Latent autoimmune diabetes in youth: a new challenge for the clinician (literature review and own data)

The 30th anniversary of Latent Autoimmune Diabetes in Adults (LADA) is a remarkable milestone in diabetes mellitus research. Described for the first time in 1993, LADA disputes the traditional binary classification of diabetes, with autoimmune features (autoimmune-mediated β-cell destruction) like that of type 1 diabetes (T1D) yet with an adult-onset pattern not requiring insulin, at least initially and, therefore, resembling type 2 diabetes (T2D).1, 2 Thus, commenced an extensive journey of scientific exploration. Although our understanding of LADA has grown substantially over this period, many questions surrounding LADA remain unresolved. Today, LADA patients constitute a significant fraction, that is, up to 12% of T2D patients, highlighting the pressing need to address these questions.3, 4 This commentary discusses such questions, the ongoing efforts by scientists/physicians and future directions in search for answers. Diagnosing LADA is challenging due to overlaps with other forms of diabetes, also making it hard to define categorical features. In fact, LADA is often initially misdiagnosed as T2D because of the resemblance in their clinical presentation.5 Furthermore, heterogeneity within LADA adds to this diagnostic challenge.2, 6 Given that LADA people must be identified early to ensure better outcomes in terms of HbA1c, co-morbidity and hypoglycaemia risk, the best strategy for such identification must be resolved. Regarding the diagnostic criteria of LADA, the Immunology of Diabetes Society proposed it includes diabetes cases age ≥30 years, positive for at least one diabetes-associated autoantibody, and without insulin requirement for at least the first six months after diagnosis.5 There are some weaknesses with this proposal. First, all criteria are non-categorical, and all the cut-off values are arbitrary, as pointed out by Groop et al.2, 6, 7 Second, there are many factors relating to diagnostic autoantibodies (e.g., how positivity is defined and which autoantibody, despite the most common being an autoantibody against glutamic acid decarboxylase [GADA]).3, 7 This issue is demonstrated by the significant variability in the percentage of LADA diagnosis among different groups of T2D-diagnosed adults, depending on the autoantibody type used for screening and method of ascertainment.3 Third, the choice of whether and when to start insulin treatment is highly physician-dependent, as highlighted by Rajkumar et al.5, 8 For these reasons, more precise standardised diagnostic criteria for LADA may be needed. As for autoantibody testing, there are no current general recommendations for adult-onset diabetes. At present, autoantibody testing is only done if there is a strong suspicion of LADA in patients with normal or low BMI; by implication patients with high BMI are not checked as they are assumed not to have LADA, which we know is incorrect.9 Pertinent to autoantibody testing, an international expert panel in their recent consensus statement on the management of LADA recommended GADA testing for all newly diagnosed T2D patients.3 Theoretically, this would improve identification of LADA patients, but there are practical issues, for example, cost implications. The panel suggested that if there are cost limitations, patients should be selected for GADA testing based on a list of different clinical factors that increase the suspicion of LADA and not only based on BMI as with the current practice. As for GADA-negative individuals who are suspected of having LADA, the panel recommended testing them for other islet autoantibodies.3 We believe this will be a viable answer to the above-mentioned question. A further issue regarding LADA diagnosis concerns the identification of LADA at an earlier stage, even before it develops into clinical diabetes and, how can this be done. More studies to address this issue are required. As in its definition, LADA patients still possess functioning β-cells when diagnosed, making effective and timely interventions crucial to preserve the residual insulin secretory capacity and improve metabolic control. However, given that there are no specific guidelines for LADA management, so appropriate management still needs answering.3 To answer the question above, it is crucial to first know the roles of different interventions, including hypoglycaemic agents. Based on the limited studies available, the current understanding of the roles of hypoglycaemic agents in LADA is summarised in Table 1.3, 8, 10-13 Like many hypoglycaemic agents, the roles of lifestyle modifications and immune interventions in LADA are unclear.3 This clearly shows the need for a better understanding of these interventions. Of note, one question to explore is whether insulin therapy should be commenced early when there is still residual β-cell function.3 Hence, more large-scale randomised clinical trials with long-term follow-up are required. This approach is in line with the conclusion of a Cochrane Review and was supported by the recent consensus statement on the management of LADA.3, 8 Besides, due to heterogeneity within LADA, the management of LADA should be tailored to each patient to ensure optimal outcomes. The panel recommended modifying the American Diabetes Association/European Association for the Study of Diabetes (EASD) algorithm for T2D to be used for the management of LADA. They suggested separating patients into three categories of C-peptide levels, which reflect the β-cell function status of the patient, to determine therapeutic decisions, as outlined in Table 2.3, 14 We think this is a rational way forward, as measuring C-peptide levels is widely accessible and inexpensive.3 However, further studies, especially clinical trials, are needed to study the outcomes (there are no such trials to date). It was observed that LADA patients' progression and long-term outcomes vary considerably, as some patients maintained their β-cell function for long periods, while in other patients it deteriorated quickly.3 Factors relevant to this rapid deterioration include both the level of GADA titre, the initial C-peptide, and the quality of glycaemic control. First, UKPDS and other studies discovered an association between high GADA levels and a higher risk of progression towards insulin requirement.15, 16 Second, a post hoc analysis of UKPDS revealed that the risk of LADA patients developing microvascular complications compared to T2D patients is lower at disease onset but can become higher as a result of poor glycaemic control. This implies that optimal control of glycaemia may prevent the risk of developing complications later.17 It will be important to identify factors involved in the more rapid metabolic deterioration, which can be targeted and by what means, to improve long-term outcomes, including insulin dependency and risks of complications. Remaining unanswered questions include the best name for LADA (recently described as slowly-evolving autoimmune diabetes (SAID)), the cause of LADA and the environmental triggers that start the autoimmune attack on pancreatic β-cells.5 Whilst there is evidence of genetic involvement in LADA, including those shared with T1D, such as higher risk in carriers of certain HLA haplotypes and those shared with T2D, further confirmation is needed.3, 18 The same also applies to the potential genetic differences between LADA and T1D and whether they are due to actual differences or to the fact that LADA represents a late onset T1D, at least from a genetic standpoint.19 Furthermore, how these genetic factors influence LADA susceptibility and progression to disease remains unclear. Some studies have revealed immunological alterations in LADA, which are essential to improve understanding of LADA's autoimmunity process and potentially inform immunomodulation strategies.5 However, they are still not fully elucidated. Additionally, drawing parallels with the partial remission stage of T1D may provide insights into the balance between autoimmunity and immunometabolism regulation, which may contribute to the broader understanding of autoimmune diabetes and allow shared therapeutic strategies. There are also knowledge gaps in LADA's epidemiology that need addressing. For example, if an increase in incidence is occurring, what are the differences between regions with low and high incidence rates of T1D, and furthermore, if there are gender differences. This may help identify risk factors. Finally, elucidation of these issues as noted above could lead to prevent LADA, much as we would like to do for T1D in children. In conclusion, the 30th anniversary of LADA illustrates our evolving understanding of diabetes. As we celebrate this milestone, we should look back at the past and recognise the knowledge gaps in our understanding of LADA, some of which have been discussed in this commentary and are summarised in Table 3. However, it is essential to note that this commentary only discussed a tiny fraction of all the unresolved questions, as summarised in Figure 1. Looking to the future of LADA, we hope that the current momentum of scientific efforts will continue with more international collaborations in the next 3 decades, which, combined with advancements in technology, to answer most, if not all, of the unresolved questions to benefit our patients. What is the definite cause of LADA? What are the environmental triggers that start the autoimmune attack on pancreatic β-cells in LADA? What specific genes are involved in LADA? How do they compare to T1D? How do they influence susceptibility to LADA and LADA progression? What are the immunological alterations and their roles in LADA? How does LADA compare to the partial remission stage of T1D? What are the epidemiological characteristics of LADA? Can LADA be prevented? How can it be done? What factors are involved in determining the progression and long-term outcomes of LADA patients? Which of the factors involved can be targeted? How can they be targeted? What should be in the diagnostic criteria of LADA? Who should undergo autoantibodies testing? Is it possible to identify LADA earlier, even before it develops into clinical diabetes? How can this be done? What are the roles of different interventions, including hypoglycaemic agents, in LADA? Should insulin therapy be commenced early when there is still enough residual β-cell function? How to tailor the management of LADA to each patient due to endotype heterogeneity to ensure optimal outcomes? Relevance from scientific meaning to clinical practice in LADA. This figure illustrates two distinct rankings of the numerous fields of study in LADA which are important to address the persistent unresolved questions, based on two different criteria: relevance to scientific meaning and relevance to clinical practice. The colour gradient represents relevance, with a darker shade indicating higher relevance and a lighter shade indicating lower relevance. Ivy Lee Jia, Raffaella Buzzetti, Richard David Leslie and Paolo Pozzilli have equally contributed to the conceptualization, writing—original draft, review and editing, approval of the final version submitted for publication. Ivy Lee Jia, Raffaella Buzzetti, Richard David Leslie and Paolo Pozzilli have no funding to be declared. No potential conflicts of interest relevant to this paper were reported for Ivy Lee Jia, Raffaella Buzzetti, Richard David Leslie and Paolo Pozzilli. This is a review article on a topic of general interest that does not require any approval by Ethical Committee. Ivy Lee Jia Jia, Raffaella Buzzetti, Richard David Leslie and Paolo Pozzilli have nothing to disclose. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1002/dmrr.3800. All the references cited in this paper are available on Pubmed.

IntroductionAdult-onset autoimmune diabetes (AID) has two different phenotypes: classic type 1 diabetes mellitus (T1DM), with insulin requirement just after diagnosis, and latent autoimmune diabetes in adults (LADA). The purpose of this study is to characterize patients with AID followed on a tertiary centre, comparing classic T1DM and LADA.MethodsWe collected data from patients with diabetes and positive islet autoantibodies, aged 30 years old and over at diagnosis. Patients who started insulin in the first 6 months were classified as T1DM and patients with no insulin requirements in the first 6 months were classified as LADA. Data regarding clinical presentation, autoantibodies, A1C and C-peptide at diagnosis, pharmacologic treatment and complications were analysed.ResultsWe included 92 patients, 46 with classic T1DM and 46 with LADA. The percentage of females was 50% in T1DM group and 52.1% in LADA group. The median age at diagnosis was 38 years (IQR–15) for T1DM and 42 years (IQR–15) for LADA (p = 0.057). The median time between diagnosis of diabetes and diagnosis of autoimmune aetiology was 0 months in T1DM group and 60 months in LADA group (p < 0.001). The mean BMI at diagnosis was 24.1 kg/m2 in T1DM group and 26.1 kg/m2 in LADA group (p = 0.042). In T1DM group, 67.4% of the patients had more than one positive autoantibody, comparing to 41.3% of LADA patients (p = 0.012). There was no statistical difference in what concerns to title of GAD autoantibodies, A1C and C-peptide at diagnosis of autoimmune aetiology. The presence of symptoms at diagnosis was associated with T1DM group (p < 0.001). The median daily insulin dose was 40 IU for T1DM (0.58 IU/kg) and 33.5 IU for LADA (0.57 IU/kg), with no statistical difference. LADA patients were more often under non-insulin antidiabetic drugs (p = 0.001). At 10 years follow up, 21.1% of T1DM patients and 63.3% of LADA patients had microvascular complications (p = 0.004). Diabetic nephropathy was present in 23.5% of T1DM patients and 53.3% of LADA patients (p = 0.047). At the last evaluation, 55.6% of T1DM and 82.6% of LADA patients had metabolic syndrome and this difference was independent of diabetes duration.ConclusionPatients with classic T1DM presented more often with symptoms, lower BMI and higher number of autoantibodies, which may be related to a more aggressive autoimmune process. Patients with LADA developed more frequently microvascular complications for the same disease duration, namely diabetic nephropathy, and had more often metabolic syndrome.

Background. Vitamin D deficiency is a global issue negatively affecting the course of autoimmune diabetes, including classical type 1 diabetes mellitus (T1DM) and latent autoimmune diabetes in adults (LADA). Vitamin D plays a vital role in immune response regulation, maintaining β-cell function of the pancreas, and metabolic balance. The purpose of the study was to evaluate the efficacy of adding cholecalciferol at a dose of 20,000 IU (once weekly for 3 months) to standard therapy to improve the metabolic status of patients with T1DM and LADA. Materials and methods. A total of 72 patients participated in the study: 36 with T1DM and 36 with LADA. They were divided into subgroups depending on the treatment received: basic therapy or basic therapy with vitamin D supplementation. A comprehensive evaluation of carbohydrate metabolism indicators (fasting glycemia, HbA1c, HOMA-IR, insulin, and C-peptide levels), autoimmune activity (antibodies to glutamic acid decarboxylase (antiGAD)), and lipid profile was conducted before and after treatment. Results. The addition of vitamin D to therapy significantly increased serum 25(OH)D levels, ensuring a substantial improvement in metabolic status of patients. In groups receiving supplemental cholecalciferol, there was a notable reduction in fasting glucose levels, HbА1с, HOMA-IR, and antiGAD titers, indicating a positive impact on glycemic control and a decrease in autoimmune activity. Additionally, patients receiving vitamin D exhibited improvements in lipid metabolism, including decreased levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and increased levels of high-density lipoprotein cholesterol. Particularly significant was an increase in C-peptide levels observed in patients with LADA, reflecting enhanced β-cell function in the pancreas. This effect may be related to the reduction in autoimmune activity as well as the anti-inflammatory properties of vitamin D, which contribute to the maintenance of β-cells and their ability to secrete insulin. The study confirms the pleiotropic effects of vitamin D: reducing autoimmune inflammation, impro­ving insulin sensitivity, normalizing lipid profiles, and supporting β-cell function. Conclusions. The findings highlight the importance of monitoring and correcting vitamin D levels in patients with T1DM and LADA, particularly in the presence of deficiency. The above data could be used to optimize therapeutic approaches and reduce the risk of complications in this patient population.

To compare the clinical parameters, C-peptide levels, pattern of islet cell-specific autoantibodies, and prevalence of predisposing genotypes in subjects with latent autoimmune diabetes in adults (LADA) and those with adult-onset type 1 diabetes with rapid progression. We evaluated the clinical parameters, C-peptide levels, and islet cell-specific autoantibodies in 54 LADA, 57 adult-onset type 1 diabetic, and 190 type 2 diabetic patients. Islet cell autoantibodies were also compared between subgroups of newly diagnosed patients with LADA and those with newly diagnosed adult-onset and childhood-onset type 1 diabetes. The genetic study was performed in subjects with LADA and those with adult-onset type 1 diabetes in comparison with a control population. There were no differences in the clinical parameters between LADA and adult-onset type 1 diabetes. Patients with LADA had lower BMI (P < 0.0001), waist-to-hip ratio (0.0029), total cholesterol (P = 0.001), and triglycerides (P = 0.001); higher HDL cholesterol levels (P < 0.0001); and lower prevalence of hypertension (P = 0.0028) compared with patients with type 2 diabetes. C-peptide levels were similar at onset (P = 0.403) but decreased less rapidly in LADA than in adult-onset type 1 diabetes (P = 0.0253). Single-autoantibody positivity was more often seen in LADA than in type 1 diabetes (P = 0.0001). The prevalence of predisposing HLA-DQB1*0302, -DR4, -DR3, and -DR3/DR4 genotypes and the DR4-DQB1*0302 haplotype were increased in both LADA and adult-onset type 1 diabetic subjects compared with the control population. There were no differences in the frequencies of these risk alleles and haplotypes between the two patient groups. Subjects with LADA had clinical characteristics similar to those with adult-onset type 1 diabetes with rapid progression. C-peptide levels did not differ at onset but decreased less rapidly in LADA. Patients with LADA rather had single islet cell-specific autoantibody positivity. The prevalence of HLA-DQB1*0302, -DR4, -DR3, and -DR3/DR4 risk alleles and the DR4-DQB1*0302 high-risk haplotype did not differ in the two forms of autoimmune diabetes.

Introduction: Latent autoimmune diabetes of adults (LADA) is an adult-onset, slowly progressing subtype of autoimmune type 1 diabetes mellitus (T1DM), that is often misdiagnosed as T2DM. We present an atypical case of LADA that was presented in an uncommonly late age with high titres of anti-glutamic acid decarboxylase antibodies(GADA). Clinical Case: A 78 year old male presented with alcohol intoxication and hyperglycemia. His serum glucose was 441mg/dL with negative urine ketones. Arterial blood gas showed pH 7.36, HCO3- 20mmol/L, pCO2 37.1mmHg. Anion gap was 11. HbA1c level was 16%. His body weight was 43.2kg with a BMI of 16.6. He was having polyuria and polydipsia, and was recently diagnosed with T2DM. His low BMI and symptoms raised suspicion for LADA. GADA titres revealed to be greater than 250IU/mL. A diagnosis of LADA was made. He was discharged on insulin. Conclusion: LADA shares the same genetic and autoimmune profiles with T1DM, but its insidious presentation overlaps with that of T2DM, often delaying diagnosis and adequate treatment. Our case of confirmed LADA at a late age of 78 is atypical, but warrants that adults newly diagnosed with diabetes should be screened for LADA if there are atypical findings. Among the anti-islet antibodies, GADAs are the most sensitive self antigen-antibody markers of autoimmune diabetes. The GADA titre is often used to stratify the risk of progression to insulin dependence in LADA, as a higher titre suggests severe β-cell loss in the pancreas. High GADA titres at the time of diagnosis at an elderly age is also an uncommon finding for LADA. Autoimmune diseases with aggressive autoimmune responses present early, while indolent progressions lead to late onset of symptoms and diagnosis. Thus it is unusual for our patient to have significantly high GADA levels. As pathophysiology of LADA is yet to be understood, further research may reveal the autoimmune process of GADA and the role of titres in disease activity and progression. There are no current therapeutic guidelines for LADA. Our patient was eventually discharged on insulin given his high HbA1c with high titres of GADA, but there were questions regarding the use of oral glycemic control agents due to his history of noncompliance. The use of oral agents for LADA remains an area of ongoing research. The general understanding is that due to its autoimmune etiology, insulin is eventually required. Early insulin therapy preserves residual β-cell function, improves glycemic control, and reduces the risk of long-term complications. As treatment goals of LADA would be to improve glycemic control with preserving residual β-cell function, further research may establish treatment guidelines for LADA. Monitoring anti-islet antibodies and c-peptide titres may play a role in establishing the timing to introduce oral agents and/or insulin for optimal treatment of LADA.

Objective To investigate the microRNA (miRNA) expression level of peripheral blood mononuclear cell (PBMC) in autoimmune diabetes mellitus (ADM) which includes type 1 diabetes mellitus (T1DM) and latent autoimmune diabetes in adults (LADA), T2DM patients, and matched healthy individuals. Methods Patients of T1DM, LADA, and T2DM were recruited in the Second Xiangya Hospital of Central South University from January 2015 to December 2016. The subjects were divided into two groups. The first group was used for high-throughput screening of differentially expressed microRNAs. The second group was used to validate the expression of miR-142-5p and miR-143-3p by real-time quantitative polymerase chain reaction (RT-qPCR). Results (1)The different miRNA expression patterns of PBMC were found among T1DM patients, LADA patients, T2DM patients, and health individuals. (2)Compared with T2DM patients and healthy controls, LADA and T1DM patients had down-regulated PBMC miR-142-5p expression, and up-regulated miR-143-3p expression. (3)RT-qPCR validation showed that the expression of miR-142-5p in LADA patients was significantly lower than that in T2DM patients (0.30±0.24 vs 1.33±1.29, P<0.05). The expression of miR-143-3p in T1DM and LADA was higher than that in T2DM and health individuals. However, no significant differences were found. Conclusion The miRNA expression patterns are different in the PBMC of T1DM patients, LADA patients, T2DM patients, and healthy individuals; the abnormal expressions of miR-142-5p and miR-143-3p may participate in the development of ADM by affecting apoptosis and immune cell differentiation. Key words: Autoimmune diabetes; Peripheral blood mononuclear cell; microRNA

The article provides up-to-date information on latent autoimmune diabetes in adults (LADA), presents data on epidemiology, factors and mechanisms of development, clinical features of this disease. The phenotypic variants of the course of LADA are described, the issues of diagnostic features and differential diagnosis are revealed. LADA is a form of diabetes characterized by a less intense autoimmune process and a wide range of clinical signs compared to classical type 1 diabetes mellitus (T1DM) and can have features of both major types of diabetes. Based on the results of epidemiological studies, the prevalence of LADA is approximately 12 % of all cases of diabetes, it is the second most common form of diabetes after type 2 diabetes mellitus (T2DM) and is the most common type of autoimmune diabetes in adults. According to the modern classification, LADA belongs to the autoimmune subtype of T1DM. Since patients do not need insulin at the beginning of the disease, the course of LADA is similar to T2DM, which is the cause of diagnostic errors. The literature data and the results of the conducted research have shown that, in addition to autoimmune damage to pancreatic beta cells, insulin resistance plays a key role in the mechanisms of LADA development, with an increase in the frequency and degree of abdominal obesity, which not only worsens metabolic control and increases the risk of metabolic syndrome, but also causes a decrease in insulin secretion and progression of the autoimmune process. In patients with LADA, the prevalence and degree of obesity, hypertension and dyslipidemia occupy an intermediate position between the classical types of diabetes. Despite having fewer metabolic risk factors compared to T2DM, patients with LADA have the same or even higher risk of death and cardiovascular diseases. The most important diagnostic markers of LADA are levels of C-peptide and autoantibodies against islet antigens. The possibility of a clear diagnosis of LADA is limited due to the significant heterogeneity of the disease due to an overlap of T1DM and T2DM symptoms. According to modern guidelines, therapeutic approaches to LADA, which are based on insulin therapy and metformin, depend on the level of C-peptide. More research is needed to improve personalized approaches to the treatment of this disease.

The intermediate type of diabetes, known as latent autoimmune diabetes in adults (LADA), has traits in common with both type 1 and type 2 diabetic mellitus (T2DM). Initial insulin independence leads to misdiagnosis of type 2 diabetes. This study sought to ascertain the prevalence and features of LADA in patients with type 2 diabetes in Port Sudan, Sudan. A comparative cross-sectional study was conducted from April 2020 to January 2024 at the Osman Degna Hospital and Ahmed Hassan Diabetic Center, Port Sudan. A total of 250 T2DM patients were recruited: 150 insulin-requiring patients after years of diagnosis (study group) and 100 non-insulin-requiring patients (control group). Structured interviews were used to gather demographic and clinical information, and a fully automated chemiluminescence immunoassay (CLIA) was used to quantify the blood levels of C-peptide, GAD-65A (glutamic acid decarboxylase 65 autoantibody), and IA-2A (Insulinoma-Associated Protein 2 Autoantibody) autoantibodies. SPSS version 26 was used for statistical analysis, and p<0.05 was chosen as the significance level. 10.7% of patients with type 2 diabetes had LADA. Compared to the non-LADA group (1.47±0.04 ng/ml, p<0.0001), the C-peptide levels in the LADA group were significantly lower (0.50±0.18 ng/ml). Compared to non-LADA patients, GAD-65A and IA-2A autoantibody titers were higher in LADA patients (p<0.0001). Patients with LADA had lower waist circumferences (79.62±15.42 cm vs. 92.55±17.24 cm, p<0.0001) and BMIs (Body Mass Index) (21.02±4.21 kg/m2 vs. 24.02±3.48 kg/m2, p<0.0001). Furthermore, 68.75% of patients with LADA had a first-degree family history of diabetes, compared to 50% of non-LADA patients. LADA is underdiagnosed, with a prevalence of 10.7% among T2DM Sudanese patients. GAD-65A autoantibodies are the most sensitive biomarker. For prompt diagnosis and treatment, early screening is recommended.

Latent autoimmune diabetes in adults (LADA) prevails as a name in diabetes research although it was ranked as the second silliest name some years ago [1]. LADA describes a subgroup of patients who develop phenotypic type 2 diabetes but with markers of autoimmunity [2, 3]. In 2005, we tried to describe the background to LADA and establish a definition based on adult age at onset, presence of autoantibodies and lack of requirement for insulin at least 6 months after diagnosis [4]. Both the age and the insulin criteria were soon questioned [1, 5], but they also gained some support [6]. The question of how to define LADA has resulted in numerous articles and debates discussing whether LADA is a disease on its own or just a variant of type 1 diabetes [7–9]. Thus, it could be questioned whether the introduction of the term LADA has been an asset or an obstacle to our understanding of diabetes. The first question we should ask is: what good has the concept of LADA done for science and patients? In defence of LADA we may note that the categorisation has put the existence of autoimmune diabetes in adults on the scientific map. We know that by including LADA in type 1 diabetes, as recommended by the WHO [10], more adults than children are affected by autoimmune diabetes [11]. We know more about cellular and humoral responses [12–15], metabolic traits [16, 17] and genetic background [18] in adult patients with autoimmune diabetes. Thus, the LADA concept has been an efficient tool for studying and communicating different pathophysiological aspects of autoimmune diabetes in adults. Another reason for classifying diabetes is to facilitate studies on treatment and prevention where strict inclusion criteria are needed. It was concluded in a recent Cochrane Review [19] that there were few randomised controlled trials of good quality available to evaluate which treatment is optimal for LADA patients, but using sulfonylurea seemed unfavourable for beta cell function. The review also noted that the definition of LADA was imprecise, which hampered comparison between the studies. Taken together, the scientific use of LADA has up to now been better and more productive than its clinical use. So, what is the problem with the concept of LADA? The main problem is how to define LADA. This leads to futile discussion that does not take our understanding of autoimmune diabetes any further; it might even be an obstacle to our way of thinking. This could be exemplified by studies trying to subgroup LADA, which already is a subgroup. There are manuscripts proposing different kinds of LADA based on the antibody titre, with low-titre and high-titre LADA [20, 21]. We even will have patients who fulfil the age and treatment criteria with T cell reactivity to O. Rolandsson (*) Family Medicine, Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden e-mail: olov.rolandsson@fammed.umu.se

Background:To estimate the frequency and characteristics of Latent Autoimmune Diabetes in Adults (LADA) in patients diagnosed with type 2 diabetes mellitus (T2DM) at a single diabetes center in Medina, Saudi Arabia.Materials and Methods:This was a cross-sectional study involving patients with T2DM aged 30–70 years with a disease duration of ≤5 years, and who had not received insulin for at least 6 months post-T2DM diagnosis. Demographics, anthropometrics, autoantibodies to Glutamic Acid Decarboxylase Autoantibodies (GADA) and islet cell antibodies (ICA), serum C-peptide, glycated hemoglobin (HbA1C), and lipid data were collected. LADA was diagnosed according to GADA and/or ICA positivity. Participants were classified into two groups: LADA and non-LADA. The clinical and biochemical characteristics of both groups were compared.Results:A total of 157 participants (mean age 50 years, 52.9% male) were enrolled, with 30 (19.1%) testing positive for GADA and/or ICA. Among them, 16 (10.2%) were positive for GADA alone, 9 (5.7%) tested positive for ICA alone, and 5 (3.2%) tested positive for both GADA and ICA. GADA was significantly more prevalent in younger individuals (30–49 years, P = 0.02) and males, who also had higher rates of dual autoantibodies compared to females (P = 0.03). LADA patients had a significantly shorter duration of diabetes, along with lower body mass index, C-peptide, and triglyceride levels, but exhibited higher HbA1c and greater insulin use.Conclusion:The study reveals a high rate of LADA within this cohort of Saudi patients diagnosed with T2DM. LADA patients display some clinical and biochemical characteristics that set them apart from conventional T2DM cases. Screening for β-cell autoantibodies in individuals with these features could aid in earlier diagnosis of LADA and allow for more tailored treatment approaches.

To investigate the prevalence and clinical features of latent autoimmune diabetes in youth (LADY) diagnosed between 15 and 29 years old as a component of an age-related autoimmune diabetes spectrum. This nationwide, multicenter, cross-sectional study continuously included 19,100 newly diagnosed diabetes patients over 15 years old across China. LADY patients were screened from 1803 subjects aged between 15 and 29 years old, with the type 2 diabetes (T2D) phenotype and positive autoantibodies against glutamic acid decarboxylase (GADA), insulinoma-associated-2 (IA-2A) or zinc transporter-8 (ZnT8A). The clinical features of LADY, including metabolic status, β-cell function and insulin resistance, were investigated and compared with those of latent autoimmune diabetes in adults (LADA) identified from 17,297 other subjects over 30 years old. The age-related characteristics of the latent autoimmune diabetes spectrum were explored. A total of 135 subjects were diagnosed as LADY, accounting for 9.0% of the T2D phenotypic youth. Compared with autoantibody-negative T2D patients, LADY patients had fewer metabolic syndrome, less insulin resistance and poorer β-cell function, which were closely related to their autoantibody status (all p < 0.05). After stratifying LADA according to age, the GADA titer decreased across the LADY, "Y-LADA" (young LADA, onset age < 60 years old) and "E-LADA" (elderly LADA, onset age ≥ 60 years old) groups, while the prevalence of metabolic syndrome and level of β-cell function increased (all p < 0.05). A high prevalence of LADY exists in youth with T2D phenotype. Latent autoimmune diabetes forms a continuous age-related spectrum from LADY to LADA, in which LADY shows greater autoimmunity.

Autoimmune diabetes is a heterogeneous disease that includes several phenotypes, such as classical type 1 diabetes mellitus (T1DM), latent autoimmune diabetes in adults (LADA) and latent autoimmune diabetes in the youth (LADY). The presence of concomitant autoimmune diseases, in particular thyroid pathologies, is one of the key criteria for their differentiation and diagnosis. Objective — to determine the features of antithyroid immunity in patients with different phenotypes of autoimmune diabetes and its relationship with clinical and metabolic parameters. Materials and methods. 106 patients with autoimmune diabetes were examined: 40 with classical T1DM, 36 with LADA and 30 with LADY. All patients were tested for antithyroid antibodies (anti-TPO, anti‑Tg), thyroid-stimulating hormone (TSH), diabetes-associated antibodies (anti-GAD, anti-IA-2), C-peptide, HbA1c, vitamin D, and anthropometric parameters (BMI, waist-to-height ratio — WHtR). Results. The frequency of anti-TPO detection was highest in the LADY group (36.7%), intermediate in T1DM (32.5%) and lowest in LADA (27.8%). The coexistence of anti-TPO and anti-Tg antibodies was observed in 20.0%, 17.5% and 13.9% of cases, respectively. The highest frequency of subclinical hypothyroidism was found in LADA (13.9%). Several phenotype-specific correlations were identified, in particular, a strong negative correlation between vitamin D and HbA1c in LADY (r=–0.487; p &lt; 0.05). Conclusions. The status of antithyroid immunity differs significantly depending on the autoimmune diabetes phenotype. LADY is associated with the highest frequency of anti-TPO carriage, indicating a more intense general autoimmune process. In LADA, subclinical hypothyroidism is more frequent, possibly related to metabolic factors. Screening for thyroid pathology should be considered in all patients with autoimmune diabetes.

Small ubiquitin-related modifier (SUMO4), located in IDDM5, has been identified as a potential susceptibility gene for type 1 diabetes mellitus (T1DM). The novel polymorphism M55V, causing an amino acid change in the evolutionarily conserved met55 residue has been shown to activate the nuclear factor kappaB (NF-kappaB), hence the suspected role of SUMO4 in the pathogenicity of T1DM. The M55V polymorphism has been shown to be associated with susceptibility to T1DM in Asians, but not in Caucasians. Latent autoimmune diabetes in adults (LADA) is a slowly progressive form of T1DM and SUMO4 M55V has not been studied in LADA to date. The current study aims to test whether Latvians are similar to Caucasians in susceptibility to autoimmune diabetes (T1DM and LADA), with respect to SUMO4 M55V. We studied, age- and sex-matched, Latvian T1DM patients (n = 100) and healthy controls (n = 90) and LADA patients (n = 45) and healthy controls (n = 95). SUMO4 M55V polymorphism was analyzed using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). The allelic frequencies of the A and G alleles were compared with HLA DR3-DR4-positive and HLA DR3-DR4-negative patients to identify any potential relation between HLA DR3-DR4 and SUMO4 M55V. We found no significant association between SUMO4 M55V and T1DM susceptibility in Latvians, the results being in concurrence with the previous studies in Caucasians of British and Canadian origin. Comparison of the A and G alleles with HLA DR3-DR4 did not result in any significant P values. No significant association was found between SUMO4 M55V and LADA. SUMO4 M55V is not associated with susceptibility to T1DM and LADA in Latvians, and Latvians exhibit similarity to other Caucasians with respect to association of SUMO4 M55V with autoimmune diabetes.

Introduction: Latent Autoimmune Diabetes of Adults (LADA) remains a poorly understood disease at both the clinical and research level and usually misdiagnosed as Type 2 Diabetes Mellitus (T2DM) and treated with Oral Hypoglycaemic Agents (OHA). This might lead to accelerated b-cell destruction leading to early insulin-dependency in these patients. Screening of T2DM and determination of C-peptide and insulin antibodies helps to differentiate this disease from LADA. Early insulinisation of these patients prevents b-cell destruction and preserves residual b cell function. Aim: To screen type 2 diabetic patients for potential LADA subjects based on LADA clinical risk score and to confirm them as LADA based on Glutamic Acid Decarboxylase (GADA) positivity and Islet Cell Cytoplasmic Autoantibodies (ICA) positivity. Materials and Methods: The hospital based cross-sectional study was done on 945 T2DM patients attending Out Patient Department (OPD) of Rajarajeswari Medical College and Hospital, Bengaluru, Karnataka, India from March 2017 to May 2019. Patients were screened using LADA clinical risk score and potential LADA subjects were identified and tested for C-peptide, GAD and IC Antibodies to confirm LADA. C-Peptide and GAD antibodies were measured by ELISA method. IC antibodies were observed using immunoflorescence microscopy. Inferential Statistics (Chi-square test, Z test, t-test) by using SPSS V20 and MS Excel was used. Results: Out of 945 T2DM patients, 188 patients (20%) were considered as potential LADA subjects based on LADA clinical risk score. All 188 subjects were tested for C-peptide, GAD and IC antibodies. 36% (68 subjects) of them had low C-peptide levels. Among them four subjects (6%) had high GADA titer confirming them as LADA subjects. Three (4%) of the subjects had low GADA titer, remaining 61 subjects did not show antibody positivity. Only one of them had both IC antibody positivity out of four subjects with high GADA titer. Remaining 64% (120 subjects) had normal C-peptide levels and antibody negative. Conclusion: Using 5-point LADA clinical risk score 20% were identified as potential LADA subjects out of 945 T2DM subjects. 6% of the potential LADA subjects had high GADA titer confirming them as LADA, who may be benefited by early insulinisation.

To investigate the detection rate of latent autoimmune diabetes in adults (LADA) among newly diagnosed type 2 diabetes mellitus (T2DM) patients and analyze their clinical characteristics, with the aim of guiding treatment and improving prognosis. Glutamic acid decarboxylase autoantibody (GADA), islet cell autoantibody (ICA), insulin autoantibody (IAA), blood pressure, height, weight, and BMI, as well as lipid profiles, fasting plasma glucose, insulin, C-peptide, HbA1c, thyroid-stimulating hormone (TSH), thyroglobulin antibody (TGAb), and thyroid peroxidase antibody (TPOAb) levels were measured in 352 newly diagnosed T2DM patients with disease duration of less than 1 year and non-ketotic onset. The incidence of LADA was calculated, and clinical characteristics of these patients were compared with those of T2DM patients without autoantibodies. The detection rate of LADA was 7.10%. Among the 25 LADA patients, 22 had GADA, 5 had ICA, 2 had IAA, and 2 were positive for all three antibodies. The percentages of GADA, ICA, and IAA among LADA patients were 88.00%, 20.00%, and 8.00%, respectively. Compared with the autoantibody-negative group, LADA patients had lower BMIs and total cholesterol, lower insulin and C-peptide levels, higher neutrophil counts, and increased abnormal TSH levels and TPOAb positivity (P < 0.05). LADA patients exhibited reduced CD4+ T cell expression levels, which were lower than those in patients without autoantibodies, while LADA patients' CD8+ T cell levels were within the normal range and slightly higher than those in patients without autoantibodies, reflecting a lower CD4+/CD8+ ratio in LADA patients. A proportion of newly diagnosed T2DM patients have LADA. Early screening for GADA, ICA, and IAA should be performed in newly diagnosed T2DM patients with low BMI and poor islet function. LADA patients may have higher expression of inflammatory immune factors, lower total cholesterol, and a lower CD4+/CD8+ ratio. The decline in [Formula: see text]-cell function in LADA patients may be associated with decreased CD4+ T cell expression.