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Background The Latent Autoimmune Diabetes in Adults (LADA) is a slowly progressive Type 1 diabetes subgroup with onset during middle age. Studies report that about 10% of adults initially diagnosed with clinical Type 2 diabetes (T2D) have LADA. Inappropriate diagnosis and mismanagement of the LADA can increase the risk of diabetic complications, which affect the quality of life and is the cause of increased mortality. In low-income countries setting, data regarding the magnitude of LADA is limited. We carried out this study to estimate the burden of misdiagnosed LADA among T2D patients in selected health facilities in Dar es Salaam and to bring awareness to the use of Glutamic Acid Decarboxylase (GAD) autoantibody in screening for LADA. Methodology We enrolled 186 phenotypically T2D patients in this cross-sectional study, through a standardized data collection tool we obtained participants’ demographic and clinical information. For testing GAD levels, we used a double-antibody Enzyme-Linked Immunosorbent Assay (ELISA). The Fisher’s Exact and student t-tests were used to test the significance of the statistical associations of the glycaemic control and diabetes complications between T2D and LADA. Results Out of 186 patients, 156 gave conclusive GAD Ab ELISA reading with LADA accounting for 5.1% (95% CI: 2.5 - 10.0). The mean age of subjects was 54.3 years (Range: 33-85 years). The parameters such as mean age, family history of diabetes mellitus status, Fasting Blood Glucose, clinical characteristics, and complications did not show significant statistical differences between patients with LADA and Type 2 diabetes. However, all LADA- Human Immunodeficiency Virus (HIV) comorbid patients had retinopathy, which was statistically insignificant in 20 (87%) T2D-HIV comorbid patients (p = 0.669). Neither neuropathy, nephropathy, nor Diabetic Mellitus (D.M.) foot syndrome was observed among LADA-HIV comorbid patients. Nevertheless, 22 (95.7%), 3 (13%), and 2 (8.7%) of T2D-HIV comorbidity had neuropathy, nephropathy, or D.M. foot syndrome, respectively. Conclusions The study established a LADA prevalence of 5.1% among T2D patients and has shown the role of GAD autoantibody in the screening for LADA. The study calls for a well- designed larger longitudinal study to generate strong evidence on the association of risk factors and complications associated with the LADA. This will develop robust evidence on the association of risk factors and complications associated with the LADA and T2D.

Jing Li,1 Songbai Lin,1 Chuiwen Deng,2 Tengda Xu1 1Department of Health Management, Peking Union Medical College Hospital, Beijing, People’s Republic of China; 2Rheumatology and Immunology Department, Peking Union Medical College Hospital, Beijing, People’s Republic of ChinaCorrespondence: Tengda XuDepartment of Health Management, Peking Union Medical College Hospital, 1# Shuaifuyuan, Dongcheng District, Beijing, 100730, People’s Republic of ChinaTel/Fax +86 10 6915 9866Email xutd@pumch.cnPurpose: To investigate the prevalence of GAD antibody (GADA) in the general adult population and to evaluate its predictive value for diabetes in China.Patients and Methods: We searched the PUMCH-HM database and identified 36,731 adult subjects with GADA test results from 2012 to 2015. We then established a retrospective cohort of 4835 nondiabetic subjects at baseline with complete annual health evaluation records through 2019. The median follow-up time was 4.8 (3.0– 7.3) years.Results: The overall prevalence of GADA was 0.53% and was higher in diabetic subjects (1.25%) than in nondiabetic subjects (0.47%). We found a decrease in baseline body mass index (BMI) from the GADA- to GADAhigh subgroups among baseline diabetic and prediabetic patients and also those who developed diabetes later in the cohort study. A total of 136 subjects (2.8%) developed diabetes after a median follow-up of 3.5 years. For GADA+ participants, BMI was not associated with the risk for diabetes. In the Cox regression model, the GADAlow and GADAhigh exhibited 2.63-fold and 4.16-fold increased risk for diabetes, respectively. This increased risk for diabetes by GADA-positivity is only found in male adults (HR 4.55, 95% CI 2.25– 9.23).Conclusion: GADA has a low prevalence in China but is associated with a 2.63– 4.16-fold increased risk for diabetes.Keywords: autoimmune diabetes, glutamic acid decarboxylase antibody, latent autoimmune diabetes in adults, obesity, prevention

Advances in molecular methods and the ability to share large population-based datasets are uncovering heterogeneity within diabetes types, and some commonalities between types. Within type 1 diabetes, endotypes have been discovered based on demographic (e.g. age at diagnosis, race/ethnicity), genetic, immunological, histopathological, metabolic and/or clinical course characteristics, with implications for disease prediction, prevention, diagnosis and treatment. In type 2 diabetes, the relative contributions of insulin resistance and beta cell dysfunction are heterogeneous and relate to demographics, genetics and clinical characteristics, with substantial interaction from environmental exposures. Investigators have proposed approaches that vary from simple to complex in combining these data to identify type 2 diabetes clusters relevant to prognosis and treatment. Advances in pharmacogenetics and pharmacodynamics are also improving treatment. Monogenic diabetes is a prime example of how understanding heterogeneity within diabetes types can lead to precision medicine, since phenotype and treatment are affected by which gene is mutated. Heterogeneity also blurs the classic distinctions between diabetes types, and has led to the definition of additional categories, such as latent autoimmune diabetes in adults, type 1.5 diabetes and ketosis-prone diabetes. Furthermore, monogenic diabetes shares many features with type 1 and type 2 diabetes, which make diagnosis difficult. These challenges to the current classification framework in adult and paediatric diabetes require new approaches. The ‘palette model’ and the ‘threshold hypothesis’ can be combined to help explain the heterogeneity within and between diabetes types. Leveraging such approaches for therapeutic benefit will be an important next step for precision medicine in diabetes. Since the first remedies for ‘honey urine’ were described over 25 centuries ago, untangling the pathways that lead to what we call today diabetes has enabled better treatments. The current classification of diabetes recognises the major forms of type 1 diabetes, type 2 diabetes, gestational diabetes and other less common types, such as monogenic diabetes (including neonatal diabetes and MODY), diseases of the exocrine pancreas (e.g. cystic fibrosis-related diabetes and pancreatogenic [or type 3c] diabetes) or drug-induced diabetes (Table 1) [1]. Advances in molecular biology and genetic methods during the past decades have facilitated the discovery of a myriad of genetic associations that suggest diverse pathophysiology within each of those types, as well as some commonalities between types. The recent acceleration in the ability to share large population-based datasets has further increased the evidence for heterogeneity within and between diabetes types [2]. Integrating our understanding of genetics, immunology and metabolic abnormalities in each type of diabetes will boost the ability to use precision medicine to tailor treatments and improve health outcomes.

Background: The detection of glutamic acid decarboxylase 65 (GAD65) autoantibodies is essential for the prediction and diag nosis of latent autoimmune diabetes in adults (LADA). The aim of the current study was to compare a newly developed electro chemiluminescence (ECL)-GAD65 antibody assay with the established radiobinding assay, and to explore whether the new assay could be used to define LADA more precisely. Methods: Serum samples were harvested from 141 patients with LADA, 95 with type 1 diabetes mellitus, and 99 with type 2 dia betes mellitus, and tested for GAD65 autoantibodies using both the radiobinding assay and ECL assay. A glutamic acid decarbox ylase antibodies (GADA) competition assay was also performed to assess antibody affinity. Furthermore, the clinical features of these patients were compared. Results: Eighty-eight out of 141 serum samples (62.4%) from LADA patients were GAD65 antibody-positive by ECL assay. Com pared with ECL-GAD65 antibody-negative patients, ECL-GAD65 antibody-positive patients were leaner (P

BackgroundThe pathogenesis of the progressive loss of beta cell function latent autoimmune diabetes in adults (LADA) remains still elusive. We aim to study the fatty acid (FA) profile in LADA.Subjects and methodsData from 116 patients with diabetes and GADA and 249 diabetes controls without GADA selected by Propensity Score Matching were collected. FA was analyzed with liquid chromatography-tandem mass spectrometry analysis.ResultsPrincipal factor analysis found component 1 explains 82.6% of total variance contained fatty acids from a mixed of lard oil, seafood, and vegetable diet, followed by diet predominantly from vegetable oil, a diet of high fat diet, and a diet of seafood diet. The FA heatmap looked clearly different among the three groups with more similar type 1 (t1dm) and LADA fatty acid profile. n-3 α-linolenic acid (ALA), n-3 long chain polyunsaturated fatty acid (n-3 LC-PUFA), such as Eicosapentaenoic Acid and Docosapentaenoic Acid, n-3/n-6 ratio and triene/tetraene ratio were higher in patients with type 2 diabetes (t2dm) compared with LADA and t1dm. Saturated FAs were lower in t2dm than t1dm and LADA. Arachidic acid and n-6 LC-PUFAs were lower in t2dm than in t1dm and LADA. The characteristics of FAs in LADA were in between of classical t1dm and t2dm. Patients were classified into 6 clusters by FA clusters. Only cluster 2, 3, 5 contained enough patients to be analyzed. Cluster 5 showed an insulin deficient phenotype containing more than 60% of patients with t1dm and LADA and only 12.8% of t2dm. Cluster 2 and 3 were similar. β cell function and glycemic control was better in cluster 3 homing 25% of t2dm. Cluster 2 held 28% of t1dm and LADA, in this cluster more than 60% of patients was t2dm. n-3 linolenic acid, n-3 LC-PUFAs, some n-6 LC-PUFAs, n-3/n-6 ratio and triene/tetraene ratio were negatively associated with GADA positivity while n-6 Arachidonic Acid was associated positively with GADA. Similar findings were found for insulin sensitivity and beta cell function.ConclusionPUFA are associated with insulin sensitivity and beta cell function, and like other clinical features, FA profile distributed differently, but could not be used as makers to differentiate LADA from t1dm and t2dm.Ethics and DisseminationThis study has been approved by the Ethical Review Committee of Second Hospital of Dalian Medical University (approval number: 2021–005).Clinical Trial Registrationnone

BackgroundLatent autoimmune diabetes in adults (LADA) is a heterogeneous form of diabetes, characterized by autoimmune destruction of pancreatic β-cells as well as insulin resistance and is triggered by environmental factors in the context of genetic susceptibility. Berberine (BBR), a small alkaloid isolated from medicinal plants, has antidiabetic, anti-inflammatory, and antibacterial effects. Inulin is a common prebiotic that has been shown to improve glycemic control, alter the gut microbiota and suppress inflammation. The primary purpose of this study was to evaluate the effects of oral BBR and inulin combined with insulin therapy on diabetes care in patients with LADA.Methods and AnalysisWe will conduct a single-center, prospective, randomized, double-blind, placebo-controlled trial. A total of 240 patients with LADA who have started insulin therapy will be randomly allocated either to the intervention or control group. After a 1-week run-in period, they will complete a 3-month treatment of BBR alone, inulin plus BBR, inulin alone, or placebo. Anthropometric and clinical data will be collected at five time points: baseline, 3 months, 6 months, 9 months, and 12 months from baseline. The primary outcome was the change in glycated hemoglobin levels. Dynamic blood glucose parameters, β-cell function, and gut microbiota, as well as adverse events and quality of life will be monitored.DiscussionGlycemic control is critical for preventing the progression of diabetes. Although insulin is a recommended treatment for patients with LADA, there are currently no drugs that can effectively prevent the progressive destruction of pancreatic β-cells or maintain their function. Several studies have found that when berberine and prebiotics are used alone, they have beneficial metabolic effects. This clinical research protocol will assess the efficacy of the combined treatment of berberine plus inulin and provide new ideas for future pharmacological research and clinical practices in diabetes care and glycemic control for LADA patients.Ethics and DisseminationThis study has been approved by the Ethics Committee of National Clinical Research Center of the Second Xiangya Hospital of Central South University (approval number: 2021–046).Clinical Trial RegistrationClinicalTrials.gov, identifier NCT04698330

Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease sharing some phenotypic, genetic, and immunological features with both type 1 and 2 diabetes. Patients with LADA have a relatively slow autoimmune process and more residual islet β-cell function at onset, allowing a time window to protect residual islet β cells and delay or inhibit disease progression. It is crucial to discover various heterogeneous factors affecting islet β-cell function for precise LADA therapy. In this review, we first describe the natural history of LADA. Thereafter, we summarize β-cell function-related heterogeneous factors in LADA, including the age of onset, body mass index, genetic background, and immune, lifestyle, and environmental factors. In parallel, we evaluate the impact of current hypoglycemic agents and immune intervention therapies for islet β-cell protection. Finally, we discuss the opportunities and challenges of LADA treatment from the perspective of islet β-cell function protection.

Antibodies (Abs) against intracellular epitopes of the tyrosine-phosphatase 2 (IA-2) are detected in type 1 diabetes. Abs directed against the IA-2(256-760) portion, with both intra- and extracellular epitopes, are present in people with latent autoimmune diabetes in adults (LADA) and in obese subjects with normal glucose tolerance (NGT). We aim to characterize distribution and clinical features of intra- and extra-cellular IA-2(256-760) immunoreactivities in people with LADA compared to obese people with NGT. The intracellular immunoreactivity represented by immune response against two intracellular IA-2 constructs (IA-2JM(601-630) and IA-2IC(605-979)) was analyzed and related to clinical and biochemical features in 101 people with LADA and in 20 NGT obese subjects, all testing positive for IA-2(256-760) Abs. IA-2 intracellular immunoreactivity showed a frequency of 40.6% in LADA while it was not detected among NGT obese (p

Latent autoimmune diabetes in adults (LADA) is a type of diabetes characterized by slow autoimmune damage of pancreatic β cells without insulin treatment in the early clinical stage. There are differences between LADA and classical type 1 diabetes (T1D) and type 2 diabetes (T2D) in genetic background, autoimmune response, rate of islet function decline, clinical metabolic characteristics, and so on. The disease progression and drug response of patients with LADA are closely related to the level of islet autoimmunity, thus exploring the pathogenesis of LADA is of great significance for its prevention and treatment. Previous studies reported that adaptive immunity and innate immunity play a critical role in the etiology of LADA. Recent studies have shown that the intestinal microbiota which impacts host immunity hugely, participates in the pathogenesis of LADA. In addition, the progression of autoimmune pancreatic β cell destruction in LADA is slower than in classical T1D, providing a wider window of opportunities for intervention. Therefore, therapies including antidiabetic drugs with immune-regulation effects and immunomodulators could contribute to promising interventions for LADA. We also shed light on potential interventions targeting the gut microbiota and gut-associated immunity, which may be envisaged to halt or delay the process of autoimmunity in LADA.

BackgroundThere is a controversy regarding Latent Autoimmune Diabetes in Adults (LADA) classification and whether it should be considered a slowly progressing form of type 1 (T1) diabetes (DM) or a distinct type of DM altogether.MethodsThis cross-sectional study assessed major genes associated with T1DM (class II HLA, PTPN22 [rs2476601] and INS [rs689]) in patients with LADA, as compared with participants with T1DM (stratified according to age of diagnosis before or after 30) and T2DM. HLA genotyping of the DRB1, DQA1 and DQB1 loci was performed by reverse PCR sequence-specific oligonucleotides. HLA haplotypes were assigned according to those most frequently described in the European population. INS and PTPN22 SNPs were genotyped by real-time PCR.ResultsA total of 578 participants were included: 248 with T1DM (70 diagnosed after the age of 30), 256 with T2DM and 74 with LADA. High risk HLA alleles were significantly more frequent in LADA than in T2DM, whereas the opposite was true for protective alleles. We found a lower frequency of the high-risk DRB1*04-DQB1*03:02-DQA1*03:01 haplotype in LADA (21.1%) than in the overall T1DM (34.7%) (pPTPN22 and INS SNPs. The G/A genotype of the PTPN22 rs2476601 was more frequent and the T/T genotype of the INS SNP rs689 was less frequent in T1DM compared to LADA. We did not find any significant differences in the frequency of the mentioned SNPs between LADA and T2DM, or between LADA and T1DM diagnosed after the age of 30.ConclusionIn this relatively small cross-sectional study, the genetic profile of subjects with LADA showed a similar T1DM-related risk allele distribution as in participants with T1DM diagnosed after the age of 30, but fewer risk alleles than those diagnosed before 30. Differences were present for HLA, as well as PTPN22 and INS genes.

Latent autoimmune diabetes in adults (LADA) is an autoimmune disease that shares some genetic, immunological and clinical features with both type 1 diabetes and type 2 diabetes. Immune cells including CD4(+) T cells, CD8(+) T cells, B cells, macrophages and dendritic cells (DCs) have been detected in the pancreas of patients with LADA and a rat model of LADA. Therefore, similar to type 1 diabetes, the pathogenesis of LADA may be caused by interactions between islet β-cells and innate and adaptive immune cells. However, the role of the immunity in the initiation and progression of LADA remains largely unknown. In this review, we have summarized the potential roles of innate immunity and immune-modulators in LADA development. Furthermore, we have examined the evidence and discussed potential innate immunological reasons for the slower development of LADA compared with type 1 diabetes. More in-depth mechanistic studies are needed to fully elucidate the roles of innate immune-associated genes, molecules and cells in their contributions to LADA pathogenesis. Undertaking these studies will greatly enhance the development of new strategies and optimization of current strategies for the diagnosis and treatment of the disease.

BackgroundLatent Autoimmune Diabetes in Adults (LADA) constitutes around 10% of all diabetes. Many LADA patients gradually lose their insulin secretion and progress to insulin dependency. In a recent trial BALAD (Behandling Av LADa) early insulin treatment compared with sitagliptin failed to preserve insulin secretion, which deteriorated in individuals displaying high levels of antibodies to GAD (GADA). These findings prompted us to evaluate a treatment that directly affects autoimmunity. Intra-lymphatic GAD-alum treatment has shown encouraging results in Type 1 diabetes patients. We therefore tested the feasibility of such therapy in LADA-patients (the GADinLADA pilot study).Material and MethodsFourteen GADA-positive (>190 RU/ml), insulin-independent patients 30-70 years old, with LADA diagnosed within < 36 months were included in an open-label feasibility trial. They received an intra-nodal injection of 4 μg GAD-alum at Day 1, 30 and 60 plus oral Vitamin D 2000 U/d from screening 30 days before (Day -30) for 4 months if the vitamin D serum levels were below 100 nmol/L (40 ng/ml). Primary objective is to evaluate safety and feasibility. Mixed Meal Tolerance Test and i.v. Glucagon Stimulation Test at baseline and after 5 and 12 months are used for estimation of beta cell function. Results will be compared with those of the recent BALAD study with comparable patient population. Immunological response is followed.ResultsPreliminary results show feasibility and safety, with almost stable beta cell function and metabolic control during follow-up so far (5 months).ConclusionsIntra-lymphatic GAD-alum treatment is an option to preserve beta cell function in LADA-patients. An ongoing trial in 14 LADA-patients show feasibility and safety. Clinical and immunological responses will determine how to proceed with future trials.

Aims/hypotheses Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. Methods Analyses were based on Swedish case–control data (collected 2010–2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984–2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case–control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. Results Smoking (RRpooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. Conclusions/interpretation Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA. Data availability Analysis codes are shared through GitHub (https://github.com/jeseds/Smoking-use-of-smokeless-tobacco-HLA-genotypes-and-incidence-of-LADA). Graphical abstract

Background - Cytokines and chemokines participate in autoimmune processes at cellular targets which include insulin-producing beta cells. To which extent such participation is reflected in the circulation has not been conclusively resolved. Aim - We compared the time course of cytokines/chemokines in Latent Autoimmune Diabetes in Adults (LADA) patients heterogeneous for high or low autoimmune activity as determined by levels of antibodies against glutamic acid decarboxylase (GADA). Methods - Serum samples to be measured were from a two-armed randomized controlled trial (RCT) in 68 LADA patients. The study encompassed 21 months with C-peptide as primary endpoint. We measured 27 immune mediators at baseline, at 9 and at 21 months (end of study). Results of measurements were analyzed by multiple linear regression. Results - At baseline, a high body mass index (BMI) (>26 kg/m2) was associated with elevated levels of the interleukins (IL) IL-1 beta, IL-1ra, IL-2, IL-5, IL-6 and IL-13. Treatment during RCT (sitagliptin vs. insulin) did not affect the time course (21 months) of levels of cytokines/chemokines (by univariate analyses). However, levels of the cytokines IL-1ra and IL-1 beta decreased significantly (p < 0.04 or less) in patients with high vs. low GADA when adjusted for BMI, age, gender (male/female), treatment (insulin/sitagliptin) and study site (Norwegian/Swedish). Conclusions - In LADA, high levels of GADA, a proxy for high autoimmune activity and linked to a decline in C-peptide, was associated with a decrease of selected cytokines over time. This implies that the decline of IL-1ra and IL-1 beta in the circulation reflects autoimmune activity and beta cell demise in LADA.

Purpose of the work. To find out the features of the course of chronic kidney disease in patients with latent autoimmune diabetes in adults (LADA) compared with the classic types of diabetes. Materials and methods. 145 patients with diabetes mellitus (DM) were examined (70 patients with LADA, 40 with type 1 DM — T1DM, 35 with type 2 DM — T2DM. Antibodies to glutamic acid decarboxylase and to tyrosine phosphatase were determined in all patients. Features of chronic kidney disease (CKD) were studied on the basis of anamnesis, clinical examination, glomerular filtration rate, microalbuminuria and the of albumin-creatinine ratio in urine. Results and discussion. According to the anamnesis, the diagnosis of CKD in patients with LADA was established on average up to 3 years from the manifestation of diabetes (in 30 % — already in the onset of the disease), while in T1DM — after 7.2 years, in T2DM — after 1.9 years. The most common stage of CKD in LADA patients was III (in 49 % of people). At the same time, the majority of patients had a nonalbuminuric phenotype of diabetic kidney disease (NARI). In terms of the characteristics of the course of CKD, LADA occupied an intermediate position, combining the signs of both main types of diabetes. Conclusions. The diagnosis of CKD in patients with LADA was established much earlier than in T1DM which indicates the incorrect use of the same recommendations for screening this complication in these patients. There was a predominance of NARI in patients with LADA. CKD in LADA requires the development of special approaches to screening, diagnosis and treatment., Цель работы — выяснить особенности течения хронической болезни почек (ХБП) у больных с латентным аутоиммунным диабетом взрослых (latent autoimmune diabetes in adults (LADA)) по сравнению с классическими типами сахарного диабета (СД). Материалы и методы. Обследованы 145 больных с СД, из них 70 лиц с LADA, 40 — с СД 1 типа, 35 — с СД 2 типа. Всем пациентам определяли антитела к декарбоксилазе глутаминовой кислоты и тирозин фосфатазе. Особенности течения ХБП изучали по данным анамнеза, клинического обследования, значению скорости клубочковой фильтрации, микроальбуминурии и соотношения альбумина и креатинина в моче. Результаты и обсуждение. По данным анамнеза, диагноз ХБП у пациентов с LADA установлен в среднем в течение 3 лет после манифестации СД (в 30 % — в дебюте заболевания), тогда как при СД 1 типа — через 7,2 года, при СД 2 типа — через 1,9 года. Чаще всего при LADA регистрировали ХБП III стадии (у 49 % лиц). У большинства больных определен неальбуминурийный фенотип диабетической болезни почек. По особенностям течения ХБП LADA занимала промежуточное место, сочетая признаки обоих основных типов диабета. Выводы. Диагноз ХБП при LADA устанавливают гораздо раньше, чем при СД 1 типа, что свидетельствует о некорректности использования одинако­вых рекомендаций по скринингу этого осложнения у упомянутых пациентов. Отмечено преобладание неальбуминурийного фенотипа диабетической бо­­лезни почек у пациентов с LADA. При LADA ХБП требует разработки особых подходов к скринингу, диагностике и лечению., Мета роботи — з’ясувати особливості перебігу хронічної хвороби нирок (ХХН) у хворих на латентний автоімунний діабет дорослих (latent autoimmune diabetes in adults (LADA)) порівняно з класичними типами цукрового діабету (ЦД). Матеріали та методи. Обстежено 145 хворих на ЦД, з них 70 осіб з LADA, 40 — з ЦД 1 типу, 35 — з ЦД 2 типу. Усім пацієнтам визначали антитіла до декарбоксилази глютамінової кислоти і тирозин фосфатази. Особливості перебігу ХХН вивчали за даними анамнезу, клінічного обстеження, значеннями швидкості клубочкової фільтрації, мікроальбумінурії та співвідношення альбуміну та креатиніну в сечі. Результати та обговорення. За даними анамнезу, діагноз ХХН у пацієнтів з LADA встановлено в середньому впродовж 3 років після маніфестації ЦД (у 30 % — у дебюті захворювання), тоді як при ЦД 1 типу — через 7,2 року, при ЦД 2 типу — через 1,9 року. Найчастіше при LADA реєстрували ХХН ІІІ стадії (у 49 % осіб). У більшості хворих визначено неальбумінурійний фенотип діабетичної хвороби нирок. За особливостями перебігу ХХН LADA посідала проміжне місце, поєднуючи ознаки обох основних типів діабету. Висновки. Діагноз ХХН при LADA встановлюють набагато раніше, ніж при ЦД 1 типу, що свідчить про некоректність використання однакових рекомендацій щодо скринінгу цього ускладнення у зазначених пацієнтів. Відзначено переважання неальбумінурійного фенотипу діабетичної хвороби нирок у пацієнтів з LADA. При LADA ХХН потребує розробки особливих підходів до скринінгу, діагностики та лікування.

Purpose of the work. To find out the features of the course of chronic kidney disease in patients with latent autoimmune diabetes in adults (LADA) compared with the classic types of diabetes. Materials and methods. 145 patients with diabetes mellitus (DM) were examined (70 patients with LADA, 40 with type 1 DM — T1DM, 35 with type 2 DM — T2DM. Antibodies to glutamic acid decarboxylase and to tyrosine phosphatase were determined in all patients. Features of chronic kidney disease (CKD) were studied on the basis of anamnesis, clinical examination, glomerular filtration rate, microalbuminuria and the of albumin-creatinine ratio in urine. Results and discussion. According to the anamnesis, the diagnosis of CKD in patients with LADA was established on average up to 3 years from the manifestation of diabetes (in 30 % — already in the onset of the disease), while in T1DM — after 7.2 years, in T2DM — after 1.9 years. The most common stage of CKD in LADA patients was III (in 49 % of people). At the same time, the majority of patients had a nonalbuminuric phenotype of diabetic kidney disease (NARI). In terms of the characteristics of the course of CKD, LADA occupied an intermediate position, combining the signs of both main types of diabetes. Conclusions. The diagnosis of CKD in patients with LADA was established much earlier than in T1DM which indicates the incorrect use of the same recommendations for screening this complication in these patients. There was a predominance of NARI in patients with LADA. CKD in LADA requires the development of special approaches to screening, diagnosis and treatment., Цель работы — выяснить особенности течения хронической болезни почек (ХБП) у больных с латентным аутоиммунным диабетом взрослых (latent autoimmune diabetes in adults (LADA)) по сравнению с классическими типами сахарного диабета (СД). Материалы и методы. Обследованы 145 больных с СД, из них 70 лиц с LADA, 40 — с СД 1 типа, 35 — с СД 2 типа. Всем пациентам определяли антитела к декарбоксилазе глутаминовой кислоты и тирозин фосфатазе. Особенности течения ХБП изучали по данным анамнеза, клинического обследования, значению скорости клубочковой фильтрации, микроальбуминурии и соотношения альбумина и креатинина в моче. Результаты и обсуждение. По данным анамнеза, диагноз ХБП у пациентов с LADA установлен в среднем в течение 3 лет после манифестации СД (в 30 % — в дебюте заболевания), тогда как при СД 1 типа — через 7,2 года, при СД 2 типа — через 1,9 года. Чаще всего при LADA регистрировали ХБП III стадии (у 49 % лиц). У большинства больных определен неальбуминурийный фенотип диабетической болезни почек. По особенностям течения ХБП LADA занимала промежуточное место, сочетая признаки обоих основных типов диабета. Выводы. Диагноз ХБП при LADA устанавливают гораздо раньше, чем при СД 1 типа, что свидетельствует о некорректности использования одинако­вых рекомендаций по скринингу этого осложнения у упомянутых пациентов. Отмечено преобладание неальбуминурийного фенотипа диабетической бо­­лезни почек у пациентов с LADA. При LADA ХБП требует разработки особых подходов к скринингу, диагностике и лечению., Мета роботи — з’ясувати особливості перебігу хронічної хвороби нирок (ХХН) у хворих на латентний автоімунний діабет дорослих (latent autoimmune diabetes in adults (LADA)) порівняно з класичними типами цукрового діабету (ЦД). Матеріали та методи. Обстежено 145 хворих на ЦД, з них 70 осіб з LADA, 40 — з ЦД 1 типу, 35 — з ЦД 2 типу. Усім пацієнтам визначали антитіла до декарбоксилази глютамінової кислоти і тирозин фосфатази. Особливості перебігу ХХН вивчали за даними анамнезу, клінічного обстеження, значеннями швидкості клубочкової фільтрації, мікроальбумінурії та співвідношення альбуміну та креатиніну в сечі. Результати та обговорення. За даними анамнезу, діагноз ХХН у пацієнтів з LADA встановлено в середньому впродовж 3 років після маніфестації ЦД (у 30 % — у дебюті захворювання), тоді як при ЦД 1 типу — через 7,2 року, при ЦД 2 типу — через 1,9 року. Найчастіше при LADA реєстрували ХХН ІІІ стадії (у 49 % осіб). У більшості хворих визначено неальбумінурійний фенотип діабетичної хвороби нирок. За особливостями перебігу ХХН LADA посідала проміжне місце, поєднуючи ознаки обох основних типів діабету. Висновки. Діагноз ХХН при LADA встановлюють набагато раніше, ніж при ЦД 1 типу, що свідчить про некоректність використання однакових рекомендацій щодо скринінгу цього ускладнення у зазначених пацієнтів. Відзначено переважання неальбумінурійного фенотипу діабетичної хвороби нирок у пацієнтів з LADA. При LADA ХХН потребує розробки особливих підходів до скринінгу, діагностики та лікування.

Background. Impaired bile acid (BA) metabolism has been associated with the progression of type 2 diabetes (T2D). However, the contribution of BAs to the pathogenesis of latent autoimmune diabetes in adults (LADA) remains unclear. This study was aimed at investigating the association of serum BAs with different diabetes types and analyzing its correlation with main clinical and laboratory parameters. Methods. Patients with LADA, patients with T2D, and healthy controls (HCs) were enrolled. Serum BA profiles and inflammatory cytokines were measured. The correlation of BA species with different indicators was assessed by Spearman’s correlation method. Results. Patients with diabetes (LADA and T2D) had significantly higher serum BAs, especially conjugated BAs, compared with those in HCs. Nevertheless, serum BA profiles had no special role in the progression of LADA, because no significant differences in BAs were observed between LADA and T2D patients. Interestingly, HbA1c levels and HOMA-β were found to be correlated with a series of BA species. Proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and anti-inflammatory cytokine (IL-10) were all positively associated with several BA species, especially the conjugated secondary BAs. Conclusion. Serum BAs regulate glucose homeostasis, but have no special value in the pathogenesis of LADA patients. Our study adds further information about the potential value of serum BAs in different types of diabetes.

Aims/hypothesis Observational studies have found an increased risk of latent autoimmune diabetes in adults (LADA) associated with low birthweight and adult overweight/obese status. We aimed to investigate whether these associations are causal, using a two-sample Mendelian randomisation (MR) design. In addition, we compared results for LADA and type 2 diabetes. Methods We identified 43 SNPs acting through the fetal genome as instrumental variables (IVs) for own birthweight from a genome-wide association study (GWAS) of the Early Growth Genetics Consortium (EGG) and the UK Biobank. We identified 820 SNPs as IVs for adult BMI from a GWAS of the UK Biobank and the Genetic Investigation of ANthropometric Traits consortium (GIANT). Summary statistics for the associations between IVs and LADA were extracted from the only GWAS involving 2634 cases and 5947 population controls. We used the inverse-variance weighted (IVW) estimator as our primary analysis, supplemented by a series of sensitivity analyses. Results Genetically determined own birthweight was inversely associated with LADA (OR per SD [~500 g] decrease in birthweight 1.68 [95% CI 1.01, 2.82]). In contrast, genetically predicted BMI in adulthood was positively associated with LADA (OR per SD [~4.8 kg/m2] increase in BMI 1.40 [95% CI 1.14, 1.71]). Robust results were obtained in a range of sensitivity analyses using other MR estimators or excluding some IVs. With respect to type 2 diabetes, the association with birthweight was not stronger than in LADA while the association with adult BMI was stronger than in LADA. Conclusions/ interpretation This study provides genetic support for a causal link between low birthweight, adult overweight/obese status and LADA. Graphical abstract

Latent autoimmune diabetes of adulthood (LADA) differs in clinical features from type 2 diabetes. Whether this difference translates into different risks of complications remains controversial. We examined the long-term risk of microvascular complications in people enrolled in the UK Prospective Diabetes Study (UKPDS), according to their diabetes autoimmunity status.We did a post-hoc analysis of 30-year follow-up data from UKPDS (UKPDS 86). UKPDS participants with diabetes autoantibody measurements available and without previous microvascular events were included. Participants with at least one detectable autoantibody were identified as having latent autoimmune diabetes, and those who tested negative for all autoantibodies were identified as having type 2 diabetes. The incidence of the primary composite microvascular outcome (first occurrence of renal failure, renal death, blindness, vitreous haemorrhage, or retinal photocoagulation) was compared between adults with latent autoimmune diabetes and those with type 2 diabetes. The follow-up ended on Sept 30, 2007. Baseline and updated 9-year mean values of potential confounders were tested in Cox models to adjust hazard ratios (HRs). UKPDS is registered at the ISRCTN registry, 75451837.Among the 5028 participants included, 564 had latent autoimmune diabetes and 4464 had type 2 diabetes. After median 17·3 years (IQR 12·6-20·7) of follow-up, the composite microvascular outcome occurred in 1041 (21%) participants. The incidence for the composite microvascular outcome was 15·8 (95% CI 13·4-18·7) per 1000 person-years in latent autoimmune diabetes and 14·2 (13·3-15·2) per 1000 person-years in type 2 diabetes. Adults with latent autoimmune diabetes had a lower risk of the composite outcome during the first 9 years of follow-up than those with type 2 diabetes (adjusted HR 0·45 [95% CI 0·30-0·68], p0·0001), whereas in subsequent years their risk was higher than for those with type 2 diabetes (1·25 [1·01-1·54], p=0·047). Correcting for the higher updated 9-year mean HbAAt diabetes onset, adults with latent autoimmune diabetes have a lower risk of microvascular complications followed by a later higher risk of complications than do adults with type 2 diabetes, secondary to worse glycaemic control. Implementing strict glycaemic control from the time of diagnosis could reduce the later risk of microvascular complications in adults with latent autoimmune diabetes.European Foundation for the Study of Diabetes Mentorship Programme (AstraZeneca).

Approximately 10% of patients with type 2 diabetes suffer from latent autoimmune diabetes in adults (LADA). This study provides a systematic assessment of the pathology of the endocrine pancreas of patients with LADA and for comparison in a first rat model mimicking the characteristics of patients with LADA. Islets in human and rat pancreases were analyzed by immunohistochemistry for immune cell infiltrate composition, by in situ RT-PCR and quantitative real-time PCR of laser microdissected islets for gene expression of proinflammatory cytokines, the proliferation marker proliferating cell nuclear antigen (PCNA), the anti-inflammatory cytokine interleukin (IL) 10, and the apoptosis markers caspase 3 and TUNEL as well as insulin. Human and rat LADA pancreases showed differences in areas of the pancreas with respect to immune cell infiltration and a changed ratio between the number of macrophages and CD8 T cells toward macrophages in the islet infiltrate. Gene expression analyses revealed a changed ratio due to an increase of IL-1β and a decrease of tumor necrosis factor-α. IL-10, PCNA, and insulin expression were increased in the LADA situation, whereas caspase 3 gene expression was reduced. The analyses into the underlying pathology in human as well as rat LADA pancreases provided identical results, allowing the conclusion that LADA is a milder form of autoimmune diabetes in patients of an advanced age.

To investigate the possibility of identifying a subtype of latent autoimmune diabetes in adults (LADA), T-LADA (T cell responses-positive and autoantibody-negative) from patients with phenotypic type 2 diabetes (T2D) by enzyme-linked immunospot (ELISPOT). Eighty-two patients with phenotypic T2D were studied. Autoantibodies against glutamic acid decarboxylase (GAD), insulinoma-associated protein-2 and zinc transporter 8 were measured by radioligand assay. Thirty-nine Ab+ and 43 Ab− patients with phenotypic T2D were enrolled for T cell assay of responses to GAD65 and C-peptide antigen by ELISPOT. (1) Eleven of 43 Ab− participants with phenotypic T2D were demonstrated interferon (IFN)-γ secreting T cells by ELISPOT, while 13 of 39 Ab+ patients with phenotypic T2D were positive for T cells responses to islet antigens. (2) The onset ages of T cell+ people with phenotypic T2D were younger than that of T cell− individuals (42.7 ± 9.3 vs. 48.2 ± 10.2 years, P = 0.025). Moreover, T cell+ patients with T2D displayed a significantly lower fasting C-peptide (FCP) compared with T cell− participants [0.28 (0.02–0.84) vs. 0.42 (0.05–1.26) nmol/L, P = 0.013]. (3) Ab−T+ group had a significantly lower FCP compared with Ab−T− group [0.31 (0.13–0.84) vs. 0.51 (0.07–1.26) nmol/L, P = 0.023]. By measuring T cell responses to islet antigens in patients with phenotypic T2D, we identified a specific subtype of LADA who may be associated with worse basal β-cell function than classic T2D (Ab−T−).

Latent Autoimmune Diabetes in Adults (LADA), although formally classified as Type 1 Diabetes (T1D), very often (at least in Western countries) appear clinically with Type 2 Diabetes (T2D)-like features as overweight and insulin resistance. LADA patients do not need exogenous insulin at the time they are diagnosed with diabetes, but a large percentage will within a few years develop need for such treatment. The decline in beta cell function progresses much faster in LADA than in T2D, presumably because of the ongoing autoimmune assault in LADA, and therefore necessitates insulin therapy much earlier in LADA than in T2D. Despite high prevalence of LADA (about 10% of the total diabetic population in many countries), the treatment of LADA patients is far less elucidated than is the case for T1D and T2D. Finding a treatment strategy for LADA from the time of diagnosis, that can reduce the decline of beta cell function, ensure adequate metabolic control and thereby reduce the risk of diabetic complications is thus an important clinical challenge. Conclusions from the randomized treatment studies so far do not indicate an optimal treatment strategy in LADA. This review aims to give an overview of current practices for the medical treatment of LADA as well as an update on results from recent studies on the treatment of the disease.

Background: In order to prevent diabetes it is important to identify common, modifiable risk factors in the population. Such knowledge is extensive for type 2 diabetes but limited for autoimmune forms of diabetes. Objective: This review aims at summarizing the limited literature on potential environmental (lifestyle) risk factors for LADA. Methods: A PubMed search identified 15 papers estimating the risk of LADA in relation to lifestyle. These were based on data from two population-based studies; one Swedish case-control study and one Norwegian cohort study. Results: Studies published to date indicate that the risk of LADA is associated with factors promoting insulin resistance and type 2 diabetes such as overweight, physical inactivity, smoking, low birth weight, sweetened beverage intake and moderate alcohol consumption (protective). Findings also indicate potential effects on autoimmunity exerted by intake of coffee (harmful) and fatty fish (protective). This supports the concept of LADA as being a hybrid form of diabetes with an etiology including factors associated with both insulin resistance and autoimmunity. Conclusion: LADA may in part be preventable through the same lifestyle modifications as type 2 diabetes including weight loss, physical activity and smoking cessation. However, current knowledge is hampered by the small number of studies and the fact that they exclusively are based on Scandinavian populations. There is a great need for additional studies exploring the role of lifestyle factors in the development of LADA.

У лекції подані сучасні відомості щодо латентного автоімунного діабету у дорослих (LADA). Наведені дані літератури щодо епідеміології, чинників і механізмів розвитку, клінічних особливостей цього захворювання. Виділені та охарактеризовані можливі варіанти перебігу LADA. Розкриті питання діагностичних особливостей, диференційної діагностики та зазначені перспективи лікування., The lecture provides modern information on latent autoimmune diabetes in adults. Data of literature on the epidemiology, factors and mechanisms of development, clinical features of this disease are presented. The possible variants of latent autoimmune diabetes in adults course are identified and characterized. The questions of diagnostic features, differential diagnosis and the prospects of treatment are outlined., В лекции представлены современные сведения о латентном аутоиммунном диабете у взрослых (LADA). Приведены данные литературы относительно эпидемиологии, факторов и механизмов развития, клинических особенностей этого заболевания. Выделены и охарактеризованы возможные варианты течения LADA. Раскрыты вопросы диагностических особенностей, дифференциальной диагностики и обозначены перспективы лечения.