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For many autoimmune diseases, including type 1 diabetes mellitus (T1DM), efforts have been made to modify the disease process through pharmacotherapy. The ultimate goal must be to develop therapies with curative potential by achieving an organ without signs of parenchymal cell destruction and without signs of immune cell infiltration. In the case of the pancreas, this means regenerated and well-preserved beta cells in the islets without activated infiltrating immune cells. Recent research has opened up the prospect of successful antibody combination therapy for autoimmune diabetes with curative potential. This goal cannot be achieved with monotherapies. The requirements for the implementation of such a therapy with curative potential for the benefit of patients with T1DM and LADA (latent autoimmune diabetes in adults) are considered., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: To analyze the degree of control based on classical glucometric parameters and Glycemia Risk Index (GRI) in real-life conditions in a cohort of patients with type 1 Diabetes Mellitus (DM) and Latent Autoimmune Diabetes in Adults (LADA) and to assess the factors that are associated with GRI., Patients and Methods: Cross-sectional study. 447 adult patients with type 1 DM and LADA users of Intermittent Continuous Glucose Monitoring (iCGM) with an adherence ≥ 70% were included. GRI was calculated with its Hypoglycemia (CHypo) and Hyperglycemia (CHyper) Components. Multivariate linear regression analysis was performed to evaluate the factors associated with GRI., Results: Mean age 44.6 years (SD 13.7); 57.7% men; 83.9% type 1 DM; 16.1% LADA; time of evolution 20.6 years (SD 12.3). In patients with type 1 DM vs. LADA, differences were observed in relation to age [-11.1 years (SD 1.7)], age of onset [-21.9 years (DE 1.5)], time of evolution [11.7 years (DE 1.5)], treatment modality (p < 0.001), Time in Range (TIR) [-6.3% (SD 2.2)], Time Below Range (TBR) [1.9% (SD 0.6)], TBR level 1 (TBR1) [1.4% (SD 0.5)], Time Above Range (TAR) level 2 (TAR2) [4.7% (SD 1.3)], Coefficient of Variation (CV) [4.6% (SD 0.9)], GRI [11.3% (SD 2.8)], CHypo [1.3% (SD 0.5)] and CHyper [4.8% (SD 1.7)]. The variables that were independently associated with GRI were TIR (β = -1.34; CI 95% -1.43 to -1.25; p < 0.001), Glucose Management Indicator (GMI) (β = -5.82; CI 95% -7.59 to -4.05; p < 0.001), CV (β = 0.67; CI 95% 0.57 to 0.77; p < 0.001) and adherence to sensor usage (β = -0.16; CI 95% -1.27 to -0.06; p < 0.002)., Conclusions: LADA present better control according to some glucometric parameters and a low GRI. However, the type of DM is not a factor that is independently associated with GRI., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims/hypothesis: The aim of this study was to clarify the impact of autoimmune disease (AD) comorbidity on the risk and prognosis of latent autoimmune diabetes in adults (LADA)., Methods: We used data from a Swedish study comprising newly diagnosed cases of LADA (n=586, stratified into LADA low and LADA high by autoantibody levels), type 2 diabetes (n=2003) and matched control participants (n=2355). Information on 33 ADs and diabetic retinopathy was obtained by linkage to regional and national registers. We estimated the ORs for LADA and type 2 diabetes in relation to ADs before diabetes diagnosis, and the HRs for diabetic retinopathy after diabetes diagnosis. We performed functional pathway analyses to explore biological mechanisms driving the associations., Results: Individuals with ADs exhibit an increased susceptibility to LADA (OR 1.70; 95% CI 1.36, 2.13), particularly those with thyroid dysfunction (OR 1.88; 95% CI 1.38, 2.56), inflammatory bowel disease (OR 1.78; 95% CI 1.00, 3.16) or vitiligo (OR 3.91; 95% CI 1.93, 7.94), with stronger associations being observed for the LADA high phenotype. Only psoriasis was linked to type 2 diabetes (OR 1.47; 95% CI 1.08, 1.99). The biological pathways shared by LADA and ADs revolved around immune responses, including innate and adaptive immune pathways. The HRs for diabetic retinopathy in LADA patients with and without AD vs those with type 2 diabetes were 2.11 (95% CI 1.34, 3.32) and 1.68 (95% CI 1.15, 2.45), respectively., Conclusions/interpretation: We confirm that several common ADs confer an excess risk of LADA, especially LADA with higher GADA levels, but having such a comorbidity does not appear to affect the risk of diabetic retinopathy., (© 2024. The Author(s).)

Aims/hypothesis: Some studies find an increased risk of type 1 diabetes in children exposed to antibiotics. We investigated if exposure to antibiotics increases the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes., Methods: We used data from a Swedish case-control study (Epidemiological Study of Risk Factors for LADA and Type 2 Diabetes [ESTRID]: LADA, n=597; type 2 diabetes, n=2065; control participants matched on participation time, n=2386) and a case-control study nested within the Norwegian Trøndelag Health Study (HUNT) (n=82/1279/2050). Anatomical Therapeutic Chemical (ATC) codes indicating antibiotic dispensations were retrieved from the Swedish National Prescribed Drug Register and Norwegian Prescription Database. Multivariable adjusted ORs with 95% CIs were estimated by conditional logistic regression and pooled using fixed-effects inverse-variance weighting., Results: We observed no increased risk of LADA with exposure to antibiotics up to 1 year (OR pooled 1.15, 95% CI 0.93, 1.41) or 1-5 years (OR pooled 0.98, 95% CI 0.80, 1.20) prior to diagnosis/matching for one or more vs no dispensation of any type of antibiotic. An increased risk was observed for one or more vs no dispensations of narrow-spectrum antibiotics, but not broad-spectrum antibiotics, 6-10 years prior to LADA diagnosis (OR pooled 1.39, 95% CI 1.01, 1.91), which was driven by the Swedish data. There was little evidence of an increased risk of type 2 diabetes associated with antibiotic exposure 1-10 years prior to diagnosis., Conclusions/interpretation: We found no evidence that exposure to broad-spectrum antibiotics up to 10 years prior to diagnosis increases the risk of LADA. There was some indication of increased LADA risk with exposure to narrow-spectrum antibiotics, which warrants further investigation., (© 2024. The Author(s).)

Latent Autoimmune Diabetes in Adults (LADA) is a type of diabetes mellitus often overlooked in clinical practice for its dual resemblance to Type 1 Diabetes Mellitus (T1DM) in pathogenesis and to Type 2 Diabetes Mellitus (T2DM) in clinical presentation. To better understand LADA's distinctiveness from T1DM and T2DM, we conducted a comprehensive review encompassing etiology, pathology, clinical features, treatment modalities, and prognostic outcomes. With this comparative lens, we propose that LADA defies simple classification as either T1DM or T2DM. The specific treatments for the disease are limited and should be based on the therapies of T1DM or T2DM that address specific clinical issues at different stages of the disease. It is crucial to identify LADA cases potentially misdiagnosed as T2DM, warranting prompt screening for poor blood sugar control, short-term blood sugar deterioration, and other conditions. If the prognosis for LADA is similar to T2DM, it can be managed as T2DM. However, if the prognosis fundamentally differs, early LADA screening is crucial to optimize patient outcomes and enhance research on tailored treatments. The pathogenesis of LADA is clear, so the prognosis may be the key to determining whether it can be classified as T2DM, which is also the direction of future research. On the one hand, this paper aims to provide suggestions for the clinical screening and treatment of LADA based on the latest progress and provide worthy directions for future research on LADA., (© 2024. The Author(s).)

Aim: To compare the incidence of end-stage renal disease (ESRD) between slowly progressive type 1 diabetes and acute-onset type 1 diabetes., Methods: This cohort study enrolled all 521 patients with childhood-onset type 1 diabetes with the year of onset from 1959 to 1996 in Hokkaido Prefecture, Japan. We calculated the ESRD incidence rate per 100,000 person-years by sex, onset year, onset age, and type 1 diabetes subtype (slowly progressive or acute-onset). We also constructed a Kaplan-Meier curve for ESRD by these risk factors., Results: The data of 391 patients were gathered, among whom 66 developed ESRD. The ESRD incidence rate per 100,000 person-years was 525 among all patients; 538 and 503 among women (n = 235) and men (n = 156); 893, 413, and 225 for onset year of 1959-1979 (n = 107), 1980-1989 (n = 201), and 1990-1996 (n = 83); 420 and 715 for onset before (n = 243) and after (n = 148) puberty; and 1388 and 432 for the slowly progressive (n = 41) and acute-onset (n = 350) subtypes, respectively. The Kaplan-Meier curve also indicated a significantly higher incidence of ESRD in slowly progressive than in acute-onset type 1 diabetes., Conclusion: The incidence of ESRD was higher in slowly progressive than acute-onset type 1 diabetes., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest regarding the present work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Diabetes is associated with numerous comorbidities, one of which is increased vulnerability to infections. This review will focus on how diabetes mellitus (DM) affects the immune system and its various components, leading to the impaired proliferation of immune cells and the induction of senescence. We will explore how the pathology of diabetes-induced immune dysfunction may have similarities to the pathways of "inflammaging", a persistent low-grade inflammation common in the elderly. Inflammaging may increase the likelihood of conditions such as rheumatoid arthritis (RA) and periodontitis at a younger age. Diabetes affects bone marrow composition and cellular senescence, and in combination with advanced age also affects lymphopoiesis by increasing myeloid differentiation and reducing lymphoid differentiation. Consequently, this leads to a reduced immune system response in both the innate and adaptive phases, resulting in higher infection rates, reduced vaccine response, and increased immune cells' senescence in diabetics. We will also explore how some diabetes drugs induce immune senescence despite their benefits on glycemic control.

Introduction: We designed and implemented a patient-centered, data-driven, holistic care model with evaluation of its impacts on clinical outcomes in patients with young-onset type 2 diabetes (T2D) for which there is a lack of evidence-based practice guidelines., Research Design and Methods: In this 3-year Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial, we evaluate the effects of a multicomponent care model integrating use of information and communication technology (Joint Asia Diabetes Evaluation (JADE) platform), biogenetic markers and patient-reported outcome measures in patients with T2D diagnosed at ≤40 years of age and aged ≤50 years. The JADE-PRISM group received 1 year of specialist-led team-based management using treatment algorithms guided by biogenetic markers (genome-wide single-nucleotide polymorphism arrays, exome-sequencing of 34 monogenic diabetes genes, C-peptide, autoantibodies) to achieve multiple treatment goals (glycated hemoglobin (HbA1c) <6.2%, blood pressure <120/75 mm Hg, low-density lipoprotein-cholesterol <1.2 mmol/L, waist circumference <80 cm (women) or <85 cm (men)) in a diabetes center setting versus usual care (JADE-only). The primary outcome is incidence of all diabetes-related complications., Results: In 2020-2021, 884 patients (56.6% men, median (IQR) diabetes duration: 7 (3-12) years, current/ex-smokers: 32.5%, body mass index: 28.40±5.77 kg/m 2 , HbA1c: 7.52%±1.66%, insulin-treated: 27.7%) were assigned to JADE-only (n=443) or JADE-PRISM group (n=441). The profiles of the whole group included positive family history (74.7%), general obesity (51.4%), central obesity (79.2%), hypertension (66.7%), dyslipidemia (76.4%), albuminuria (35.4%), estimated glomerular filtration rate <60 mL/min/1.73 m 2 (4.0%), retinopathy (13.8%), atherosclerotic cardiovascular disease (5.2%), cancer (3.1%), emotional distress (26%-38%) and suboptimal adherence (54%) with 5-item EuroQol for Quality of Life index of 0.88 (0.87-0.96). Overall, 13.7% attained ≥3 metabolic targets defined in secondary outcomes. In the JADE-PRISM group, 4.5% had pathogenic/likely pathogenic variants of monogenic diabetes genes; 5% had autoantibodies and 8.4% had fasting C-peptide <0.2 nmol/L. Other significant events included low/large birth weight (33.4%), childhood obesity (50.7%), mental illness (10.3%) and previous suicide attempts (3.6%). Among the women, 17.3% had polycystic ovary syndrome, 44.8% required insulin treatment during pregnancy and 17.3% experienced adverse pregnancy outcomes., Conclusions: Young-onset diabetes is characterized by complex etiologies with comorbidities including mental illness and lifecourse events., Trial Registration Number: NCT04049149., Competing Interests: Competing interests: JCNC and RCWM hold patents for using genetic markers to predict diabetes and its complications for personalized care. JCNC, RCWM and CL are cofounders of a start-up biotech company partially supported by the Technology Start-up Support Scheme for Universities (TSSSU) of the Hong Kong Government Innovation and Technology Commission., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To compare the efficacy and safety of saxagliptin/dapagliflozin and insulin glargine in people with latent autoimmune diabetes in adults (LADA)., Methods: In this phase 2b multicentre, open-label, comparator-controlled, parallel-group, non-inferiority study, we randomly assigned 33 people with LADA who had a fasting C-peptide concentration ≥0.2 nmol/L (0.6 ng/mL) to receive 1-year daily treatment with either the combination of saxagliptin (5 mg) plus dapagliflozin (10 mg) or insulin glargine (starting dose: 10 IU), both on top of metformin. The primary outcome was the 2-h mixed meal-stimulated C-peptide area under the curve (AUC), measured 12 months after randomization. Secondary outcomes were glycated haemoglobin (HbA1c) levels, change in body mass index (BMI), and hypoglycaemic events., Results: In the modified intention-to-treat analysis, the primary outcome was similar in participants assigned to saxagliptin/dapagliflozin or to insulin glargine (median C-peptide AUC: 152.0 ng*min/mL [95% confidence interval {CI} 68.2; 357.4] vs. 122.2 ng*min/mL [95% CI 84.3; 255.8]; p for noninferiority = 0.0087). Participants randomized to saxagliptin/dapagliflozin lost more weight than those randomized to insulin glargine (median BMI change at the end of the study: -0.4 kg/m 2 [95% CI -1.6; -0.3] vs. +0.4 kg/m 2 [95% CI -0.3; +1.1]; p = 0.0076). No differences in HbA1c or in the number of participants experiencing hypoglycaemic events were found., Conclusions: Saxagliptin/dapagliflozin was non-inferior to glargine in terms of β-cell function in this 12-month, small, phase 2b study, enrolling people with LADA with still viable endogenous insulin production. Weight loss was greater with saxagliptin/dapagliflozin, with no differences in glycaemic control or hypoglycaemic risk., (© 2024 John Wiley & Sons Ltd.)

Immune-mediated cerebellar ataxias (IMCAs) have diverse etiologies. Patients with IMCAs develop cerebellar symptoms, characterized mainly by gait ataxia, showing an acute or subacute clinical course. We present a novel concept of latent autoimmune cerebellar ataxia (LACA), analogous to latent autoimmune diabetes in adults (LADA). LADA is a slowly progressive form of autoimmune diabetes where patients are often initially diagnosed with type 2 diabetes. The sole biomarker (serum anti-GAD antibody) is not always present or can fluctuate. However, the disease progresses to pancreatic beta-cell failure and insulin dependency within about 5 years. Due to the unclear autoimmune profile, clinicians often struggle to reach an early diagnosis during the period when insulin production is not severely compromised. LACA is also characterized by a slowly progressive course, lack of obvious autoimmune background, and difficulties in reaching a diagnosis in the absence of clear markers for IMCAs. The authors discuss two aspects of LACA: (1) the not manifestly evident autoimmunity and (2) the prodromal stage of IMCA's characterized by a period of partial neuronal dysfunction where non-specific symptoms may occur. In order to achieve an early intervention and prevent cell death in the cerebellum, identification of the time-window before irreversible neuronal loss is critical. LACA occurs during this time-window when possible preservation of neural plasticity exists. Efforts should be devoted to the early identification of biological, neurophysiological, neuropsychological, morphological (brain morphometry), and multimodal biomarkers allowing early diagnosis and therapeutic intervention and to avoid irreversible neuronal loss., (© 2023. The Author(s).)

Aims/hypothesis: Type 1 diabetes is a T cell-mediated autoimmune disease characterised by pancreatic beta cell destruction. In this study, we explored the pathogenic immune responses in initiation of type 1 diabetes and new immunological targets for type 1 diabetes prevention and treatment., Methods: We obtained peripheral blood samples from four individuals with newly diagnosed latent autoimmune diabetes in adults (LADA) and from four healthy control participants. Single-cell RNA-sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells to uncover transcriptomic profiles of early LADA. Validation was performed through flow cytometry in a cohort comprising 54 LADA, 17 adult-onset type 2 diabetes, and 26 healthy adults, matched using propensity score matching (PSM) based on age and sex. A similar PSM method matched 15 paediatric type 1 diabetes patients with 15 healthy children. Further flow cytometry analysis was performed in both peripheral blood and pancreatic tissues of non-obese diabetic (NOD) mice. Additionally, cell adoptive transfer and clearance assays were performed in NOD mice to explore the role of this monocyte subset in islet inflammation and onset of type 1 diabetes., Results: The scRNA-seq data showed that upregulated genes in peripheral T cells and monocytes from early-onset LADA patients were primarily enriched in the IFN signalling pathway. A new cluster of classical monocytes (cluster 4) was identified, and the proportion of this cluster was significantly increased in individuals with LADA compared with healthy control individuals (11.93% vs 5.93%, p=0.017) and that exhibited a strong IFN signature marked by SIGLEC-1 (encoding sialoadhesin). These SIGLEC-1 + monocytes expressed high levels of genes encoding C-C chemokine receptors 1 or 2, as well as genes for chemoattractants for T cells and natural killer cells. They also showed relatively low levels of genes for co-stimulatory and HLA molecules. Flow cytometry analysis verified the elevated levels of SIGLEC-1 + monocytes in the peripheral blood of participants with LADA and paediatric type 1 diabetes compared with healthy control participants and those with type 2 diabetes. Interestingly, the proportion of SIGLEC-1 + monocytes positively correlated with disease activity and negatively with disease duration in the LADA patients. In NOD mice, the proportion of SIGLEC-1 + monocytes in the peripheral blood was highest at the age of 6 weeks (16.88%), while the peak occurred at 12 weeks in pancreatic tissues (23.65%). Adoptive transfer experiments revealed a significant acceleration in diabetes onset in the SIGLEC-1 + group compared with the SIGLEC-1 - or saline control group., Conclusions/interpretation: Our study identified a novel group of SIGLEC-1 + monocytes that may serve as an important indicator for early diagnosis, activity assessment and monitoring of therapeutic efficacy in type 1 diabetes, and may also be a novel target for preventing and treating type 1 diabetes., Data Availability: RNA-seq data have been deposited in the GSA human database ( https://ngdc.cncb.ac.cn/gsa-human/ ) under accession number HRA003649., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The applicability of a UK-validated genetic risk score (GRS) was assessed in 158 participants in the Fremantle Diabetes Study Phase II diagnosed between 20 and <40 years of age with type 1 or type 2 diabetes or latent autoimmune diabetes of adults (LADA). For type 1 versus type 2/LADA, the area under the receiver operating characteristic curve (AUC) was highest for serum C-peptide (0.93) and lowest for the GRS (0.66). Adding age at diagnosis and body mass index to C-peptide increased the AUC minimally (0.96). The GRS appears of modest diabetes diagnostic value in young Australians., (© 2024 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Aims: Infections are proposed risk factors for type 1 diabetes in children. We examined whether a diagnosis of infectious disease also confers an increased risk of latent autoimmune diabetes in adults (LADA)., Materials and Methods: We used data from a population-based Swedish case-control study with incident cases of LADA (n = 597) and matched controls (n = 2386). The history of infectious disease was ascertained through national and regional patient registers. We estimated adjusted odds ratios (OR) with 95% confidence intervals for ≥1 respiratory (any/upper/lower), gastrointestinal, herpetic, other or any infectious disease episode, or separately, for 1 and ≥2 infectious disease episodes, within 0-1, 1-3, 3-5 and 5-10 years before LADA diagnosis/matching. Stratified analyses were performed on the basis of HLA risk genotypes and Glutamic acid decarboxylase antibodies (GADA) levels., Results: Individuals who developed LADA did not have a higher prevalence of infectious disease 1-10 years before diabetes diagnosis. For example, OR was estimated at 0.87 (0.66, 1.14) for any versus no respiratory infectious disease within 1-3 years. Similar results were seen for LADA with high-risk HLA genotypes (OR 0.95 [0.64, 1.42]) or high GADA levels (OR 1.10 [0.79, 1.55]), ≥2 episodes (OR 0.89 [0.56, 1.40]), and in infections treated using antibiotics (OR 1.03 [0.73, 1.45]). The only significant association was observed with lower respiratory disease the year preceding LADA diagnosis (OR 1.67 [1.06, 2.64])., Conclusions: Our findings do not support the idea that exposure to infections increases the risk of LADA. A higher prevalence of respiratory infection in the year before LADA diagnosis could reflect increased susceptibility to infections due to hyperglycemia., (© 2023 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Purpose: Developmental abnormalities in B cells is one of the key players in autoimmune diabetes, but little is known about its role in latent autoimmune diabetes in adults (LADA). This study aimed to investigate the distribution of B cell subsets in different types of diabetes and to analyze their correlations with other biochemical parameters., Methods: A total of 140 participants were prospectively enrolled from January 2021 to December 2022. Diabetes-related autoantibodies and laboratory indicators were tested. Flow cytometry was used to analyze the percentage of circulating B cell subsets and T follicular cells. The correlation of B cell subsets with different indicators was assessed by Spearman's correlation method., Results: We observed that the Naïve phenotype cells tended to be less frequent in patients with diabetes than in healthy controls. The frequency of plasmablasts (PB) and Breg cell-related phenotype (B10) were significantly higher in LADA. Notably, the percentage of PB was positively associated with levels of islet cell antibody (ICA) and insulin autoantibody (IAA), but inversely associated with fasting C-peptide (FCP), further indicating that PB may promote the destruction of β-cell in patients with diabetes., Conclusions: This study showed that patients with LADA had significantly altered frequencies of B cell subsets, particularly in the naïve to memory B cell ratio. Our study provided valuable information on the distribution characteristics of B cell subsets in LADA and suggested the feasibility of B-cell targeted therapy in LADA patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The diagnostic criteria for slowly progressive type 1 diabetes (slowly progressive insulin-dependent diabetes mellitus; SPIDDM) have been revised by the Committee on Type 1 Diabetes of the Japan Diabetes Society. All of the following three criteria must be met for 'a definitive diagnosis of SPIDDM': (1) presence of anti-islet autoantibodies at some point in time during the disease course; (2) absence of ketosis or ketoacidosis at the diagnosis of diabetes with no requirement for insulin treatment to correct hyperglycemia immediately after diagnosis in principle; and (3) gradual decrease of insulin secretion over time, with insulin treatment required at more than 3 months after diagnosis, and the presence of severe endogenous insulin deficiency (fasting serum C-peptide immunoreactivity <0.6 ng/mL) at the last observed point in time. When a patient fulfills only (1) and (2), but not (3), he/she is diagnosed with 'SPIDDM (probable)' because the diabetes is non-insulin-dependent type., (© 2024 The Japan Diabetes Society (JDS). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/introduction: Different types of diabetes show distinct genetic characteristics, but the specific genetic susceptibility factors remain unclear. Our study aimed to explore the associations between the ribosomal protein S26 (RPS26) gene rs1131017 polymorphisms and susceptibility to type 1 diabetes mellitus, latent autoimmune diabetes in adults (LADA) and type 2 diabetes mellitus in the Chinese Han population, and their correlations with clinical features., Materials and Methods: Genotyping of the rs1131017 variant was carried out for 1,006 type 1 diabetes mellitus patients, 210 LADA patients, 642 type 2 diabetes mellitus patients and 2,099 control individuals., Results: We found that the rs1131017 C allele was a risk locus for both type 1 diabetes mellitus and LADA (odds ratio [OR] 1.50, 95% confidence interval [CI] 1.33-1.69, P < 0.001; OR 1.31, 95% CI 1.04-1.64, P = 0.021, respectively). Nevertheless, this association was not found for type 2 diabetes mellitus. Carrying the C allele genotype was associated with a lower postprandial C-peptide for type 1 diabetes mellitus (OR 1.41, 95% CI 1.11-1.80, P = 0.006) and lower fasting C-peptide for LADA (OR 1.55, 95% CI 1.01-2.38, P = 0.047). Interestingly, a lower GC frequency was noted for LADA than for type 1 diabetes mellitus, regardless of classification based on age at diagnosis, C-peptide or glutamic acid decarboxylase antibody positivity., Conclusions: The RPS26 polymorphism was associated with susceptibility and clinical characteristics of type 1 diabetes mellitus and LADA in the Chinese population, but was not related to type 2 diabetes mellitus. Thus, it might serve as a novel biomarker for particular types of diabetes., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Source Citation: Wei Y, Herzog K, Ahlqvist E, et al. All-cause mortality and cardiovascular and microvascular diseases in latent autoimmune diabetes in adults. Diabetes Care. 2023;46:1857-1865. 37635682., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=J23-0107.

Background: The prevalence of diabetes mellitus (DM) is dramatically increasing around the world, and patients are getting younger with changes in living standards and lifestyle. This study summarized and analyzed the clinical characteristics of different types of newly diagnosed diabetes mellitus patients with an onset age between 18 and 40 years to provide clinical evidence for the early diagnosis and treatment of diabetes, reduce short-term and long-term complications and offer scientific and personalized management strategies., Methods: A total of 655 patients newly diagnosed with early-onset diabetes mellitus in the Department of Endocrinology, the First Medical Center of PLA General Hospital from January 2012 to December 2022 were retrospectively enrolled in this study, with an onset age of 18-40 years. Their clinical data were collected and investigated. All patients were divided into two groups according to whether they presented with diabetic microangiopathy. Similarly, patients with early-onset type-2 diabetes were grouped in accordance with whether they had ketosis at the time of diagnosis. Binary logistic regression analysis was performed to analyze risk factors, and receiver-operating characteristic (ROC) analysis was used to explore the predictive value of significant risk factors., Results: The findings were as follows: (1) Of 655 enrolled patients, 477 (72.8%) were male and 178 (27.1%) were female, with a mean age of onset of was 29.73 years ± 0.24 SD. (2) The prevalence of early-onset diabetes was gradually increasing. Type-2 diabetes was the most common type of early-onset diabetes (491, 75.0%). The ages of onset of early-onset type-1 diabetes, type-2 diabetes and LADA were mainly 18-24 years, 25-40 years and 33-40 years, respectively. (3) Initial clinical manifestations of early-onset diabetes were classic diabetes symptoms (361, 55.1%), followed by elevated blood glucose detected through medical examination (207, 31.6%). (4) Binary logistic regression analysis suggested that high serum uric acid (UA), a high urinary albumin-to-creatinine ratio (UACR) and diabetic peripheral neuropathy (DPN) were risk factors for microangiopathy in early-onset diabetes patients (P < 0.05). The area under the curve (AUC) on ROC analysis of the combination of UA, UACR and DPN was 0.848, 95% CI was 0.818 ~ 0.875, sensitivity was 73.8% and specificity was 85.9%, which had higher predictive value than those of UA, UACR and DPN separately. (5) Weight loss, high glycosylated hemoglobin (HbA1c) and young onset age were risk factors for ketosis in patients with early-onset type-2 diabetes (P < 0.05)., Conclusion: (1) Men were more likely to have early-onset diabetes than women. (2) Early-onset diabetes patients with high serum uric acid levels, high UACRs and peripheral neuropathy were prone to microangiopathy. Comprehensive evaluation of these risk factors could have higher predictive value in the prediction, diagnosis and treatment of microvascular lesions. (3) Patients with weight loss at onset, high HbA1c and young onset age were more likely to develop ketosis. Attention should be given to the metabolic disorders of these patients., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: Latent autoimmune diabetes in adults (LADA) is a heterogenous, slowly progressing autoimmune diabetes. We aim to contribute new knowledge on the long-term prognosis of LADA with varying degrees of autoimmunity by comparing it to type 2 diabetes and adult-onset type 1 diabetes., Research Design and Methods: This Swedish population-based study included newly diagnosed LADA (n = 550, stratified into LADAlow and LADAhigh by median autoimmunity level), type 2 diabetes (n = 2,001), adult-onset type 1 diabetes (n = 1,573), and control subjects without diabetes (n = 2,355) in 2007-2019. Register linkages provided information on all-cause mortality, cardiovascular diseases (CVDs), diabetic retinopathy, nephropathy, and clinical characteristics during follow-up., Results: Mortality was higher in LADA (hazard ratio [HR] 1.44; 95% CI 1.03, 2.02), type 1 (2.31 [1.75, 3.05]), and type 2 diabetes (1.31 [1.03, 1.67]) than in control subjects. CVD incidence was elevated in LADAhigh (HR 1.67; 95% CI 1.04, 2.69) and type 2 diabetes (1.53 [1.17, 2.00]), but not in LADAlow or type 1 diabetes. Incidence of retinopathy but not nephropathy was higher in LADA (HR 2.25; 95% CI 1.64, 3.09), including LADAhigh and LADAlow than in type 2 diabetes (unavailable in type 1 diabetes). More favorable blood pressure and lipid profiles, but higher HbA1c levels, were seen in LADA than type 2 diabetes at baseline and throughout follow-up, especially in LADAhigh, which resembled type 1 diabetes in this respect., Conclusions: Despite having fewer metabolic risk factors than type 2 diabetes, LADA has equal to higher risks of death, CVD, and retinopathy. Poorer glycemic control, particularly in LADAhigh, highlights the need for improved LADA management., (© 2023 by the American Diabetes Association.)

Introduction: Latent autoimmune diabetes in adults (LADA) is a highly heterogeneous autoimmune condition with clinical and genetic characteristics that fall between those of type 1 diabetes mellitus and type 2 diabetes mellitus; therefore, there are no uniform criteria for the selection of therapeutic agents. We conducted a network meta-analysis to evaluate the efficacy of various therapeutic agents for LADA by comparing their effects on various indicators used to reflect LADA., Methods: We searched the PubMed, Cochrane Library, Embase and Web of Science databases from their inception to March 2023 and collected data from 14 randomized controlled trials on glucose-lowering drugs for LADA, including 23 studies and 15 treatment regimens. The effectiveness of drugs was ranked and evaluated by combining surface under the cumulative ranking (SUCRA) plots and forest plots. Factors that may influence study heterogeneity were also searched and analyzed by combining subgroup analysis, publication bias, funnel plots and sensitivity analysis., Results: The results of the network meta-analysis showed that insulin had the most significant effect on the control of change from baseline in glycosylated hemoglobin, type A1 (ΔHbA1c). Insulin combined with dipeptidyl peptidase-4 (DPP-4) inhibitors performed the best in reducing fasting blood glucose and body mass index. Treatment regimens involving thiazolidinediones were the most advantageous in HbA1c, fasting C-peptide and postprandial C-peptide control. Longer dosing may be more beneficial in maintaining islet β-cell function in the LADA population., Conclusion: LADA is an immune condition with high heterogeneity, and treatment should be administered according to the C-peptide level of the LADA population. For this population with LADA with a certain level of β-cell function, combinations of insulin with DPP-4 inhibitors or thiazolidinediones probably can be more effective treatment options to maintain islet function and normal blood glucose., Trial Registration: PROSPERO CRD42023410795., (© 2023. The Author(s).)

Background: Insulin resistance (IR) is one of the risk factors for chronic kidney disease (CKD) and diabetes. The triglyceride-glucose (TyG) index is considered a reliable alternative marker of IR. We investigated the correlation between the TyG index and the severity of CKD in patients with latent autoimmune diabetes in adults (LADA)., Methods: This cross-sectional study included 288 patients with LADA in the department of endocrinology at our hospital between January 2018 and January 2022. The TyG index was calculated as Ln [TG (mg/dl) × fasting blood glucose (FBG) (mg/dl) / 2]. All individuals were divided into either a LADA + CKD group or a LADA + non-CKD group according to the presence or absence of CKD. A correlation analysis, logistic regression analysis and receiver operating characteristics curve analysis were performed., Results: A total of 130 (45.1%) participants were identified as having CKD. Compared with the non-CKD group, the CKD group had a longer disease duration and a higher proportion of smokers; patients were more likely to have hypertension and higher serum creatinine, triglyceride, cholesterol, low-density lipoprotein cholesterol, FBG, uric acid estimated glomerular filtration rates (eGFR) and TyG levels as well as lower high-density lipoprotein cholesterol levels (all P < 0.05). The positive relationship between the TyG index and the urinary albumin/creatinine ratio was significant (r = 0.249, P = 0.010). There was also a significant correlation between the TyG index and the eGFR (r = - 0.211, P = 0.034) after adjusting for confounding factors. The area-under-the-curve value of the TyG index was 0.708 (95% confidence interval: 0.61-0.81, P < 0.001)., Conclusions: The TyG index is significantly associated with the severity of CKD in patients with LADA. This conclusion supports the clinical application of the TyG index for the assessment of kidney disease in patients with LADA., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Aims: The objective of this study is to explore the relationship between red blood cell distribution and islet β-cell function indexes in patients with Latent Autoimmune Diabetes in Adults., Methods: A total of 487 LADA patients were enrolled in this cross-sectional study. Patients were divided into three groups according to RDW tertiles. Clinical and laboratory measurements of age, height, weight, duration of diabetes, blood pressure, RDW, glycosylated hemoglobin A1c (HbA1c), C-peptide and blood lipids were performed. Homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of β-cell function (HOMA-β) were assessed using homeostasis model assessment (HOMA) based on fasting blood glucose (FBG) and fasting C-peptide index (FCP). Correlations and multiple linear regressions were implemented to determine the association of RDW and islet function indexes., Results: As the increase of serum RDW level, the presence of β-cell secretion increased(P < 0.05). Correlation analysis indicated that there were significant correlations between RDW and male sex, age, duration, TG, Cr, FCP, and HOMA-β in all subjects. Multiple linear regressions indicated that RDW was significantly correlated with HOMA-β in the total population in both unadjusted and adjusted analysis. This finding could be reproduced in the subgroup of low GAD titers for HOMA-β. RDW were significantly associated with HbA1c in LADA patients with high GAD titers, but the correlation was not found in subgroup with low GAD titers in either unadjusted analyses or adjusted analysis., Conclusions: RDW is associated with β-cell function assessed by HOMA-β after adjusting for covariates in LADA patients with low GAD titers., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Purpose: To estimate if newly diagnosed patients with different subphenotypes of type 2 diabetes (T2DM) or latent autoimmune diabetes of adults (LADA) differ with respect to subclinical retinal microvascular structure or diabetic retinopathy (DR)., Methods: This population-based, cross-sectional study of 340 patients (675 eyes) classified patients with recently diagnosed T2DM in different subphenotypes according to beta cell function and insulin sensitivity in to; classical (n = 218), hyperinsulinaemic (n = 86), insulinopenic (n = 20), or LADA (n = 16). Retinal 6-field images were graded according to the International Clinical DR Severity Scale by a retinal expert. Retinal microvascular structures were analysed in eyes by a semiautomatic software., Results: Median age and duration of diabetes were 58.1 (49.9; 65.5) and 0.9 (0.5; 2.4) years, respectively, and 56.8% were male. In a multivariate linear mixed model regression analysis of eyes without DR (n = 570), there was no statistically significant difference in retinal venular or arteriolar width between subtypes and patients with classical T2DM. In addition, eyes from different subphenotypes did not differ according to vessel density, tortuosity or fractal dimension. In a multivariate logistic regression model adjusted for age, sex, HbA1c, diabetes duration, body mass index, mean arterial blood pressure and history of cardiovascular disease, there was a tendency towards persons with hyperinsulinaemic T2DM to be more likely to have DR (OR 1.97, 95% CI 0.95; 4.09) compared to classical T2DM., Conclusion: We found no difference in retinal microvascular structure in patients with newly diagnosed subtypes of T2DM. However, DR may be more prevalent in newly diagnosed patients with hyperinsulinaemic T2DM compared to individuals with classical T2DM., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Aims/introduction: This study aimed to compare the positivity rates of glutamic acid decarboxylase autoantibodies (GADA) and ElisaRSR™ 3 Screen ICA™ (3 Screen ICA), a newly developed assay for the simultaneous measurement of GADA, insulinoma-associated antigen-2 autoantibodies (IA-2A), and zinc transporter 8 autoantibodies (ZnT8A), in recently obtained sera from patients who had been previously diagnosed with slowly progressive type 1 diabetes (SPIDDM)., Materials and Methods: We enrolled 53 patients with SPIDDM who were positive for GADA at the diagnosis and 98 non-diabetic individuals, and investigated the diagnostic accuracy of the 3 Screen ICA (cutoff index ≥30 units) compared with that of GADA. In addition, we compared the clinical characteristics of patients with SPIDDM who were negative or positive on 3 Screen ICA., Results: The positivity rates of 3 Screen ICA, GADA, IA-2A, and ZnT8A were 88.7, 86.8, 24.5, and 13.2%, respectively. The respective sensitivity, specificity, and positive and negative predictive values for SPIDDM were 88.7, 100, 100, and 94.2% by 3 Screen ICA and 86.8, 100, 100.0, and 93.3% by GADA. There were no significant differences in age at onset, duration of diabetes, body mass index, glycated hemoglobin and C-peptide levels, and the prevalence of autoimmune thyroiditis between patients with SPIDDM who were positive or negative on 3 Screen ICA. However, the prevalence of insulin users was significantly higher in those who were positive than in those who were negative on 3 Screen ICA., Conclusions: Similar to GADA, 3 Screen ICA may be a useful diagnostic tool for detecting patients with SPIDDM., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Context: We aimed to investigate whether human leukocyte antigen (HLA) Class I loci differentially modulated the risk for and clinical features of Chinese people with classic type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA)., Methods: In this case-control study, genotypes of HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 loci were obtained from 1067 cases with classic T1D, 1062 cases with LADA, and 1107 normal controls using next-generation sequencing., Results: Despite 4 alleles shared between classic T1D and LADA (protective: A*02:07 and B*46:01; susceptible: B*54:01 and C*08:01), 7 Class I alleles conferred risk exclusively for classic T1D (A*24:02, B*15:02, B*15:18, B*39:01, B*40:06, B*48:01, and C*07:02) whereas only A*02:01 was an additional risk factor for LADA. Class I alleles affected a wide spectrum of T1D clinical features, including positive rate of protein tyrosine phosphatase autoantibody and zinc transporter 8 autoantibody (A*24:02), C-peptide levels (A*24:02), and age at diagnosis (B*46:01, C*01:02, B*15:02, C*07:02, and C*08:01). By contrast, except for the detrimental effect of C*08:01 on C-peptide concentrations in LADA, no other Class I associations with clinical characteristics of LADA could be reported. The addition of Class I alleles refined the risk model consisting only of DR-DQ data in classic T1D while the overall predictive value of the LADA risk model comprising both Class I and II information was relatively low., Conclusion: The attenuated HLA Class I susceptibility to LADA was indicative of a less deleterious immunogenetic nature compared with classic T1D. These autoimmune diabetes-related Class I variants might serve as additional markers in future screening among Chinese people., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Latent autoimmune diabetes in adults (LADA) has clinical and metabolic features of type 1 and type 2 diabetes. LADA does not have specific features for its diagnosis apart from autoantibody detection; however, these tests are not affordable in clinical settings. In this cross-sectional study, we analyzed clinical criteria, metabolic control, pharmacological treatment, and diabetic complications in two groups of patients with diabetes -LADA and T2D- in order to identify specific characteristic of these clinical entities. Finally, we evaluated if the estimated glucose disposal rate (eGDR) and age at diagnosis of diabetes could be used as a diagnostic criterion for LADA. Demographic, biochemical, clinical and treatment were measured in 377 individuals with diabetes. The diagnostics of LADA were determined using Glutamic acid decarboxylase autoantibodies levels. Chi-square test or t-Student test were used to establish differences between groups. To identify factors associated with LADA, a logistic regression analysis was used. Finally, a ROC curve was plotted to assess the possible variables as diagnostic criteria for LADA. The 377 patients with diabetes were separated into 59 patients with LADA and 318 patients with T2D. Patients with LADA showed lower fasting glucose values, fewer diabetic complications, younger age at diagnosis of diabetes, higher insulin use, and higher eGDR in comparison to patients with T2D. Both groups had a mean BMI classified as overweight. The ROC evaluated the sensitivity and specificity, this analysis indicated that an age younger than 40.5 years and an eGDR value higher than 9.75 mg/kg/min correlated better with LADA. These parameters could be useful to identify patients suspected to have LADA at the first level of medical care in the population of southeastern Mexico and refer them to a second level of care., (© 2023. The Author(s).)

Gestational diabetes mellitus (GDM) is a state of pre-diabetic impaired glucose tolerance initially occurring during pregnancy. Although abnormalities in glucose metabolism normally resolve rapidly after delivery, women with GDM have a higher lifetime risk of developing diabetes mellitus than those without GDM; thus, postpartum healthcare is essential. Of all GDM patients, 5%-10% test positive for diabetes-related autoantibodies, which increase the risk of developing type 1 diabetes mellitus (T1DM). Autoantibody measurement in GDM screening remains debatable; however, it may be useful for the postnatal follow-up of GDM patients at high risk of developing T1DM. We treated a 29-year-old woman who was GDM positive for anti-glutamic acid decarboxylase antibody (GADA) requiring high-dose insulin therapy during pregnancy. As the patient tested positive for GADA, she received judicious postpartum management, allowing for early diagnosis of T1DM and resumption of treatment. Her insulin secretory capacity was preserved at 1 year after parturition, suggesting either slowly progressive insulin-dependent T1DM or latent autoimmune diabetes in adults. This was a rare case of slowly progressive insulin-dependent T1DM or latent autoimmune diabetes in adults in the early postpartum period, but the fact that GADA was positive during pregnancy enabled early treatment without overlooking it. Measuring diabetes-related autoantibodies in patients considered to be at a high risk for T1DM, such as those who are of slim build, young, or suffering from autoimmune thyroid disorders, may be important for appropriate individualized follow-up.

Background: Five novel subtypes of adult-onset diabetes were identified in 2018. We aimed to investigate whether childhood adiposity increases the risks of these subtypes using a Mendelian randomisation design, and to explore genetic overlaps between body size (self-reported perceived body size [ie, thinner, about average, or plumper] in childhood, and BMI measured in adulthood) and these subtypes., Methods: The Mendelian randomisation and genetic correlation analyses were based on summary statistics from European genome-wide association studies of childhood body size (n=453 169), adult BMI (n=359 983), latent autoimmune diabetes in adults (n=8581), severe insulin-deficient diabetes (n=3937), severe insulin-resistant diabetes (n=3874), mild obesity-related diabetes (n=4118), and mild age-related diabetes (n=5605). We identified 267 independent genetic variants as instrumental variables for childhood body size in the Mendelian randomisation analysis of latent autoimmune diabetes in adults and 258 independent genetic variants as instrumental variables for other diabetes subtypes. The inverse variance-weighted method was used as the primary estimator in the Mendelian randomisation analysis, supplemented by other Mendelian randomisation estimators. We calculated overall genetic correlations (rg) between childhood or adult adiposity and different subtypes using linkage disequilibrium score regression., Findings: A large childhood body size was associated with increased risk of latent autoimmune diabetes in adults (odds ratio [OR] 1·62, 95% CI 1·95-2·52), severe insulin-deficient diabetes (OR 2·45, 1·35-4·46), severe insulin-resistant diabetes (OR 3·08, 1·73-5·50), and mild obesity-related diabetes (OR 7·70, 4·32-13·7), but not mild age-related diabetes in the main Mendelian randomisation analysis. Other Mendelian randomisation estimators gave similar results and did not support the existence of horizontal pleiotropy. There was genetic overlap between childhood body size and mild obesity-related diabetes (rg 0·282; p=0·0003), and between adult BMI and all diabetes subtypes., Interpretation: This study provides genetic evidence that higher childhood adiposity is a risk factor for all subtypes of adult-onset diabetes, except mild age-related diabetes. It is therefore important to prevent and intervene in childhood overweight or obesity. There is shared genetic contribution to childhood obesity and mild obesity-related diabetes., Funding: The study was supported by the China Scholarship Council, the Swedish Research Council (grant number 2018-03035), Research Council for Health, Working Life and Welfare (grant number 2018-00337), and Novo Nordisk Foundation (grant number NNF19OC0057274)., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Aim: To characterize the exosomal miRNA profiles of latent autoimmune diabetes in adults (LADA) and evaluate the biomarker potential of selected miRNAs to distinguish LADA from type 2 diabetes (T2D)., Methods: Plasma-derived exosomal miRNA expression profiles were measured in patients with LADA (N = 5) and control subjects (N = 5). Five differentially expressed miRNAs were selected to validate their expression levels and assess their diagnostic potential by quantitative real-time PCR (qRT-PCR) in a larger cohort., Results: Seventy-five differentially expressed plasma-derived exosomal miRNAs were identified in LADA patients compared to healthy subjects. The expression levels of three exosomal miRNAs (hsa-miR-146a-5p, hsa-miR-223-3p and hsa-miR-21-5p) were significantly different between the LADA group and the T2D group. The three miRNAs exhibited areas under the receiver operating characteristic curves of 0.978, 0.96 and 0.809, respectively., Conclusions: This study uncovers the miRNA profiles of plasma-derived exosomes from LADA patients and identifies exosomal miRNAs as potential biomarkers to discriminate LADA from T2D for the first time. Our data demonstrate the function of exosomal miRNAs in the development of LADA and contribute to an in-depth understanding of the precise mechanisms underlying the pathogenesis of LADA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In clinical practice, the distinction between type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) can be challenging, leaving patients with "ambiguous" diabetes type. Insulin-treated patients (n=115) previously diagnosed with T2DM had to be re-classified based on clinical phenotype and laboratory results, and were operationally defined as having an ambiguous diabetes type. They were compared against patients with definite T1DM and T2DM regarding 12 clinical and laboratory features typically different between diabetes types. Characteristics of patients with ambiguous diabetes type, representing approximately 6% of all patients with T1DM or T2DM seen at our specialized clinic, fell in between those of patients with definite T1DM and T2DM, both regarding individual features and with respect to a novel classification based on multi-variable regression analysis (P<0.0001). In conclusion, a substantial proportion of diabetes patients in a tertiary care centre presented with an "ambiguous" diabetes type. Their clinical characteristics fall in between those of definite T1DM or T2DM patients.

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 (RR pooled 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 )., (© 2022. The Author(s).)

Aims: This study aimed to explore the clinical features and spontaneous brain activity among patients with latent autoimmune diabetes in adults (LADA) and to investigate the relationship among these characteristics., Methods: We conducted a cross-sectional study using cognitive assessments and resting-state functional magnetic resonance imaging (rs-fMRI) to evaluate the cognitive function and brain activities of healthy controls (HCs) and patients with LADA. Functional connectivity (FC) analysis was performed on the brain regions that showed significantly different activation in regional homogeneity (ReHo) analysis between the two groups. Furthermore, a linear regression model was conducted for the association between metabolism and cognition., Results: This study enrolled patients with LADA (and age-, sex-, and education-matched HCs). Patients with LADA had worse cognitive status at the general level and poorer memory than controls. Rs-fMRI analysis among patients with LADA showed decreased ReHo values in the right occipital lobe and temporal lobe and decreased seed-based FC in the right parietal lobe compared to those of controls. The seed-based FC values in the right parietal lobe were positively associated with word fluency and processing speed in patients with LADA. Furthermore, low-density lipoprotein cholesterol was negatively correlated with Montreal Cognitive Assessment scores in patients with LADA., Conclusions: Patients with LADA had worse cognitive function and decreased spontaneous brain activity in the temporal lobe and occipital lobe compared to controls. Moreover, glycolipid metabolism was closely related to brain structure and function in patients with LADA., (© 2022 John Wiley & Sons Ltd.)

Aims: To investigate glycaemic variability (GV) patterns in patients with type 1 diabetes (T1D), type 2 diabetes (T2D), and latent autoimmune diabetes in adults (LADA)., Materials and Methods: A total of 842 subjects (510 T1D, 105 LADA, 227 T2D) were enrolled and underwent 1 week of continuous glucose monitoring (CGM). Clinical characteristics and CGM parameters were compared among T1D, LADA, and T2D. LADA patients were divided into two subgroups based on glutamic acid decarboxylase autoantibody titres (≥180 U/mL [LADA-1], <180 U/mL [LADA-2]) and compared. The C-peptide cut-offs for predicting a coefficient of variation (CV) of glucose ≥36% and a time in range (TIR) > 70% were determined using receiver operating characteristic analysis., Results: Twenty-seven patients (9 T1D, 18 T2D) were excluded due to insufficient CGM data. Sex, diabetes duration and HbA1c were comparable among the three groups. Fasting and 2-h postprandial C-peptide (FCP, 2hCP) increased sequentially across T1D, LADA, and T2D. T1D and LADA patients had comparable TIR and GV, whereas those with T2D had much higher TIR and lower GV (p < 0.001). The GV of LADA-1 was close to that of T1D, while the GV of LADA-2 was close to that of T2D. CP exhibited the strongest negative correlation with GV. The cut-offs of FCP/2hCP for predicting a CV ≥ 36% and TIR >70% were 121.6/243.1 and 128.9/252.8 pmol/L, respectively., Conclusions: GV presented a continuous spectrum across T1D, LADA-1, LADA-2, and T2D. More frequent glucose monitoring is suggested for patients with impaired insulin secretion., Clinical Trail Registration: Chinese Clinical Trial Registration (ChiCTR) website approved by WHO; http://www.chictr.org.cn/ - ChiCTR2200065036., (© 2022 John Wiley & Sons Ltd.)

Background: We aimed to explore the performance of detrended fluctuation function (DFF) in distinguishing patients with latent autoimmune diabetes in adults (LADA) from type 2 diabetes mellitus (T2DM) with glucose data derived from continuous glucose monitoring., Methods: In total, 71 LADA and 152 T2DM patients were enrolled. Correlations between glucose parameters including time in range (TIR), mean glucose, standard deviation (SD), mean amplitude of glucose excursions (MAGE), coefficient of variation (CV), DFF and fasting and 2-hour postprandial C-peptide (FCP, 2hCP) were analyzed and compared. Receiver operating characteristics curve (ROC) analysis and 10-fold cross-validation were employed to explore and validate the performance of DFF in diabetes classification respectively., Results: Patients with LADA had a higher mean glucose, lower TIR, greater SD, MAGE and CV than those of T2DM ( P <0.001). DFF achieved the strongest correlation with FCP (r = -0.705, P <0.001) as compared with TIR (r = 0.485, P <0.001), mean glucose (r = -0.337, P <0.001), SD (r = -0.645, P <0.001), MAGE (r = -0.663, P <0.001) and CV (r = -0.639, P <0.001). ROC analysis showed that DFF yielded the greatest area under the curve (AUC) of 0.862 (sensitivity: 71.2%, specificity: 84.9%) in differentiating LADA from T2DM as compared with TIR, mean glucose, SD, MAGE and CV (AUC: 0.722, 0.650, 0.800, 0.820 and 0.807, sensitivity: 71.8%, 47.9%, 63.6%, 72.7% and 78.8%, specificity: 67.8%, 83.6%, 80.9%, 80.3% and 72.4%, respectively). The kappa test indicated a good consistency between DFF and the actual diagnosis (kappa = 0.551, P <0.001). Ten-fold cross-validation showed a stable performance of DFF with a mean AUC of 0.863 (sensitivity: 78.8%, specificity: 77.8%) in 10 training sets and a mean AUC of 0.866 (sensitivity: 80.9%, specificity: 84.1%) in 10 test sets., Conclusions: A more violent glucose fluctuation pattern was marked in patients with LADA than T2DM. We first proposed the possible role of DFF in distinguishing patients with LADA from T2DM in our study population, which may assist in diabetes classification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Tian, Guo, Wu, Ye, Ding, Zhou, Huang, Li, Zhou and Yang.)

Aims/introduction: The optimal therapy for latent autoimmune diabetes in adults (LADA) remains undefined. Increasing evidence has shown that sitagliptin and insulin treatment can benefit patients with LADA, but the efficacy still lacks systematic evaluation. We carried out this systematic review and meta-analysis to summarize the current data on the efficacy and safety of sitagliptin combined with insulin on LADA, providing a reliable reference for the effective therapeutic treatment of LADA patients., Materials and Methods: We retrieved the literature in PubMed, Cochrane Library, Embase, Web of Science and CNKI from inception to August 2021. Randomized controlled trials comparing the effects of sitagliptin plus insulin with insulin alone in LADA patients were identified. The outcome measures included parameters of glycemic control, β-cell function, body mass index and adverse events. The Review Manager 5.2 and Stata 14.0 were utilized for data analysis., Results: Eight randomized controlled trials involving 295 participants were identified. Sitagliptin and insulin treatment lowered hemoglobin A1c (weighted mean difference -0.36, 95% confidence interval -0.61 to -0.10, I 2  = 91.6%), increased fasting C-peptide (weighted mean difference 0.08, 95% confidence interval -0.02 to 0.17, I 2  = 88.8%) and had fewer adverse events compared with insulin alone. The inter-study heterogeneity, potential publication bias and other factors might interpret asymmetrical presentation of funnel plots. There was no significant association between sitagliptin plus insulin treatment and levels of hemoglobin A1c or fasting C-peptide, regardless of the duration of intervention and sample size., Conclusions: Sitagliptin combined with insulin can achieve better glycemic control and improve islet β-cell function with lower incidence of hypoglycemia compared with insulin alone, which provides an effective and tolerated therapeutic regimen for LADA patients. However, further well-designed and rigorous randomized controlled trials are required to validate this benefit due to the limited methodology quality of included trials., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

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/m 2 ] 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., (© 2022. The Author(s).)

Purpose: Autoimmune diabetes (AD) in adults includes both the classical form of type 1 diabetes mellitus (T1DM) and latent autoimmune diabetes in adults (LADA). LADA shares clinical and metabolic features with type 1 and type 2 diabetes mellitus (T2DM). Ceramide (Cer) levels negatively correlate with insulin sensitivity in humans and animal models. However, only a few studies have focused on other sphingolipids, including sphingomyelin (SM). Therefore, we determined sphingolipids in patients with newly diagnosed diabetes as possible diagnostic biomarkers., Materials and Methods: We evaluated sphingolipids in a cohort of 59 adults with newly diagnosed diabetes without prior hypoglycemic pharmacotherapy to distinguish diabetes mellitus types and for precise LADA definition. All patients with newly diagnosed diabetes were tested for the concentrations of individual Cer and SM species by gas-liquid chromatography. The study included healthy controls and patients with T1DM, T2DM and LADA., Results: SM species were significantly altered in patients with newly diagnosed diabetes compared to healthy controls. SM-C16:0, C16:1, -C18:0, -C18:1, -C18:2, -C18:3, -C20:4, and -C22:6 species were found to be significantly elevated in LADA patients. In contrast, significant differences were observed for Cer species with saturated acyl chains, especially Cer-C14:0, -C16:0, -C18:0 (AD and T2DM), -C22:0, and -C24:0 (T1DM). Following ROC analysis, SM-C16:0, and particularly -C18:1, and -C20:4 may be supportive diagnostic markers for LADA., Conclusion: SM profiling in patients with newly diagnosed diabetes could be potentially helpful for differential diagnosis of LADA, T1DM, and T2DM in more challenging cases., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest to disclose for this study., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

T lymphocytes are key players in the pathogenesis of autoimmune diabetes. We recruited subjects with T1D (n=81), LADA (n=82), T2D (n=95) and NGT (n=218) and analyzed the percentages of T-lymphocyte subsets, including T helper 1 (Th1), T helper 2 (Th2), T helper 17 (Th17), T cytotoxic 1 (Tc1), regulatory T cells (Tregs), effector T (Teff), naïve T, central memory T (Tcm), and effector memory T (Tem) cells by flow cytometry. LADA patients possessed similar frequencies of IFN-γ + CD4 + T (Th1), IFN-γ + CD8 + T and CD4 + Teff cells compared with T1D patients, but much lower than those of NGT subjects. Like T2D patients, LADA patients had increased frequencies of CD4 + Tem and CD8 + Tem cells with respect to T1D and NGT subjects. In LADA patients, Th2 cells were decreased while CD4 + Tcm cells were increased compared with NGT subjects. Notably, we observed significant negative correlations between the CD4 + Tcm cell frequency and C-peptide in LADA subjects. These data demonstrates that LADA patients possess T-cell subset changes resembling both T1D and T2D and represent the middle of the diabetes spectrum between T1D and T2D. Based on these T-cell subset alterations, we speculate that autoimmunity-induced β-cell destruction and inflammation-induced insulin resistance might both be involved in the pathogenesis of LADA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tan, Xiang, Deng, Cao, Ren, Huang and Zhou.)

Background: There 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., Methods: This 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., Results: A 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%) (p<0.05), whereas no differences were found between these groups for DRB1*03-DQB1*02:01-DQA1*05:01 or for protective alleles. Only 12% the overall T1DM group had no risk alleles vs 30% of LADA (p<0.0005). However, HLA allele distribution was similar in LADA and T1DM diagnosed after the age of 30. A total of 506 individuals (195 with T1DM [21 diagnosed after age 30] 253 with T2DM and 58 with LADA) were genotyped for the  PTPN22  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., Conclusion: In 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hernández, Nóvoa-Medina, Faner, Palou, Esquerda, Castelblanco, Wägner and Mauricio.)

Aim: 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., Research Design and Methods: 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., Results: 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)., Conclusions: 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., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)