Blood methylome signatures in children exposed to maternal type 1 diabetes are linked to protection against islet autoimmunity

Epigenetic differences at immune and type 1 diabetes susceptibility genes in blood from young children after COVID-19 infection.

Introduction: A family history of type 1 diabetes (T1D) increases T1D risk, but the increase is lower for maternal compared to paternal T1D. We aimed to identify epigenetic markers of this parent-of-origin effect by testing whether the effect of DNA methylation on T1D risk differs by T1D family history in The Environmental Determinants of Diabetes in the Young (TEDDY) Study. Methods: For 106 T1D cases and 99 matched controls in TEDDY, methylation was measured in 1,424 peripheral blood samples collected prospectively from 3-75 months of age using the MethylationEPIC Beadchip. Following data processing, we performed an epigenome-wide association study across 534,790 CpGs using linear regression adjusted for age, sex, and HLA-DR3/4. We used an interaction term to test whether the difference in mean longitudinal methylation (%) between T1D cases and controls differed by T1D family history (affected: mother, N=19; father or sibling, N=50; none, N=136). Results: We identified 141 CpGs where the effect of methylation on T1D risk differed by T1D family history (FDR-adjusted Pinteraction<0.01). Among children exposed to maternal T1D in utero, methylation levels differed between cases and controls; however, in those with no T1D family history or with an affected father or sibling there was no difference in methylation. In those with an affected mother, the largest effect sizes included hypomethylation in T1D cases near glucose metabolism genes ASTN2 (-11.3%) and ACOT7 (-7.8%), and hypermethylation near PTEN (11.3%), a key insulin signaling gene. Over 24% (35/141) of CpGs localized in previously identified loci exhibiting allele-specific methylation, implicating genetic-epigenetic interplay. Conclusion: We identified epigenetic changes preceding T1D that differ by T1D family history. At these loci, methylation differences occurred only among children exposed to T1D in utero and localized near glucose metabolism genes, suggesting epigenetic mechanisms may be involved in the long-described maternal effect in T1D risk. Disclosure R.K. Johnson: None. S.D. Slack: None. L.A. Vanderlinden: None. K. Hohsfield: None. P.M. Carry: None. S. Onengut-Gumuscu: None. S.S. Rich: None. M. Rewers: Advisory Panel; Sanofi. Other Relationship; Sanofi. Consultant; Janssen Pharmaceuticals, Inc. Research Support; Juvenile Diabetes Research Foundation (JDRF). Consultant; Provention Bio, Inc. Research Support; Hemsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases. K. Kechris: None. J.M. Norris: None. Funding The Leona M. and Harry B. Helmsley Charitable Trust (2103-05094). The TEDDY Study is a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF), and Centers for Disease Control and Prevention (CDC).

Concordance for persistent islet autoimmunity (IA) and type 1 diabetes (T1D) in monozygotic twins (MZ) after one twin is diagnosed has been highly variable (30-70%), while risk for development of IA in dizygotic twins (DZ) is thought to be similar to non-twin siblings. Since 1995, the Twin Family Study at the Barbara Davis Center has followed 336 twins (168 twin probands diagnosed with T1D and 168 cotwins) with a median follow-up of 14 years (ICR:10-18 years). Zygosity testing confirmed a total of 80 MZ pairs and 88 DZ pairs. Cotwins were followed for the development of IA and celiac autoimmunity (CDA). In MZ cotwins, cumulative incidence for IA was 14% by age 20 and 63% by age 45, while development of CDA was 10% by 20 years. Development of IA and CDA by age 20 was 9.2% and 12.3% in DZ cotwins respectively, with development of IA reaching 70% by age 30 (Figure). In Cox proportional hazards models, only the proband’s age at diagnosis, but not sex, HLA-DR3 nor DR4 were associated with time to IA and CDA in cotwins. In MZ twins, younger age of the proband was associated with an increased hazard ratio (HR) for both IA and CDA, while younger age in DZ twins was associated with an increased HR for IA only. In conclusion, CDA risk does not appear to increase after age 15. With long term follow-up, cumulative incidence for IA is high in DZ twins, similar to MZ twins, suggesting a role of possible early environmental factors shared by T1D-discordant cotwins. Disclosure T.M. Triolo: None. A.R. Fouts: None. L. Pyle: None. L. Yu: None. P. Gottlieb: Advisory Panel; Self; Bristol-Myers Squibb Company. Research Support; Self; Caladrius Biosciences, Inc.. Advisory Panel; Self; Eli Lilly and Company. Board Member; Self; ImmunoMolecular Therapeutics. Consultant; Self; Kamada. Research Support; Self; JDRF, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk Inc., MacroGenics, Inc., Pfizer Inc.. Advisory Panel; Self; Viacyte, Inc.. Research Support; Self; GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc.. A. Steck: None.

T1D is a progressive, autoimmune-mediated condition associated with numerous comorbidities and significant premature mortality. The offspring of fathers diagnosed with T1D exhibit a 2-3 times higher risk of developing T1D than the offspring of mothers diagnosed with T1D. Individuals with T1D who have an affected father present with a more aggressive disease phenotype at diagnosis. Yet the impact of paternal T1D (P-T1D) vs. maternal T1D (M-T1D) on health outcomes in individuals with T1D is unknown. We previously developed and validated a subgroup discovery algorithm that identifies highly contrasted patterns occurring with a significant difference in prevalence between two subgroups (e.g., P-T1D vs. M-T1D). Here we used this computational deep exploratory data mining method to analyze publicly-accessible data from the T1D Exchange Clinic Registry (2010-12; 2015-17). We used an Apache Spark high performance computing environment to apply our algorithm to family history, gender, and medical conditions data in the Registry. We identified multiple phenotypic contrasts between individuals with P-T1D (2010-12 data: n = 1011; 2015-17 data: n = 652) vs. M-T1D (2010-12 data: n = 528; 2015-17 data: n = 342). Using Fisher’s exact tests to determine statistical significance, P-T1D associated with hypothyroidism and male gender in 7.2% of cases (47/652), compared to 3.2% of cases (11/342) of M-T1D (p = 0.01). M-T1D was associated with hypertension (HTN) in 36.0% of cases (123/342), compared to 22.3% of cases (146/652) in P-T1D (p < 0.001). M-T1D was associated with diabetes-related neuropathy and HTN in 10.8% of cases (37/342), compared to 4.9% of cases (32/652) in P-T1D (p = 0.001). Complex patterns generated with this algorithm may yield contrast patterns that provide insights about personalized interventions to improve health outcomes. Whether contrast mining can be used to predict health trajectories of individuals with T1D remains to be determined. Disclosure E.M. Tallon: None. M.A. Clements: Consultant; Self; Glooko, Inc. Other Relationship; Self; Glooko, Inc. D. Liu: None. K. Boles: None. R.A. Stuck: None. C. Shyu: None. Funding National Institutes of Health (5T32LM012410)

Introduction and Objective: Type 1 diabetes (T1D) can impact reproductive health in males. Given the potential impact of environmental stimuli, including hyperglycemia, on epigenetic marks, we assessed DNA methylation (DNAm) in sperm from men with T1D. Methods: We recruited 29 weight and age-matched men, 19 with T1D and 10 normoglycemic controls (CON). Samples were collected at baseline and after 3 months. We analyzed reproductive hormones, sperm quality, and sperm DNA methylation (Infinium MethylationEPIC), analyzed using SeSAMe pipeline. Results: Men with T1D had higher levels of luteinizing hormone (LH) (46%, p=0.03) and sex hormone binding globulin (SHBG) (91%, p=0.01), but similar testosterone levels and sperm quality vs. CON. Sperm DNAm remained stable in repeated samples over 3-months in both T1D and CON. Of the 755,827 CpG on the array, 97,723 (12.9%) were differentially methylated (FDR<0.05) in men with T1D vs. CON, adjusted for BMI; DNAm at these sites was increased in 91.7% and reduced in 8.3%. Differential methylation was attenuated after adjustment for HbA1c, suggesting glucose impact on methylation. Ontology analysis of differentially methylated loci revealed annotation to genes regulating helper T cell differentiation, natural killer cell chemotaxis, lysine deacetylation and lipoprotein lipase activity. Among differentially methylated sites, methylation was increased at multiple CpG sites within the human leukocyte antigen (HLA) complex, including HLA-DQA2, DQB2, DRA, DRB1, DPA1, DMB, and C (FDR<0.05). Conclusion: Men with T1D exhibited significantly higher levels of DNA methylation in sperm vs. CON. Whether differential DNA methylation in sperm could alter early post-fertilization phenotypes in offspring and contribute to disease risk remains unknown. Given the association between HLA genotype and T1D risk, ongoing analysis will determine whether differentially methylated loci within the HLA complex are associated with specific HLA risk alleles. Disclosure R. Ferraz-Bannitz: None. B. Ozturk: None. V. Efthymiou: None. H. Wang: None. A. Cruz: None. C.J. Cummings: None. J. Patel: None. H. Pan: None. J. Dreyfuss: None. E.M. Isganaitis: None. M. Patti: Research Support; Dexcom, Inc. Other Relationship; Recordati, Fractyl Health, Inc. Consultant; Spruce Biosciences, Premier, Cello, Alpha sight, Boxer Capital. Other Relationship; Amylyx. Funding Beatson FoundationIacocca Foundation

Cow's milk intake has been inconsistently associated with islet autoimmunity (IA) and type 1 diabetes (T1D) development. Genetic and environmental factors may modify the effect of cow's milk on IA and T1D risk. The Diabetes Autoimmunity Study in the Young (DAISY) follows children at increased T1D risk of IA (presence of autoantibodies to insulin, GAD65, or IA-2 twice in succession) and T1D development. We examined 1835 DAISY children with data on cow's milk intake: 143 developed IA, 40 subsequently developed T1D. Cow's milk protein and lactose intake were calculated from prospectively collected parent- and self-reported food frequency questionnaires (FFQ). High risk HLA-DR genotype: HLA-DR3/4,DQB1*0302; low/moderate risk: all other genotypes. We examined interactions between cow's milk intake, age at cow's milk introduction, and HLA-DR genotype in IA and T1D development. Interaction models contained the base terms (e.g., cow's milk protein and HLA-DR genotype) and an interaction term (e.g., cow's milk protein*HLA-DR genotype). In survival models adjusted for total calories, FFQ type, T1D family history, and ethnicity, greater cow's milk protein intake was associated with increased IA risk in children with low/moderate risk HLA-DR genotypes [hazard ratio (HR): 1.41, 95% confidence interval (CI): 1.08-1.84], but not in children with high risk HLA-DR genotypes. Cow's milk protein intake was associated with progression to T1D (HR: 1.59, CI: 1.13-2.25) in children with IA. Greater cow's milk intake may increase risk of IA and progression to T1D. Early in the T1D disease process, cow's milk intake may be more influential in children with low/moderate genetic T1D risk.

Background: Prior research found that children at risk for type 1 diabetes (T1D) with increased dietary intake of sugar and higher glycemic index foods had quicker progression from islet autoimmunity (IA) to T1D diagnosis. However, this has not yet been studied in another population. Objective: To investigate the role of macronutrients in the progression to T1D in TrialNet’s cohort of individuals with IA, including older children and adults. Methods: Baseline dietary data derived from a food frequency questionnaire (FFQ) estimating intake over the past year, and longitudinal clinical data until development of T1D were obtained for individuals with IA from TrialNet’s Pathway to Prevention Study. Proportional hazard regression analysis stratified by age group (1-4 yrs, 5-12 yrs, 13-22 yrs, and 23+ yrs old) was used to evaluate the time from IA detection to T1D diagnosis, with regard to average daily dietary intake of carbohydrates, protein, fat, sugar, fiber, glycemic index, and glycemic load, after adjusting for confounders. Results: A total of 881 individuals age 1-51 years with at least one autoantibody were included, among whom 73/138 toddlers, 160/388 children, 48/166 adolescent/young adults (AYA), and 27/189 adults developed T1D. Given multiple comparisons, there was no significant association between rate of progression from IA to T1D and daily dietary intake of any macronutrients analyzed, after adjusting for baseline age, BMI, and number of autoantibodies, high risk HLA, and time from IA detection to FFQ completion. Borderline association with higher protein intake among AYA (HR 1.04, 95% CI 1.00-1.08) persisted after sensitivity analysis restricted to those with 2+ autoantibodies (HR 1.05, 95% CI 1.01-1.09). Conclusions: Baseline dietary macronutrient intake does not appear to influence rate of T1D diagnosis in children, adolescents, or adults with IA. Further study of dietary factors’ complex role in T1D progression is warranted, including effects of a change in diet over time. Disclosure E. L. Lundgrin: None. A. Viswanathan: None. S. B. Johnson: None. J. M. Norris: None. H. M. Ismail: None. J. R. Wood: Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Insulet Corporation, Speaker’s Bureau; Self; Xeris Pharmaceuticals, Inc. A. J. Thomas: None. D. J. Becker: None. Funding Rainbow Babies & Children’s Foundation; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF

Background and Aim: Worldwide, incidence of childhood obesity and early-onset type 1 diabetes (T1D) has risen over the past decades. Epidemiological studies have shown that in addition to genetic predisposition, environmental factors such as air pollution and temperature are associated with body mass index (BMI), T1D and its presymptomatic stage of autoimmunity to pancreatic islet cells. This study aimed to investigate the effect of exposure to light at night (LAN) on standardized BMI and islet autoimmunity (having 2 or more islet autoantibodies) in children in Bavaria, Germany. Methods: Exposure to LAN at baseline was assigned to the residential addresses of 52,636 children (<6 years of age) participating in the Fr1da study from 2015 to 2019. Information on demographic characteristics was extracted from self-administered questionnaires. We investigated the association of LAN with standardized BMI using linear regression and with islet autoimmunity using generalized additive models, segmented regression and quartile analysis. All models were adjusted for sex, age, family history of diabetes and area-level socioeconomic status (SES). Results: The mean standardized BMI was 0.12 ± 1.04 and 225 children showed islet autoimmunity. A 10 nW/cm2/sr increase in LAN was significantly associated with a 2.14% increase in standardized BMI (95% confidence interval (CI): 0.86-3.45). Also, LAN exposure was linearly associated with a significantly higher odds of islet autoimmunity in children with exposure levels up to 11 nW/cm2/sr (Odds ratio (OR): 1.98; 95% CI: 1.14-3.45). Similar, quartile analyses showed a greater risk of islet autoimmunity especially for the third quartile (Q3: 5.2-11.6 nW/cm2/sr) of LAN compared to the lowest quartile (Q1: 0.0-2.0 nW/cm2/sr; OR: 1.71; 95% CI: 1.19-2.47). Conclusion: Exposure to LAN might be a further environmental risk factor contributing to higher BMI and islet autoimmunity in children. Keywords: Light at night, light pollution, body mass index, islet autoimmunity

BackgroundThere is no longer a question as to whether viruses contribute to the pathogenesis of type 1 diabetes (T1D), as we recently reviewed, but rather how they contribute and, in particular, the role of viral diversity and evolution in the disease process. The recent finding of enterovirus (EV) capsid protein VP1 in pancreatic autopsy samples from the JDRF Network for Pancreatic Organ Donors with Diabetes (nPOD) supports earlier case series in which EVs (Coxsackievirus B, CVB)were isolated from pancreatic tissue and inoculated into human islets, causing functional impairment and β-cell death. The most interesting observation from the nPOD data is the patchy distribution of insulitis, with MHC class II hyper-expression on β-cells, which was co-located with viral protein. Indeed, it is well established that specific EV strains demonstrate β-cell tropism; we and others have shown that EVs infect and replicate in β-cells (Fig. 1), inducing inflammation, cytokine production and functional damage. There is also substantial epidemiological evidence that EVs have more than an occasional role in the disease; in our meta-analysis of >4000 cases, the odds ratio (OR) was ∼10 for EV infection at T1D onset vs controls, and OR∼4 for EV infection and islet autoimmunity (IA). While the genetic and immunological components of disease are not in question, the capacity for EVs to evolve is completely unexplored in the pathogenesis of human T1D. This information is critical for development of EV vaccines to prevent T1D, which is currently underway.HYPOTHESIS-1: Variation in the capsid and non-structural regions of the EV genome determine β-cell tropismAIM-1: To characterize human EV isolates in cases of IA and T1D using NGS – to identify regions in the EV genome associated with β-cell tropismHYPOTHESIS-2: Increased genetic diversity of EVs at the full genome level is associated with seroconversion to IA and T1DAIM-2: To examine the evolutionary dynamics and genetic diversity of EVs at the full genome level from children with IA and T1D, and to quantify the extent of intra-host evolution of EVs within an infection and the kinetics of intra-host virus evolution between infections.Research Plan and MethodsEV prototype strains and clinical isolates from children with AI and T1D that infect and replicate in β-cells. Cohorts: Viruses in Genetically at Risk (VIGR), Environmental Determinants of Islet Autoimmunity (ENDIA), and children at onset of T1D (EET1DPP2). Samples collected at the study visit or at diagnosis of T1D. RNA extracted with QIAamp viral RNA, quantitative RT-PCR were performed on the Roche LC-480 platform. NGS: Full-length EV genomes were amplified as a single 7.4 kb fragment by RT-PCR, and NGS performed using the Illumina MiSeq sequencer. Phylogenetic analysis of the full-length viral consensus sequences performed using the neighbour joining and maximum likelihood method. Statistical analysis with R software. Trees were constructed from alignment of complete genome sequences by using best-fit models and visualised using FigTree (Figure2). Comparisons were performed with Viral Epidemiology Signature Pattern Analysis (VESPA).Results and DiscussionTwo of the EVs from IA+ cases had an N to S amino acid (AA) substitution within the 2C protein, which became dominant after 10 days passage in the islets. The 2C protein encodes for the viral helicase and lies just upstream of the viral region that shares significant homology with human GAD65. EV isolate from another IA+ case has 5 AA differences within the capsid protein VP4 at residues 3, 16, 18, 50 and 61 (Figure3). VP4 is an internal capsid protein linked to the genome. VP4 has been shown in vitro to be a target of human antibodies that enhance CVB induced synthesis of interferon α (IFN-α). CVB-induced IFN-α plays a role in the initiation and/or maintenance of chronic CVB infection in human islets. Antibodies directed towards the region 11–30 of the VP4 capsid enhance infection of peripheral blood cells with CVB4 in vitro. Therefore, our preliminary data suggest VP4 may be a determinant of ‘diabetogenicity’. Our novel NGS data will contribute to vaccine development from a global perspective. Our ultimate goal is to reduce the future burden of T1D.

Both genetic and environmental factors are implicated in type 1 diabetes (T1D). Because environmental factors can trigger epigenetic changes, we hypothesized that variations in histone post-translational modifications (PTMs) at the promoter/enhancer regions of T1D susceptible genes may be associated with T1D. We therefore evaluated histone PTM variations at known T1D susceptible genes in blood cells from T1D patients versus healthy nondiabetic controls, and explored their connections to T1D. We used the chromatin immunoprecipitation-linked to microarray approach to profile key histone PTMs, including H3-lysine 4 trimethylation (H3K4me3), H3K27me3, H3K9me3, H3K9 acetylation (H3K9Ac), and H4K16Ac at genes within the T1D susceptible loci in lymphocytes, and H3K4me3, H3K9me2, H3K9Ac, and H4K16Ac at the insulin-dependent diabetes mellitus 1 region in monocytes of T1D patients and healthy controls separately. We screened for potential variations in histone PTMs using computational methods to compare datasets from T1D and controls. Interestingly, we observed marked variations in H3K9Ac levels at the upstream regions of HLA-DRB1 and HLA-DQB1 within the insulin-dependent diabetes mellitus 1 locus in T1D monocytes relative to controls. Additional experiments with THP-1 monocytes demonstrated increased expression of HLA-DRB1 and HLA-DQB1 in response to interferon-γ and TNF-α treatment that were accompanied by changes in H3K9Ac at the same promoter regions as that seen in the patient monocytes. These results suggest that the H3K9Ac status of HLA-DRB1 and HLA-DQB1, two genes highly associated with T1D, may be relevant to their regulation and transcriptional response toward external stimuli. Thus, the promoter/enhancer architecture and chromatin status of key susceptible loci could be important determinants in their functional association to T1D susceptibility.

Genome-wide association studies (GWAS) have identified more than 40 T1D loci associated with type 1 diabetes (T1D). How these polymorphisms interact with environmental factors to trigger T1D is unknown, but recent evidence suggests that epigenetic mechanisms could play a role. To begin to explore the contribution of epigenetics to T1D, we have examined DNA methylation in a pilot study of whole blood cells DNA from 10 young T1D patients and 10 young controls. Through the study of >900 000 CG loci across a diverse set of functionally relevant genomic regions using a custom DNA methylation array, we identified 250 T1D-differentially methylated region (DMR) at p < 0.05 and 1 DMR using next a permutation-based multiple testing correction method. This DMR is located in an imprinted region previously associated with T1D on the chromosome 14 that encompasses RTL1 gene and 2 miRNAs (miR136 and miR432). Using pyrosequencing-based bisulfite PCR, we replicated this association in a different and larger set of T1D patients and controls. DNA methylation at this DMR was inversely correlated with RTL1 gene expression and positively correlated with miR136 expression in human placentas. The DMR identified in this study presents suggestive evidence for altered methylation site in T1D and provide a promising new candidate gene. RTL1 is essential for placental permeability function in the mid-to-late fetal stages. We suggest that hypo-methylation could increase the fetal exposure to environmental factors in T1D susceptibility.

Background/aim Exposure to the intrauterine hyperglycemic environment has been suggested to increase the offspring’s later overweight and metabolic risk, but conclusive evidence for pregnancies affected by maternal type 1 diabetes (T1D) is still lacking. Further, it is unknown whether changes in the offspring’s metabolome are in the potential pathway. Methods We analysed data from 610 and 2169 offspring having a first-degree relative with T1D from the TEENDIAB and BABYDIAB/BABYDIET cohorts, respectively. Associations of maternal T1D with anthropometric and metabolic outcomes in the offspring, assessed longitudinally at 0.3–18 years of age, were investigated using mixed regression models. Non-targeted metabolomics measurements were carried out in 500 fasting serum samples from TEENDIAB and associated with maternal T1D and offspring overweight. Results Offspring of T1D mothers had a higher body mass index standard deviation score (SDS) and an increased risk for overweight than offspring of non-diabetic mothers (e.g. odds ratio for overweight in TEENDIAB: 2.40 (95% confidence interval: 1.41; 4.06)). Further, waist circumference SDS, fasting levels of insulin and C-peptide, as well as insulin resistance and abdominal obesity were significantly increased in offspring of T1D mothers, even when adjusted for potential confounders and birth weight. Metabolite patterns related to androgenic steroids and branched-chain amino acids were found to be associated with offspring’s overweight, but no significant associations were observed between maternal T1D and metabolite concentrations in the offspring. Conclusion Maternal T1D is associated with offspring’s overweight and metabolic health in later life, but this is not likely due to alterations in the offspring’s metabolome.

After completing this article, readers should be able to: 1. Outline the current concepts of the pathogenesis of type 1 diabetes (T1D) with regard to dietary triggers and genetic susceptibility. 2. Discuss the evidence, both epidemiologic and that derived from studies of animal models, that supports the association between infant feeding practices and T1D. 3. Describe the roles for intestinal immunity and permeability in supporting the hypothetical model of cow milk protein mediation of T1D autoimmunity. 4. Delineate the goals and rationale for prospective clinical trials evaluating neonatal nutrition and the development of T1D. 5. List the putative dietary modulators of T1D. Type 1 diabetes (T1D), a disease that has unacceptably high morbidity and mortality, is increasing in incidence, prompting the redoubling of efforts toward its prevention. Progress toward prevention and cure relies on elucidation of the disease’s pathogenesis, which, to date, has remained poorly defined. The defining features of T1D, insulin deficiency and hyperglycemia, result from an immune-mediated destruction of insulin-secreting beta cells in the pancreatic islets. The loss of beta cell mass is believed to be gradual for most individuals, accounting for the sometimes prolonged asymptomatic periods of autoimmunity preceding overt diabetes (Fig. 1). Indeed, the chronic autoimmune nature of the disease is well established, as is the genetic predisposition. Specific associations with molecules of the human lymphocyte antigen (HLA) define both susceptibility to and protection from T1D. However, T1D is a polygenic disorder with more than 20 loci associated with susceptibility or resistance to the disease, of which the HLA may account for less than 50% of the genetic predisposition. Genetics clearly comprises a major component of the development of T1D, but the interaction between the environment and the immune system abnormalities is believed to weigh heavily in disease development. Indeed, trends in T1D incidence, both geographic and temporal, suggest a strong …

Differential DNA methylation with hyperglycemia is significantly associated with Type 2 Diabetes (T2D). Longtime extended exposure to high blood glucose levels can affect the epigenetic signatures in all organs. However, the relevance of the differential DNA methylation changes with hyperglycemia in blood with pancreatic islets remains unclear. We investigated differential DNA methylation in relation to glucose homeostasis based on the Oral Glucose Tolerance Test (OGTT) in a population-based cohort. We found a total of 382 differential methylation sites from blood DNA in hyperglycemia and type 2 diabetes subgroups using a longitudinal and cross-sectional approach. Among them, three CpG sites were overlapped; they were mapped to the MSI2 and CXXC4 genes. In a DNA methylation replication study done by pyrosequencing (n = 440), the CpG site of MSI2 were shown to have strong associations with the T2D group (p value = 2.20E-16). The differential methylation of MSI2 at chr17:55484635 was associated with diabetes-related traits, in particular with insulin sensitivity (QUICKI, p value = 2.20E-16) and resistance (HOMA-IR, p value = 1.177E-07). In human pancreatic islets, at the single-base resolution (using whole-genome bisulfite sequencing), the 292 CpG sites in the ±5kb at chr17:55484635 were found to be significantly hypo-methylated in donors with T2D (average decrease = 13.91%, 95% confidence interval (CI) = 4.18~ 17.06) as compared to controls, and methylation patterns differed by sex (-9.57%, CI = -16.76~ -6.89) and age (0.12%, CI = -11.17~ 3.77). Differential methylation of the MSI2 gene (chr17:55484635) in blood and islet cells is strongly related to hyperglycemia. Our findings suggest that epigenetic perturbation on the target site of MSI2 gene in circulating blood and pancreatic islets should represent or affect hyperglycemia.

Background/Aim of the study: Exposure to maternal diabetes is considered one of the most common in utero insults that can result in an increased risk of complications later in life with a permanent effect on offspring health. In this study, we aim to assess the level of risk associated with each type of maternal diabetes on obesity, glucose intolerance, cardiovascular diseases (CVD), and neurodevelopmental disorders in offspring. Methods: We conducted a systematic review of the literature utilizing PubMed for studies published between January 2007 and March 2022. Our search included human cohorts and case control studies following offspring exposed at least to two different types of maternal diabetes clearly identified during pregnancy. Collected outcomes included prevalence, incidence, odds ratio, hazard ratio and risk ratio. Results: Among 3579 published studies, 19 cohorts were eligible for inclusion in our review. The risks for overweight, obesity, type 2 diabetes (T2D), glucose intolerance, metabolic syndrome, and CVD were increased for all types of maternal diabetes during pregnancy. The risk of overweight or obesity in infancy and in young adults was similar between gestational diabetes mellitus (GDM) and type 1 diabetes (T1D). The risk for T2D or abnormal glucose tolerance was double for offspring from GDM mothers compared to offspring from T1D mothers. In contrast, the risk for T1D in offspring at any age until young adulthood was increased when mothers had T1D compared to GDM and T2D. The risk for CVD was similar for all types of maternal diabetes, but more significant results were seen in the occurrence of heart failure and hypertension among offspring from T2D mothers. The risk of autism spectrum disorders and attention deficit/hyperactivity disorders was mainly increased after in utero exposure to preexisting T1D, followed by T2D. Conclusions: Offspring of diabetic mothers are at increased risk for multiple adverse outcomes with the highest risk detected among offspring from T2D mothers. Future work warrants large multiethnic prospective cohort studies that aim to identify the risks associated with each type of maternal diabetes separately.