,观察其临床特征变化.采用卡方榆验比较初诊2型糖尿病组、健康对照组和初诊1型糖尿病组IAA阳性率,采用t检验比较IAA阳性组和阴性匹配组空腹胰岛素(FINS)水平下降速率.结果 (1)初诊2型糖尿病患者IAA阳性率3.39%(34/1003)高于健康埘照组0.95%(3/317)(X2=5.3,P<0.05),但低于1型糖尿病组21.82%(24/110)(x2=68.2,P<0.01).(2)初诊2型糖尿病患者三种抗体联合检测阳性率为10.47%(105/1003),高于GADA 6.58%(66/1003)、IA-2A 2.79%(28/1003)、IAA3.39%(34/1003)单个抗体检测(x2值分别为9.2、37.8和46.2,P值均<0.05).IAA联合检测可提高LADA阳性检出率2.39%.(3)在4年随访期间,IAA阳性者逐年转阴,4例中的2例患者合并GADA阳性;IAA阳性组FINS水平下降速率较阴性匹配组呈增高趋势(分别为15.37%和5.29%;t=1.7,P=0.059).结论 IAA对初诊2型糖尿病患者筛查LADA有一定价值;联合检测IAA、GADA、IA-2A能提高LADA诊断效率.     

应用高胰岛素正葡萄糖钳夹技术评价我国LADA患者的胰岛素抵抗

目的应用高胰岛素正葡萄糖钳夹技术评估我国成人隐匿性自身免疫性糖尿病（LADA）患者的胰岛素抵抗。方法研究对象分为LADA组、2型糖尿病（T2DM）组、正常对照（NC）组。糖尿病患者均为初诊未治,经2周胰岛素强化治疗血糖控制达标后进行研究。对全部研究对象空腹测定临床参数及生化指标,应用高胰岛素正葡萄糖钳夹技术测定胰岛素敏感性指数（ISI）。结果LADA组FC-P及Fins显著低于NC组（P〈0．05）,年龄、BMI、wHR、SBP、DBP、TC、TG、LDL—C、HDL-C与NC组比较,均无统计学差异。LADA组BMI、WHR、SBP、Fins、FC-P、TC、TG、LDL-C均显著低于T2DM组（P均〈0．05）。NC组、LADA组、T2DM组ISI分别为12．83±1．09、6．70±0．71、3．80±0．20,三组间比较有统计学差异（P〈0．05）。结论与NC组相比,LADA患者存在胰岛素抵抗,其程度较T2DM组轻。