B cell metabolism in autoimmune diseases: signaling pathways and interventions.

Autoimmune diseases are heterogeneous disorders believed to stem from the immune system's inability to distinguish between auto- and foreign- antigens. B lymphocytes serve a crucial role in humoral immunity as they generate antibodies and present antigens. Dysregulation of B cell function induce the onset of autoimmune disorders by generating autoantibodies and pro-inflammatory cytokines, resulting in an imbalance in immune regulation. New research in immunometabolism shows that cellular metabolism plays an essential role in controlling B lymphocytes immune reactions by providing the energy and substrates for B lymphocytes activation, differentiation, and function. However, dysregulated immunometabolism lead to autoimmune diseases by disrupting self-tolerance mechanisms. This review summarizes the latest research on metabolic reprogramming of B lymphocytes in autoimmune diseases, identifying crucial pathways and regulatory factors. Moreover, we consider the potential of metabolic interventions as a promising therapeutic strategy. Understanding the metabolic mechanisms of B cells brings us closer to developing novel therapies for autoimmune disorders.

Hepatocyte nuclear factor 1B deletion, but not intragenic mutation, might be more susceptible to hypomagnesemia.

AIMS: HNF1B syndrome is caused by defects in the hepatocyte nuclear factor 1B (HNF1B) gene, which leads to maturity-onset diabetes of the young type 5 and congenital organ malformations. This study aimed to identify a gene defect in a patient presenting with diabetes and severe diarrhea, while also analyzing the prevalence of hypomagnesemia and its correlation with the HNF1B genotype. MATERIALS AND METHODS: Whole exome sequencing was used to identify responsible point mutations and small indels in the proband and their family members. Multiplex ligation-dependent probe amplification was carried out to identify HNF1B deletions. Furthermore, an analysis of published data on 539 cumulative HNF1B cases, from 29 literature sources, was carried out to determine the correlation between the HNF1B genotype and the phenotype of serum magnesium status. RESULTS: Using multiplex ligation-dependent probe amplification, we identified a de novo heterozygous HNF1B deletion in the patient, who showed dorsal pancreas agenesis and multiple kidney cysts, as detected by magnetic resonance imaging. Magnesium supplementation effectively alleviated the symptoms of diarrhea. Hypomagnesemia was highly prevalent in 192 out of 354 (54.2%) patients with HNF1B syndrome. Compared with patients with intragenic mutations, those with HNF1B deletions were more likely to suffer from hypomagnesemia, with an odds ratio of 3.1 (95% confidence interval 1.8-5.4). CONCLUSIONS: Hypomagnesemia is highly prevalent in individuals with HNF1B syndrome, and those with HNF1B deletion are more susceptible to developing hypomagnesemia compared with those with intragenic mutations. The genotype-phenotype associations in HNF1B syndrome have significant implications for endocrinologists in terms of genotype detection, treatment decisions and prognosis assessment.

Myo9b mutations are associated with altered dendritic cell functions and increased susceptibility to autoimmune diabetes onset.

The regulation of autoimmunity against pancreatic islet ß cells for type 1 diabetes (T1D) onset is still unclear. NOD/ShiLtJ (NOD) mice are prone to the onset of autoimmune diabetes, but its congenic strain, ALR/Lt (ALR), is not. Here we show that dendritic cells (DC) in ALR mice have impaired migratory and T-cell priming capability. Genomic comparative analysis maps a 33-bp deletion in the ALR Myosin IXb (Myo9b) gene when compared with NOD genome; meanwhile, data from knock-in models show that this ALR Myo9b allele impairs phenotypic and functional maturation of DCs, and prevents the development and progression of spontaneous autoimmune diabetes in NOD mice. In parallel, while the ALR 33-bp deletion of Myo9b is not conserved in human, we find a MYO9B R133Q polymorphism associating with increased risk of T1D and enhanced DC function in patients with T1D. Our results thus hint that alterations in Myo9b may contribute to altered DC function and autoimmune diabetes onset.

Toxicological evaluation of TBBPA by common carp (Cyprinus carpio) about the in vivo/vitro disturbance of the AHR pathway.

Tetrabromobisphenol A (TBBPA) is a widely used plastic additive with high bioaccumulation potential and toxicity on both humans and wildlife. Currently, research on its ecotoxicity and the underlying mechanism is limited. Using common carp (Cyprinus carpio), we evaluated the toxicity of TBBPA, especially focusing on its alteration of a key metabolism-related pathway aryl hydrocarbon receptor (AHR), using in vivo/vitro assays and in silico simulation. The 96 h LC50 of TBBPA of common carp was 4.2 mg/L and belonged to the acute toxic level II. The bioaccumulation potential of TBBPA follows the role of liver > gill > brain and varies between 3- and 14-day exposure. On the AHR pathway respect, as expected, the metabolism-related cyp1a1 and cyp1b1 were upregulated in the liver and brain. Ahr2, the receptor, was also upregulated in the brain under TBBPA exposure. The alteration of gene expression was tissue-specific while the difference between 3- or 14-day exposure was minor. AHR inhibition assay indicated the 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-induced AHR transactivation can be inhibited by TBBPA suggesting it is not a potent agonist but a competitive antagonist. In silico analysis indicated TBBPA can be successfully docked into the binding cavity with similar poses but still have AHR-form-specific interactions. Molecular dynamics simulation proved TBBPA can be more flexible than the coplanar ligand TCDD, especially in ccaAHR1b with greater root-mean-square deviation (RMSD), of which TCDD-induced transactivation seemed not to be blocked by TBBPA. This research increased the understanding of TBBPA toxicity and alteration of the AHR pathway, and pointed out the need to perform additional toxicology evaluation of emerging contaminants, especially on non-model species.

Association between vitamin D deficiency and lipid profiles in overweight and obese adults: a systematic review and meta-analysis.

OBJECTIVE: The association between vitamin D deficiency and lipid profiles in adults with overweight or obesity remains unclear and inconsistent. The aim of our study was to determine the relationship between lipid profiles and vitamin D deficiency in the overweight and obese adults. METHODS: Four databases, including PubMed, the Web of Science, EMBASE and the Cochrane Library, were used to identify all studies on vitamin D status and lipid levels, including the serum levels of triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL). The Weighted mean difference (WMD) with 95% confidence intervals (CIs) using random-effects models was used to assess the association between the lipid profile and vitamin D deficiency. RESULTS: Twenty-one articles that included a total of 7952 adults with overweight or obesity (BMI ≥ 25 kg/m2) were included. The overall results revealed that compared with the controls, individuals with vitamin D deficiency showed higher levels of TG (WMD = 15.01; 95%CI, 2.51-27.52) and TC (WMD = 8.61; 95%CI, 1.31-15.92). Moreover, vitamin D deficiency was related to an increased level of LDL (WMD = 6.12; 95%CI, 0.02-12.23). HDL level was inversely associated with the vitamin D deficiency status (WMD = -2.57; 95%CI, -4.26, -0.88). CONCLUSIONS: Among the adults with overweight or obesity, the vitamin D deficient group displayed impaired lipid profiles, including increased TG, TC and LDL levels and reduced HDL level.

Distinct signatures of gut microbiota and metabolites in different types of diabetes: a population-based cross-sectional study.

Background: Patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) present intestinal disturbances. Recent epidemiological data have showed that, worldwide, over half of newly diagnosed T1D patients were adults. However, the gut microbial alterations in adult-onset T1D are unclear. We aimed to identify the signatures of gut microbiota and metabolites in patients with adult-onset T1D systematically, comparing with T2D patients and healthy controls (HCs). Methods: This study enrolled 218 subjects from February 2019 to April 2022 (discovery cohort: 36 HCs, 51 patients with adult-onset T1D and 56 patients with T2D; validation cohort: 28 HCs, 27 patients with adult-onset T1D and 20 patients with T2D). Gut microbial profiles of the study subjects were investigated by metagenomic sequencing, and their faecal and serum metabolites were measured with targeted metabolomics. The study was registered on ClinicalTrials.gov (NCT05252728). Findings: Patients with adult-onset T1D had significant differences in the composition of bacteria and their metabolites, characterized by notable depletion of short-chain fatty acid-producing bacteria, especially Eubacterium rectale. This was associated with a severe loss of phenolic acids and their derivatives, including gallic acid (associated with glucose metabolism) and 3,4-dihydroxyhydrocinnamic acid (linked with glucose metabolism and pancreatic beta cell autoimmunity). A predictive model based on six bacteria and six metabolites simultaneously discriminated adult-onset T1D from T2D and HCs with high accuracy. Interestingly, bacterial-viral or bacterial-fungal trans-kingdom relationships, especially positive correlations between bacteriophages and beneficial bacteria, were significantly reduced in adult-onset T1D compared to HCs. Interpretation: Adult-onset T1D patients exhibit unique changes in host-microbiota-metabolite interactions. Gut microbiota and metabolite-based algorithms could be used as additional tools for differential diagnosis of different types of diabetes and beyond. Funding: National Key Research and Development Program of China, the National Natural Science Foundation of China.

Visual Analytics of Multidimensional Oral Health Surveys: Data Mining Study.

BACKGROUND: Oral health surveys largely facilitate the prevention and treatment of oral diseases as well as the awareness of population health status. As oral health is always surveyed from a variety of perspectives, it is a difficult and complicated task to gain insights from multidimensional oral health surveys. OBJECTIVE: We aimed to develop a visualization framework for the visual analytics and deep mining of multidimensional oral health surveys. METHODS: First, diseases and groups were embedded into data portraits based on their multidimensional attributes. Subsequently, group classification and correlation pattern extraction were conducted to explore the correlation features among diseases, behaviors, symptoms, and cognitions. On the basis of the feature mining of diseases, groups, behaviors, and their attributes, a knowledge graph was constructed to reveal semantic information, integrate the graph query function, and describe the features of intrigue to users. RESULTS: A visualization framework was implemented for the exploration of multidimensional oral health surveys. A series of user-friendly interactions were integrated to propose a visual analysis system that can help users further achieve the regulations of oral health conditions. CONCLUSIONS: A visualization framework is provided in this paper with a set of meaningful user interactions integrated, enabling users to intuitively understand the oral health situation and conduct in-depth data exploration and analysis. Case studies based on real-world data sets demonstrate the effectiveness of our system in the exploration of oral diseases.

Umbilical cord blood and peripheral blood-derived regulatory T cells therapy: Progress in type 1 diabetes.

Regulatory T cells (Tregs) are key regulators for the inflammatory response and play a role in maintaining the immune tolerance. Type 1 diabetes (T1D) is a relatively common autoimmune disease that results from the loss of immune tolerance to ß-cell-associated antigens. Preclinical models have demonstrated the safety and efficacy of Tregs given in transplant rejection and autoimmune diseases such as T1D. Adoptive transfer of Tregs has been utilized in clinical trials for over a decade. However, the achievement of the adoptive transfer of Tregs therapy in clinical application remains challenging. In this review, we highlight the characterization of Tregs and compare the differences between umbilical cord blood and adult peripheral blood-derived Tregs. Additionally, we summarize conditional modifications in the expansion of Tregs in clinical trials, especially for the treatment of T1D. Finally, we discuss the existing technical challenges for Tregs in clinical trials for the treatment of T1D.

Elevated glucose metabolism driving pro-inflammatory response in B cells contributes to the progression of type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the immune system's failure to maintain self-tolerance, resulting in the autoimmune destruction of pancreatic beta cells. Although T1D has conventionally been viewed as a T-cell-dominant disease, recent research has emphasized the contribution of B cells in the onset of the disease. However, the mechanism underlying aberrant B cell responses remains unknown. B cell metabolism is a crucial prerequisite for B cell function and the development of adaptive immune responses. Here, we investigated the metabolic features of B cells, first in a cross-sectional cohort and subsequently in non-obese diabetic (NOD) mice, and revealed that there is an increased frequency of high-glucose-avidity (2-NBDGhigh) B cell population that may contribute to T1D progression. Further characterization of the metabolic, transcriptional and functional phenotype of B cells in NOD mice found that elevated glucose avidity is associated with a greater capacity for co-stimulation, proliferation and inflammatory cytokine production. Mechanistically, elevated Myc signaling orchestrated the glucose metabolism and the pro-inflammatory response of B cells in T1D. In vitro experiments demonstrated that pharmacological inhibition of glucose metabolism using metformin and 2-DG reduced pro-inflammatory cytokine production and B cell proliferation. Moreover, the combination of these inhibitors successfully delayed insulitis development, onset of diabetes, and improved high blood glucose levels in streptozotocin (STZ)-induced diabetic mice model. Taken together, our work has uncovered these high-glucose-avidity B cells as novel adjuvant diagnostic and therapeutic targets for T1D.

Weight loss and metabolic benefits of bariatric surgery in China: A multicenter study.

BACKGROUND: This retrospective multicenter study evaluated the efficacy and safety of bariatric surgery in Chinese patients with obesity. METHODS: Patients with obesity who underwent laparoscopic sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass and completed a 12-month follow-up between February 2011 and November 2019 were enrolled. Weight loss, glycemic and metabolic control, insulin resistance, cardiovascular risk, and surgery-related complications at 12 months were analyzed. RESULTS: We enrolled 356 patients aged 34.3 ± 0.6 years with a mean body mass index of 39.4 ± 0.4 kg/m2 . Successful weight loss occurred in 54.6%, 86.8%, and 92.7% of patients at 3, 6, and 12 months, respectively, with no difference in percent excess weight loss between the laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass surgery groups. The average percentage of total weight loss was 29.5% ± 0.6% at 12 months; 99.4%, 86.8%, and 43.5% of patients achieved at least 10%, 20%, and 30% weight loss, respectively, at 12 months. Significant improvements in metabolic indices, insulin resistance, and inflammation biomarkers were observed at 12 months. CONCLUSIONS: Bariatric surgery resulted in successful weight loss and improved metabolic control, insulin resistance, and cardiovascular risk in Chinese patients with obesity. Both laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass are suitable approaches for such patients.

Association of the rs1990760, rs3747517, and rs10930046 polymorphisms in the IFIH1 gene with susceptibility to autoimmune diseases: a meta-analysis.

Objective: Interferon induced with helicase C domain 1 (IFIH1) single-nucleotide polymorphisms (SNP) rs1990760, rs3747517, and rs10930046 have been shown to be closely related to the risk of autoimmune diseases. The aim of this study was firstly to examine the association of the rs1990760 with type 1 diabetes (T1D) in a Chinese population. Secondly, to assess the association of SNP rs1990760, rs3747517, and rs10930046 with autoimmune diseases susceptibility. Methods: A total of 1,273 T1D patients and 1,010 healthy control subjects in a Chinese population were enrolled in this case-control study. Subsequently, we performed a meta-analysis on the association of the SNP rs1990760, rs3747517, and rs10930046 in the IFIH1 gene with susceptibility to autoimmune diseases. The random and fixed genetic effects models were used to evaluate the association and the effect sizes, including odds ratios (OR) and 95% confidence intervals (CI). Stratification analyses based on ethnicity and the type of autoimmune diseases were performed. Results: IFIH1 SNP rs1990760 was not associated with a significant risk of T1D in the Chinese population in the case-control study. A total of 35 studies including 70,966 patients and 124,509 controls were identified and included in the meta-analysis. The results displayed significant associations between IFIH1 rs1990760 A allele and rs3747517 C allele and autoimmune diseases risk (OR=1.09, 95% CI: 1.01~1.17; OR=1.24, 95% CI: 1.15~1.25, respectively). Stratified analysis indicated a significant association rs1990760 and rs3747517 with autoimmune diseases risk in the Caucasian population (OR=1.11, 95% CI: 1.02~1.20, OR=1.29, 95% CI: 1.18~1.41, respectively). Conclusions: This study revealed no association between IFIH1 SNP rs1990760 and T1D in Chinese. Furthermore, the meta-analysis indicated that rs1990760 and rs3747517 polymorphisms, confer susceptibility to autoimmune diseases, especially in the Caucasian population.

Prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy in adults with diabetes in China.

The current epidemic status of diabetic retinopathy in China is unclear. A national prevalence survey of diabetic complications was conducted. 50,564 participants with gradable non-mydriatic fundus photographs were enrolled. The prevalence rates (95% confidence intervals) of diabetic retinopathy and vision-threatening diabetic retinopathy were 16.3% (15.3%-17.2%) and 3.2% (2.9%-3.5%), significantly higher in the northern than in the southern regions. The differences in prevalence between those who had not attained a given metabolic goal and those who had were more pronounced for Hemoglobin A1c than for blood pressure and low-density lipoprotein cholesterol. The participants with vision-threatening diabetic retinopathy had significantly higher proportions of visual impairment and blindness than those with non-vision-threatening diabetic retinopathy. The likelihoods of diabetic retinopathy and vision-threatening diabetic retinopathy were also associated with education levels, household income, and multiple dietary intakes. Here, we show multi-level factors associated with the presence and the severity of diabetic retinopathy.

Fat-to-muscle ratio is associated with insulin resistance and cardiometabolic disorders in adults with type 1 diabetes mellitus.

AIMS: This study aimed to investigate the correlation of the fat-to-muscle ratio (FMR) with insulin resistance (IR) and cardiometabolic disorders (CMD) in patients with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: We retrospectively recruited 420 adults with T1DM [52.6% men, median age 32.4 (24.5, 43.0) years]. Body composition was assessed by bioelectrical impedance analysis and FMR was calculated. The characteristics of the overall participants were compared between tertiles of FMR. Logistic regression analyses were performed to assess the association of FMR tertiles with IR and cardiometabolic risk factors. RESULTS: Median age and median haemoglobin A1c of all participants were 32.4 (24.5, 43.0) years and 7.4 (6.5, 8.7)%, respectively. The prevalence of IR and CMD was 18% and 38.6%. The FMR significantly differed between men and women [0.39 (0.31, 0.53) vs. 0.74 (0.63, 0.92), respectively, p < .001]. The proportion of IR and CMD gradually increased as the FMR increased. The multivariable-adjusted odd ratios for IR and CMD in FMR tertile 3 compared with tertile 1 were 4.8 [95% confidence interval (CI): (1.9, 12.1)] and 9.7 (95% CI: 4.2, 22.3), respectively, in men. For women, the corresponding odd ratios were 4.0 (95% CI: 1.2, 12.9) for IR and 5.8 (95% CI: 2.4, 13.6) for CMD. CONCLUSIONS: FMR is associated with IR and CMD in adults with T1DM and could be used as a promising parameter for targeting treatment in T1DM.

Prevalence, clinical characteristics and HLA genotypes of idiopathic type 1 diabetes: A cross-sectional study.

AIMS: Idiopathic type 1 diabetes (T1D) is a neglected subtype of T1D. Our aim was to investigate the frequency, clinical characteristics, and human leucocyte antigen (HLA) genotypes of idiopathic T1D. METHODS: We enrolled 1205 newly diagnosed T1D patients in our analysis. To exclude monogenic diabetes in autoantibody-negative patients, we utilised a custom monogenic diabetes gene panel. Individuals negative for autoantibodies and subsequently excluded for monogenic diabetes were diagnosed with idiopathic T1D. We collected clinical characteristics, measured islet autoantibodies by radioligand assay and obtained HLA data. RESULTS: After excluding 11 patients with monogenic diabetes, 284 cases were diagnosed with idiopathic T1D, accounting for 23.8% (284/1194) of all newly diagnosed T1D cases. When compared with autoimmune T1D, idiopathic T1D patients showed an older onset age, higher body mass index among adults, lower haemoglobin A1c, higher levels of fasting C-peptide and 2-h postprandial C-peptide, and were likely to have type 2 diabetes (T2D) family history and carry 0 susceptible HLA haplotype (all p < 0.01). A lower proportion of individuals carrying 2 susceptible HLA haplotypes in idiopathic T1D was observed in the adult-onset subgroup (15.7% vs. 38.0% in child-onset subgroup, p < 0.001) and in subgroup with preserved beta-cell function (11.0% vs. 30.1% in subgroup with poor beta-cell function, p < 0.001). Multivariable correlation analyses indicated that being overweight, having T2D family history and lacking susceptible HLA haplotypes were associated with negative autoantibodies. CONCLUSIONS: Idiopathic T1D represents about 1/4 of newly diagnosed T1D, with adult-onset and preserved beta-cell function patients showing lower HLA susceptibility and more insulin resistance.

Role of E3 ubiquitin ligases and deubiquitinating enzymes in SARS-CoV-2 infection.

Ever since its emergence in 2019, COVID-19 has rapidly disseminated worldwide, engendering a pervasive pandemic that has profoundly impacted healthcare systems and the socio-economic milieu. A plethora of studies has been conducted targeting its pathogenic virus, SARS-CoV-2, to find ways to combat COVID-19. The ubiquitin-proteasome system (UPS) is widely recognized as a crucial mechanism that regulates human biological activities by maintaining protein homeostasis. Within the UPS, the ubiquitination and deubiquitination, two reversible modifications, of substrate proteins have been extensively studied and implicated in the pathogenesis of SARS-CoV-2. The regulation of E3 ubiquitin ligases and DUBs(Deubiquitinating enzymes), which are key enzymes involved in the two modification processes, determines the fate of substrate proteins. Proteins associated with the pathogenesis of SARS-CoV-2 may be retained, degraded, or even activated, thus affecting the ultimate outcome of the confrontation between SARS-CoV-2 and the host. In other words, the clash between SARS-CoV-2 and the host can be viewed as a battle for dominance over E3 ubiquitin ligases and DUBs, from the standpoint of ubiquitin modification regulation. This review primarily aims to clarify the mechanisms by which the virus utilizes host E3 ubiquitin ligases and DUBs, along with its own viral proteins that have similar enzyme activities, to facilitate invasion, replication, escape, and inflammation. We believe that gaining a better understanding of the role of E3 ubiquitin ligases and DUBs in COVID-19 can offer novel and valuable insights for developing antiviral therapies.

ZNF451 favors triple-negative breast cancer progression by enhancing SLUG-mediated CCL5 transcriptional expression.

Triple-negative breast cancer (TNBC) is the most aggressive subtype with limited effective therapies because of the absence of definitive targets. Here, we demonstrate that the expression of ZNF451, a poorly characterized vertebrate zinc-finger protein, is upregulated in TNBC and associated with a poor prognosis. Elevated ZNF451 expression facilitates TNBC progression by interacting with and enhancing the activity of the transcriptional activator snail family transcriptional repressor 2 (SLUG). Mechanistically, the ZNF451-SLUG complex preferentially recruits the acetyltransferase p300/CBP-associated factor (PCAF) to the CCL5 promoter, selectively facilitating CCL5 transcription by enhancing the acetylation of SLUG and local chromatin, leading to recruitment and activation of tumor-associated macrophages (TAMs). Disturbing the ZNF451-SLUG interaction using a peptide suppresses TNBC progression by reducing CCL5 expression and counteracting the migration and activation of TAMs. Collectively, our work provides mechanistic insights into the oncogene-like functions of ZNF451 and suggests that ZNF451 is a potential target for development of effective therapies against TNBC.

Type 2 diabetes family history as a significant index on the clinical heterogeneity differentiation in type 1 diabetes.

AIMS: Family history of type 2 diabetes (T2D) is a significant but neglected parameter; however, its role in identifying the heterogeneity and subtypes of type 1 diabetes (T1D) remains unclear. Herein, we investigated the impact of family history of T2D on the clinical phenotype of T1D patients and evaluated its value in T1D classification. METHODS: A total of 1410 T1D patients were enrolled in this prospective study. Information on family history of T2D in first-degree relatives was collected by research nurses using a semi-structured questionnaire as previously described. The impact of family history of T2D on clinical characteristics was evaluated in overall and subgroups of T1D patients stratified by islet autoantibodies, onset age, and human leukocyte antigen (HLA) genotype. Cluster analysis was performed to identify family history of T2D -related subgroups. RESULTS: Ten percent (141/1410) patients had at least one first-degree relatives diagnosed with T2D. A milder phenotype associated with family history of T2D was presented in overall T1D patients, including older onset age (p < 0.001), higher body mass index (p < 0.001), higher fasting and postprandial C-peptide levels (all p < 0.01), lower positive rates of all islet autoantibodies and susceptible HLA genotypes (all p < 0.05). Clinical heterogeneity associated with family history of T2D in the T1D subgroup stratified by autoimmunity, age of onset, and HLA genotypes was consistent. Using family history of T2D as a cluster variable, T1D patients were divided into five clusters, and patients in the T2D family history cluster displayed a milder phenotype than others. CONCLUSIONS: Family history of T2D should be considered as an important indicator for precise sub-classification of T1D patients based on clinical heterogeneity.