Home capillary sampling and screening for type 1 diabetes, celiac disease, and autoimmune thyroid disease in a Swedish general pediatric population: the TRIAD study.

Objective: To screen a general pediatric population for type 1 diabetes (T1D), celiac disease (CD), and autoimmune thyroid disease (AITD) after home capillary sampling. Methods: Swedish schoolchildren between 6-9 years and 13-16 years of age were invited to screening by taking a capillary sample at home. Samples were returned by mail and assessed for autoantibodies associated with T1D, CD, and AITD. Persistently autoantibody-positive children were referred for clinical follow-up. Results: Of 19,593 invited, 3,527 (18.0%) consented to participate and 2,315/3,527 (65.6%) returned a blood sample of sufficient volume. Hemolysis occurred in 830/2,301 (36.1%) samples. After exclusion of 42 children with previously known T1D, CD, or AITD, and two autoantibody-positive children who declined a confirmatory sample, 2,271/19,593 (11.6%) were included. 211/2,271 (9.3%) had persistent autoantibodies: 60/2,271 (2.6%) with T1D autoantibodies, 61/2,271 (2.7%) with CD autoantibodies, and 99/2,271 (4.4%) with AITD autoantibodies; 9/2,271 (0.4%) were autoantibody positive for ≥1 disease. After clinical follow-up, 3/2,271 (0.1%) were diagnosed with T1D, 26/2,271 (1.1%) with CD, and 6/2,271 (0.3%) with AITD. Children with a first-degree relative (FDR) with T1D, CD, and/or AITD, had higher occurrence of autoantibodies compared to children without an FDR (63/344, 18.3%, vs. 148/1,810, 8.2%) (p < 0.0001, OR 2.52, 95% CI 1.83-3.47), and higher occurrence of screening-detected diagnosis (14/344, 4.1%, vs. 21/1,810, 1.2%) (p < 0.0001, OR 3.61, 95% CI 1.82-7.18). Half of these children screened positive for another disease than the FDR. Conclusion: Screening for T1D, CD, and AITD by home capillary sampling in a Swedish general pediatric population detected autoimmunity in 9.3% and undiagnosed disease in 1.5%.

Elevated cathepsin S serum levels in new-onset type 1 diabetes and autoantibody-positive siblings.

Accumulating data suggest a role for the lysosomal protease cathepsin S (CTSS) in type 1 diabetes. Circulating CTSS is increased in type 1 diabetes; however, whether CTSS has protective or deleterious effects is unclear. The study's objectives were to examine the biomarker potential of CTSS in new-onset type 1 diabetes, and to investigate the expression and secretion of CTSS in human islets and ß cells. The CTSS level was analyzed in serum from children with new-onset type 1 diabetes and autoantibody-positive and -negative siblings by ELISA. The expression and secretion of CTSS were evaluated in isolated human islets and EndoC-ßH5 cells by real-time qPCR, immunoblotting, and ELISA. The CTSS serum level was elevated in children with new-onset type 1 diabetes and positively associated with autoantibody status in healthy siblings. Human islets and EndoC-ßH5 cells demonstrated induction and secretion of CTSS after exposure to pro-inflammatory cytokines, a model system of islet inflammation. Analysis of publicly available single-cell RNA sequencing data on human islets showed that elevated CTSS expression was exclusive for the ß cells in donors with type 1 diabetes as compared to non-diabetic donors. These findings suggest a potential of CTSS as a diagnostic biomarker in type 1 diabetes.

The INNODIA Type 1 Diabetes Natural History Study: a European cohort of newly diagnosed children, adolescents and adults.

AIMS/HYPOTHESIS: Type 1 diabetes is an heterogenous condition. Characterising factors explaining differences in an individual's clinical course and treatment response will have important clinical and research implications. Our aim was to explore type 1 diabetes heterogeneity, as assessed by clinical characteristics, autoantibodies, beta cell function and glycaemic outcomes, during the first 12 months from diagnosis, and how it relates to age at diagnosis. METHODS: Data were collected from the large INNODIA cohort of individuals (aged 1.0-45.0 years) newly diagnosed with type 1 diabetes, followed 3 monthly, to assess clinical characteristics, C-peptide, HbA1c and diabetes-associated antibodies, and their changes, during the first 12 months from diagnosis, across three age groups: <10 years; 10-17 years; and ≥18 years. RESULTS: The study population included 649 individuals (57.3% male; age 12.1±8.3 years), 96.9% of whom were positive for one or more diabetes-related antibodies. Baseline (IQR) fasting C-peptide was 242.0 (139.0-382.0) pmol/l (AUC 749.3 [466.2-1106.1] pmol/l × min), with levels increasing with age (p<0.001). Over time, C-peptide remained lower in participants aged <10 years but it declined in all age groups. In parallel, glucose levels progressively increased. Lower baseline fasting C-peptide, BMI SD score and presence of diabetic ketoacidosis at diagnosis were associated with lower stimulated C-peptide over time. HbA1c decreased during the first 3 months (p<0.001), whereas insulin requirement increased from 3 months post diagnosis (p<0.001). CONCLUSIONS/INTERPRETATION: In this large cohort with newly diagnosed type 1 diabetes, we identified age-related differences in clinical and biochemical variables. Of note, C-peptide was lower in younger children but there were no main age differences in its rate of decline.

Influence of sphingolipid enzymes on blood glucose levels, development of diabetes, and involvement of pericytes.

AIMS: Sulfatide is a chaperone for insulin manufacturing in beta cells. Here we explore whether the blood glucose values normally could be associated with this sphingolipid and especially two of its building enzymes CERS2 and CERS6. Both T1D and T2D have low blood sulfatide levels, and insulin resistance on beta cells at clinical diagnosis. Furthermore, we examined islet pericytes for sulfatide, and beta-cell receptors for GLP-1, both of which are related to the insulin production. MATERIALS AND METHODS: We examined mRNA levels in islets from the DiViD and nPOD studies, performed genetic association analyses, and histologically investigated pericytes in the islets for sulfatide. RESULTS: Polymorphisms of the gene encoding the CERS6 enzyme responsible for synthesising dihydroceramide, a precursor to sulfatide, are associated with random blood glucose values in non-diabetic persons. This fits well with our finding of sulfatide in pericytes in the islets, which regulates the capillary blood flow in the islets of Langerhans, which is important for oxygen supply to insulin production. In the islets of newly diagnosed T1D patients, we observed low levels of GLP-1 receptors; this may explain the insulin resistance in their beta cells and their low insulin production. In T2D patients, we identified associated polymorphisms in both CERS2 and CERS6. CONCLUSIONS: Here, we describe several polymorphisms in sulfatide enzymes related to blood glucose levels and HbA1c in non-diabetic individuals. Islet pericytes from such persons contain sulfatide. Furthermore, low insulin secretion in newly diagnosed T1D may be explained by beta-cell insulin resistance due to low levels of GLP-1 receptors.

Assisting the implementation of screening for type 1 diabetes by using artificial intelligence on publicly available data.

The type 1 diabetes community is coalescing around the benefits and advantages of early screening for disease risk. To be accepted by healthcare providers, regulatory authorities and payers, screening programmes need to show that the testing variables allow accurate risk prediction and that individualised risk-informed monitoring plans are established, as well as operational feasibility, cost-effectiveness and acceptance at population level. Artificial intelligence (AI) has the potential to contribute to solving these issues, starting with the identification and stratification of at-risk individuals. ASSET (AI for Sustainable Prevention of Autoimmunity in the Society; www.asset.healthcare ) is a public/private consortium that was established to contribute to research around screening for type 1 diabetes and particularly to how AI can drive the implementation of a precision medicine approach to disease prevention. ASSET will additionally focus on issues pertaining to operational implementation of screening. The authors of this article, researchers and clinicians active in the field of type 1 diabetes, met in an open forum to independently debate key issues around screening for type 1 diabetes and to advise ASSET. The potential use of AI in the analysis of longitudinal data from observational cohort studies to inform the design of improved, more individualised screening programmes was also discussed. A key issue was whether AI would allow the research community and industry to capitalise on large publicly available data repositories to design screening programmes that allow the early detection of individuals at high risk and enable clinical evaluation of preventive therapies. Overall, AI has the potential to revolutionise type 1 diabetes screening, in particular to help identify individuals who are at increased risk of disease and aid in the design of appropriate follow-up plans. We hope that this initiative will stimulate further research on this very timely topic.

Clinical care advice for monitoring of islet autoantibody positive individuals with presymptomatic type 1 diabetes.

BACKGROUND/AIM: Type 1 diabetes is an autoimmune disease that involves the development of autoantibodies against pancreatic islet beta-cell antigens, preceding clinical diagnosis by a period of preclinical disease activity. As screening activity to identify autoantibody-positive individuals increases, a rise in presymptomatic type 1 diabetes individuals seeking medical attention is expected. Current guidance on how to monitor these individuals in a safe but minimally invasive way is limited. This article aims to provide clinical guidance for monitoring individuals with presymptomatic type 1 diabetes to reduce the risk of diabetic ketoacidosis (DKA) at diagnosis. METHODS: Expert consensus was obtained from members of the Fr1da, GPPAD, and INNODIA consortia, three European diabetes research groups. The guidance covers both specialist and primary care follow-up strategies. RESULTS: The guidance outlines recommended monitoring approaches based on age, disease stage and clinical setting. Individuals with presymptomatic type 1 diabetes are best followed up in specialist care. For stage 1, biannual assessments of random plasma glucose and HbA1c are suggested for children, while annual assessments are recommended for adolescents and adults. For stage 2, 3-monthly clinic visits with additional home monitoring are advised. The value of repeat OGTT in stage 1 and the use of continuous glucose monitoring in stage 2 are discussed. Primary care is encouraged to monitor individuals who decline specialist care, following the guidance presented. CONCLUSIONS: As type 1 diabetes screening programs become more prevalent, effective monitoring strategies are essential to mitigate the risk of complications such as DKA. This guidance serves as a valuable resource for clinicians, providing practical recommendations tailored to an individual's age and disease stage, both within specialist and primary care settings.

A Gluten-Free Diet during Pregnancy and Early Life Increases Short Chain Fatty Acid-Producing Bacteria and Regulatory T Cells in Prediabetic NOD Mice.

The incidence of the autoimmune disease type 1 diabetes is increasing, likely caused by environmental factors. A gluten-free diet has previously been shown to ameliorate autoimmune diabetes in non-obese diabetic (NOD) mice and humans. Although the exact mechanisms are not understood, interventions influencing the intestinal microbiota early in life affect the risk of type 1 diabetes. Here, we characterize how NOD mice that are fed a gluten-free (GF) diet differ from NOD mice that are fed a gluten-containing standard (STD) diet in terms of their microbiota composition by 16S rRNA gene amplicon sequencing and pancreatic immune environment by real-time quantitative PCR at the prediabetic stage at 6 and 13 weeks of age. Gut microbiota analysis revealed highly distinct microbiota compositions in both the cecum and the colon of GF-fed mice compared with STD-fed mice. The microbiotas of the GF-fed mice were characterized by an increased Firmicutes/Bacteroidetes ratio, an increased abundance of short chain fatty acid (particularly butyrate)-producing bacteria, and a reduced abundance of Lactobacilli compared with STD mice. We found that the insulitis score in the GF mice was significantly reduced compared with the STD mice and that the markers for regulatory T cells and T helper 2 cells were upregulated in the pancreas of the GF mice. In conclusion, a GF diet during pre- and early post-natal life induces shifts in the cecal and colonic microbiota compatible with a less inflammatory environment, providing a likely mechanism for the protective effect of a GF diet in humans.

ß Cell and Autophagy: What Do We Know?

Pancreatic ß cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in ß cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy results in ß cell loss of function and apoptosis and, as a result, diabetes initiation and progress. It has been shown that in response to endoplasmic reticulum stress, inflammation, and high metabolic demands, autophagy affects ß cell function, insulin synthesis, and secretion. This review highlights recent evidence regarding how autophagy can affect ß cells' fate in the pathogenesis of diabetes. Furthermore, we discuss the role of important intrinsic and extrinsic autophagy modulators, which can lead to ß cell failure.

Characterization of the functional and transcriptomic effects of pro-inflammatory cytokines on human EndoC-ßH5 beta cells.

Objective: EndoC-ßH5 is a newly established human beta-cell model which may be superior to previous model systems. Exposure of beta cells to pro-inflammatory cytokines is widely used when studying immune-mediated beta-cell failure in type 1 diabetes. We therefore performed an in-depth characterization of the effects of cytokines on EndoC-ßH5 cells. Methods: The sensitivity profile of EndoC-ßH5 cells to the toxic effects of interleukin-1ß (IL-1ß), interferon γ (IFNγ) and tumor necrosis factor-α (TNFα) was examined in titration and time-course experiments. Cell death was evaluated by caspase-3/7 activity, cytotoxicity, viability, TUNEL assay and immunoblotting. Activation of signaling pathways and major histocompatibility complex (MHC)-I expression were examined by immunoblotting, immunofluorescence, and real-time quantitative PCR (qPCR). Insulin and chemokine secretion were measured by ELISA and Meso Scale Discovery multiplexing electrochemiluminescence, respectively. Mitochondrial function was evaluated by extracellular flux technology. Global gene expression was characterized by stranded RNA sequencing. Results: Cytokines increased caspase-3/7 activity and cytotoxicity in EndoC-ßH5 cells in a time- and dose-dependent manner. The proapoptotic effect of cytokines was primarily driven by IFNγ signal transduction. Cytokine exposure induced MHC-I expression and chemokine production and secretion. Further, cytokines caused impaired mitochondrial function and diminished glucose-stimulated insulin secretion. Finally, we report significant changes to the EndoC-ßH5 transcriptome including upregulation of the human leukocyte antigen (HLA) genes, endoplasmic reticulum stress markers, and non-coding RNAs, in response to cytokines. Among the differentially expressed genes were several type 1 diabetes risk genes. Conclusion: Our study provides detailed insight into the functional and transcriptomic effects of cytokines on EndoC-ßH5 cells. This information should be useful for future studies using this novel beta-cell model.

Integrated glycomics and genetics analyses reveal a potential role for N-glycosylation of plasma proteins and IgGs, as well as the complement system, in the development of type 1 diabetes.

AIMS/HYPOTHESIS: We previously demonstrated that N-glycosylation of plasma proteins and IgGs is different in children with recent-onset type 1 diabetes compared with their healthy siblings. To search for genetic variants contributing to these changes, we undertook a genetic association study of the plasma protein and IgG N-glycome in type 1 diabetes. METHODS: A total of 1105 recent-onset type 1 diabetes patients from the Danish Registry of Childhood and Adolescent Diabetes were genotyped at 183,546 genetic markers, testing these for genetic association with variable levels of 24 IgG and 39 plasma protein N-glycan traits. In the follow-up study, significant associations were validated in 455 samples. RESULTS: This study confirmed previously known plasma protein and/or IgG N-glycosylation loci (candidate genes MGAT3, MGAT5 and ST6GAL1, encoding beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase, alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase and ST6 beta-galactoside alpha-2,6-sialyltransferase 1 gene, respectively) and identified novel associations that were not previously reported for the general European population. First, novel genetic associations of IgG-bound glycans were found with SNPs on chromosome 22 residing in two genomic intervals close to candidate gene MGAT3; these include core fucosylated digalactosylated disialylated IgG N-glycan with bisecting N-acetylglucosamine (GlcNAc) (pdiscovery=7.65 × 10-12, preplication=8.33 × 10-6 for the top associated SNP rs5757680) and core fucosylated digalactosylated glycan with bisecting GlcNAc (pdiscovery=2.88 × 10-10, preplication=3.03 × 10-3 for the top associated SNP rs137702). The most significant genetic associations of IgG-bound glycans were those with MGAT3. Second, two SNPs in high linkage disequilibrium (missense rs1047286 and synonymous rs2230203) located on chromosome 19 within the protein coding region of the complement C3 gene (C3) showed association with the oligomannose plasma protein N-glycan (pdiscovery=2.43 × 10-11, preplication=8.66 × 10-4 for the top associated SNP rs1047286). CONCLUSIONS/INTERPRETATION: This study identified novel genetic associations driving the distinct N-glycosylation of plasma proteins and IgGs identified previously at type 1 diabetes onset. Our results highlight the importance of further exploring the potential role of N-glycosylation and its influence on complement activation and type 1 diabetes susceptibility.

Low-grade inflammation in type 2 diabetes: a cross-sectional study from a Danish diabetes outpatient clinic.

OBJECTIVES: To investigate low-grade inflammation in type 2 diabetes and explore associations to clinical aspects as well as microvascular and macrovascular complications. DESIGN: Cross-sectional analysis. SETTING: The outpatient diabetes clinic at the Department of Endocrinology at Aalborg University Hospital, Denmark. PARTICIPANTS: 100 participants with type 2 diabetes confirmed by a haemoglobin A1c (HbA1c)≥6.5% for a minimum of 1 year and 21 healthy controls. OUTCOME MEASURES: Serum levels of 27 inflammation-related biomarkers measured by immunoassay. Associations with microvascular and macrovascular complications, body weight, glycaemic control, medication and sex were investigated in the diabetes cohort. RESULTS: Serum levels of tumour necrosis factor (TNF)-α and eotaxin were elevated in type 2 diabetes (p<0.05), while interleukin (IL)-7 was decreased (p<0.001). IL-12/IL-23p40, IL-15, macrophage-derived chemokine (MDC) and C reactive protein (CRP) levels were increased with body weight (p<0.05), while eotaxin and TNF-α were increased with elevated HbA1c levels (p<0.04). Dipeptidyl peptidase-4 inhibitor therapy was associated with lower levels of induced protein-10, MDC and thymus and activation regulated chemokine (p<0.02), while females had higher levels of MDC (p=0.027). Individuals with ≥3 diabetic complications had elevated levels of IL-6, IL-10, IL-12/IL-23p40, IL-15 and CRP compared with those with ≤3 (p<0.05). CONCLUSION: The level of low-grade inflammation in type 2 diabetes is associated with obesity, glycaemic regulation, therapeutical management, sex and complications. Our results underline the importance of addressing inflammatory issues in type 2 diabetes, as these may predispose for crippling comorbidities.

Pro-Inflammatory Cytokines Promote the Transcription of Circular RNAs in Human Pancreatic ß Cells.

Circular RNAs (circRNAs) have recently been implicated in impaired ß-cell function in diabetes. Using microarray-based profiling of circRNAs in human EndoC-ßH1 cells treated with pro-inflammatory cytokines, this study aimed to investigate the expression and possible regulatory roles of circRNAs in human ß cells. We identified ~5000 ß-cell-expressed circRNAs, of which 84 were differentially expressed (DE) after cytokine exposure. Pathway analysis of the host genes of the DE circRNAs revealed the enrichment of cytokine signaling pathways, indicative of circRNA transcription from inflammatory genes in response to cytokines. Multiple binding sites for ß-cell-enriched microRNAs and RNA-binding proteins were observed for the highly upregulated circRNAs, supporting their function as 'sponges' or 'decoys'. We also present evidence for circRNA sequence conservation in multiple species, the presence of cytokine-induced regulatory elements, and putative protein-coding potential for the DE circRNAs. This study highlights the complex regulatory potential of circRNAs, which may play a crucial role during immune-mediated ß-cell destruction in type 1 diabetes.

PDE12 in type 1 diabetes.

Type 1 diabetes (T1D) incidence is increased after COVID-19 infection in children under 18 years of age. Interferon-α-activated oligoadenylate synthetase and downstream RNAseL activation degrade pathogen RNA, but can also damage host RNA when RNAseL activity is poorly regulated. One such regulator is PDE12 which degrades 2'-5' oligoadenylate units, thereby decreasing RNAseL activity. We analyzed PDE12 expression in islets from non-diabetic donors, individuals with newly (median disease duration 35 days) and recently (5 years) diagnosed T1D, and individuals with type 2 diabetes (T2D). We also analyzed PDE12 single-nucleotide polymorphisms (SNPs) relative to T1D incidence. PDE12 expression was decreased in individuals with recently diagnosed T1D, in three of five individuals with newly diagnosed T1D, but not in individuals with T2D. Two rare PDE12 SNPs were found to have odds ratios of 1.80 and 1.74 for T1D development. We discuss whether decreased PDE12 expression after COVID-19 infection might be part of the up to 2.5-fold increase in T1D incidence.

High-Throughput Human Complement C3 N-Glycoprofiling Identifies Markers of Early Onset Type 1 Diabetes Mellitus in Children.

Recently, it was shown that children at the onset of type 1 diabetes (T1D) have a higher proportion of oligomannose glycans in their total plasma protein N-glycome compared to their healthy siblings. The most abundant complement component, glycoprotein C3, contains two N-glycosylation sites occupied exclusively by this type of glycans. Furthermore, complement system, as well as C3, was previously associated with T1D. It is also known that changes in glycosylation can modulate inflammatory responses, so our aim was to characterize the glycosylation profile of C3 in T1D. For this purpose, we developed a novel high-throughput workflow for human C3 concanavalin A lectin affinity enrichment and subsequent LC-MS glycopeptide analysis which enables protein-specific N-glycosylation profiling. From the Danish Childhood Diabetes Register, plasma samples of 61 children/adolescents newly diagnosed with T1D and 84 of their unaffected siblings were C3 N-glycoprofiled. Significant changes of C3 N-glycan profiles were found. T1D was associated with an increase in the proportion of unprocessed glycan structures with more mannose units. A regression model including C3 N-glycans showed notable discriminative power between children with early onset T1D and their healthy siblings with area under curve of 0.879. This study confirmed our previous findings of plasma high-mannose glycan changes in a cohort of recent onset T1D cases, suggesting the involvement of C3 N-glycome in T1D development. Our C3 glycan-based discriminative model could be valuable in assessment of T1D risk in children.

The effect of saffron supplementation on glycemic parameters: An overview of systematic reviews.

Due to the widespread use of herbal medicine and evidence pointing to the health benefits of saffron supplementation, this review was performed to evaluate the effects of saffron supplementation on glycemic parameters and lipid profiles based on previous reviews. Relevant articles were retrieved from various databases, which included PubMed, Scopus, ProQuest, Web of Science, Embase, and Cochrane until 2020, with no date restrictions. The quality of the included reviews was assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist. Finally, of 877 obtained articles, eight reviews meeting the inclusion criteria were included for analysis. Among the eight included reviews, seven articles were meta-analyses. In addition, one review had an average quality while seven had a good quality. A narrative description of the included reviews was performed, while a network meta-analysis was not conducted. A brief review of the results was reported according to the weighted mean difference and mean difference. Seven included reviews assessed the effects of saffron or crocin supplementation on glycemic parameters, and six examined these effects on lipid profile parameters. Almost half of the articles reported significant effects of these supplements on glycemic parameters and lipid profiles. Taken together, results suggest that saffron supplementation may improve glycemic and lipid profile parameters; however, further high-quality studies are needed to confirm the clinical efficacy of saffron on glycemic parameters and lipid profiles.

Differentially Expressed miRNAs in Ulcerative Colitis and Crohn's Disease.

Differential microRNA (miRNA or miR) regulation is linked to the development and progress of many diseases, including inflammatory bowel disease (IBD). It is well-established that miRNAs are involved in the differentiation, maturation, and functional control of immune cells. miRNAs modulate inflammatory cascades and affect the extracellular matrix, tight junctions, cellular hemostasis, and microbiota. This review summarizes current knowledge of differentially expressed miRNAs in mucosal tissues and peripheral blood of patients with ulcerative colitis and Crohn's disease. We combined comprehensive literature curation with computational meta-analysis of publicly available high-throughput datasets to obtain a consensus set of miRNAs consistently differentially expressed in mucosal tissues. We further describe the role of the most relevant differentially expressed miRNAs in IBD, extract their potential targets involved in IBD, and highlight their diagnostic and therapeutic potential for future investigations.

The metabolic syndrome is frequent in children and adolescents with type 1 diabetes compared to healthy controls.

OBJECTIVE: There is a rise in overweight and obesity among children and adolescents with type 1 diabetes (T1D) in parallel with the rise in the metabolic syndrome (MetS) among children and adolescents. The aim of the study was to describe the prevalence and characteristics of MetS in children and adolescents with T1D compared to their healthy counterparts. RESEARCH DESIGN AND METHODS: The study includes two Danish cohorts; (i) the Copenhagen cross sectional cohort 2016 of 277 children and adolescents with T1D that attend the pediatric outpatient clinic at a large hospital in greater Copenhagen and (ii) the CHAMPS-study DK which is a population-based cohort study of Danish children and adolescents (control cohort). Participants were categorized to have MetS if at least two of the following criteria were met: (i) systolic and/or diastolic blood pressure ≥ 90th percentile, (ii) waist circumference ≥90th percentile, and (iii) triglyceride ≥90th percentile and/or HDL ≤10th percentile. RESULTS: The prevalence of children with Mets in the T1D cohort was higher than in the control cohort (p = 0.002). Moreover, participants with T1D had MetS at a lower level of BMI (p < 0.001) and waist circumference (p < 0.001) than participants with MetS from the control cohort (z-scores = 0.90 and 1.51). Participants with MetS were younger than the other T1D participants (median 12.8 [9.9,14.8] vs. median 14.6 [11.2,16.9] years, p = 0.006). CONCLUSIONS: Children and adolescents with T1D have an increased risk of MetS compared to healthy controls and clinicians and caretakers should consider early prevention and health promotion strategies.

Anti-diabetic potential of Urtica Dioica: current knowledge and future direction.

Aim: This review summarizes studies on the anti-diabetic effect of Urtica Dioica (UD) in Type-2-diabetes. Materials and methods: We studied worldwide traditional medicines, old texts, and published literature for anti-diabetic effect of UD. Electronic databases comprising PubMed, Web of Science, Science Direct, Scopus and Google Scholar were searched to collect articles published between 1990 and 2021 years. Results: Our literature investigation suggests UD as a glucose lowering, blood lipid regulating, anti-inflammatory and anti-oxidation plant. Conclusions: UD's anti-diabetic properties make it potential traditional therapeutics for lowering the clinical manifestations of T2DM through affecting hyperglycemia and therefore suggest it as a proper medication with no or limited side effects.

Reference serum percentile values of adiponectin, leptin, and adiponectin/leptin ratio in healthy Danish children and adolescents.

The adipokines adiponectin and leptin play key roles in human metabolic regulation and have gained great attention as biomarkers for various metabolic pathologies. Though, pediatric reference values are few and needed. This study aims to establish age- and sex-specific adipokine reference percentiles based on healthy Danish school children. Further, it elucidates sex-specific differences in associations between z-scores of examined adipokines and metabolic variables. Serum adiponectin and serum leptin from 853 observations of healthy Danish schoolchildren aged 8-17 years (median 10.0) were quantified by immunoassays. Age- and sex-specific adipokine reference percentiles were calculated cross-sectionally using the LMS method, and adipokine z-scores were calculated from the fitted model. Multiple linear regression models were used to examine sex-specific differences in associations between adipokine z-scores and various metabolic variables. Girls had a higher median value of adiponectin (11.31 vs. 10.65 µg/mL, p < .001) and leptin (2.30 vs. 1.00 ng/mL, p < .001) and a lower median value of adiponectin/leptin ratio (4.64 vs. 10.76, p < .001) compared to boys. Sex-specific differences were found in associations between adiponectin z-score and HDL (p = .010), between leptin z-score and waist circumference z-score (p = .027) and LDL (p = .048), and between adiponectin/leptin ratio z-scores and waist circumference z-score (p = .044) and LDL (p = .040). Reference percentiles of adiponectin, leptin, and adiponectin/leptin ratio are presented in this paper. To our knowledge, this study is the first to demonstrate sex-specific differences in associations between adipokine z-scores and waist circumference z-score and lipids, respectively in healthy children and adolescents.

Children at onset of type 1 diabetes show altered N-glycosylation of plasma proteins and IgG.

AIMS/HYPOTHESIS: Individual variation in plasma N-glycosylation has mainly been studied in the context of diabetes complications, and its role in type 1 diabetes onset is largely unknown. Our aims were to undertake a detailed characterisation of the plasma and IgG N-glycomes in patients with recent onset type 1 diabetes, and to evaluate their discriminative potential in risk assessment. METHODS: In the first part of the study, plasma and IgG N-glycans were chromatographically analysed in a study population from the DanDiabKids registry, comprising 1917 children and adolescents (0.6-19.1 years) who were newly diagnosed with type 1 diabetes. A follow-up study compared the results for 188 of these participants with those for their 244 unaffected siblings. Correlation of N-glycan abundance with the levels and number of various autoantibodies (against IA-2, GAD, ZnT8R, ZnT8W), as well as with sex and age at diagnosis, were estimated by using general linear modelling. A disease predictive model was built using logistic mixed-model elastic net regression, and evaluated using a 10-fold cross-validation. RESULTS: Our study showed that onset of type 1 diabetes was associated with an increase in the proportion of plasma and IgG high-mannose and bisecting GlcNAc structures, a decrease in monogalactosylation, and an increase in IgG disialylation. ZnT8R autoantibody levels were associated with higher IgG digalactosylated glycan with bisecting GlcNAc. Finally, an increase in the number of autoantibodies (which is a better predictor of progression to overt diabetes than the level of any individual antibody) was accompanied by a decrease in the proportions of some of the highly branched plasma N-glycans. Models including age, sex and N-glycans yielded notable discriminative power between children with type 1 diabetes and their healthy siblings, with AUCs of 0.915 and 0.869 for addition of plasma and IgG N-glycans, respectively. CONCLUSIONS/INTERPRETATION: We defined N-glycan changes accompanying onset of type 1 diabetes, and developed a predictive model based on N-glycan profiles that could have valuable potential in risk assessment. Increasing the power of tests to identify individuals at risk of disease development would be a considerable asset for type 1 diabetes prevention trials.