Publications by authors named "Marian Rewers"

343 Publications

Characteristics of children diagnosed with type 1 diabetes before vs after 6 years of age in the TEDDY cohort study.

Diabetologia 2021 Jul 22. Epub 2021 Jul 22.

National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, MD, USA.

Aims/hypothesis: Prognostic factors and characteristics of children diagnosed with type 1 diabetes before 6 years of age were compared with those diagnosed at 6-13 years of age in the TEDDY study.

Methods: Genetically high-risk children (n = 8502) were followed from birth for a median of 9.9 years; 328 (3.9%) were diagnosed with type 1 diabetes. Cox proportional hazard model was used to assess the association of prognostic factors with the risk of type 1 diabetes in the two age groups.

Results: Children in the younger group tended to develop autoantibodies earlier than those in the older group did (mean age 1.5 vs 3.5 years), especially insulin autoantibodies (IAA), which developed earlier than GAD autoantibodies (GADA). Children in the younger group also progressed to diabetes more rapidly than the children in the older group did (mean duration 1.9 vs 5.4 years). Children with autoantibodies first appearing against insulinoma antigen-2 (IA-2A) were found only in the older group. The significant diabetes risk associated with the country of origin in the younger group was no longer significant in the older group. Conversely, the diabetes risk associated with HLA genotypes was statistically significant also in the older group. Initial seroconversion after and before 2 years of age was associated with decreased risk for diabetes diagnosis in children positive for multiple autoantibodies, but the diabetes risk did not decrease further with increasing age if initial seroconversion occurred after age 2. Diabetes risk associated with the minor alleles of rs1004446 (INS) was decreased in both the younger and older groups compared with other genotypes (HR 0.67). Diabetes risk was significantly increased with the minor alleles of rs2476601 (PTPN22) (HR 2.04 and 1.72), rs428595 (PPIL2) (HR 2.13 and 2.10), rs113306148 (PLEKHA1) (HR 2.34 and 2.21) and rs73043122 (RNASET2) (HR 2.31 and 2.54) (HR values represent the younger and older groups, respectively).

Conclusions/interpretations: Diabetes at an early age is likely to be preceded by IAA autoantibodies and is a more aggressive form of the disease. Among older children, once multiple autoantibodies have been observed there does not seem to be any association between progression to diabetes and the age of the child or family history.

Trial Registration: ClinicalTrials.gov identifier: NCT00279318.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-021-05514-3DOI Listing
July 2021

Improving clinical utility of GAD65 autoantibodies by electrochemiluminescence assay and clinical phenotype when identifying autoimmune adult-onset diabetes.

Diabetologia 2021 Jul 16. Epub 2021 Jul 16.

Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Aims/hypothesis: It is important to differentiate the two major phenotypes of adult-onset diabetes, autoimmune type 1 diabetes and non-autoimmune type 2 diabetes, especially as type 1 diabetes presents in adulthood. Serum GAD65 autoantibodies (GADA) are the most sensitive biomarker for adult-onset autoimmune type 1 diabetes, but the clinical value of GADA by current standard radiobinding assays (RBA) remains questionable. The present study focused on the clinical utility of GADA differentiated by a new electrochemiluminescence (ECL) assay in patients with adult-onset diabetes.

Methods: Two cohorts were analysed including 771 diabetic participants, 30-70 years old, from the Action LADA study (n = 6156), and 2063 diabetic participants, 20-45 years old, from the Diabetes in Young Adults (DiYA) study. Clinical characteristics of participants, including requirement of early insulin treatment, BMI and development of multiple islet autoantibodies, were analysed according to the status of RBA-GADA and ECL-GADA, respectively, and compared between these two assays.

Results: GADA was the most prevalent and predominant autoantibody, >90% in both cohorts. GADA positivity by either RBA or ECL assay significantly discriminated clinical type 1 from type 2 diabetes. However, in both cohorts, participants with ECL-GADA positivity were more likely to require early insulin treatment, have multiple islet autoantibodies, and be less overweight (for all p < 0.0001). However, clinical phenotype, age at diagnosis and BMI independently improved positive predictive value (PPV) for the requirement of insulin treatment, even augmenting ECL-GADA. Participants with GADA detectable by RBA, but not confirmed by ECL, had a phenotype more similar to type 2 diabetes. These RBA-GADA positive individuals had lower affinity GADA compared with participants in which GADA was confirmed by ECL assay.

Conclusions/interpretation: Detection of GADA by ECL assay, given technical advantages over RBA-GADA, identified adult-onset diabetes patients at higher risk of requiring early insulin treatment, as did clinical phenotype, together allowing for more accurate clinical diagnosis and management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-021-05492-6DOI Listing
July 2021

Tutorial: best practices and considerations for mass-spectrometry-based protein biomarker discovery and validation.

Nat Protoc 2021 Jul 9. Epub 2021 Jul 9.

Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.

Mass-spectrometry-based proteomic analysis is a powerful approach for discovering new disease biomarkers. However, certain critical steps of study design such as cohort selection, evaluation of statistical power, sample blinding and randomization, and sample/data quality control are often neglected or underappreciated during experimental design and execution. This tutorial discusses important steps for designing and implementing a liquid-chromatography-mass-spectrometry-based biomarker discovery study. We describe the rationale, considerations and possible failures in each step of such studies, including experimental design, sample collection and processing, and data collection. We also provide guidance for major steps of data processing and final statistical analysis for meaningful biological interpretations along with highlights of several successful biomarker studies. The provided guidelines from study design to implementation to data interpretation serve as a reference for improving rigor and reproducibility of biomarker development studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41596-021-00566-6DOI Listing
July 2021

Islet Autoimmunity and HLA Markers of Presymptomatic and Clinical Type 1 Diabetes: Joint Analyses of Prospective Cohort Studies in Finland, Germany, Sweden, and the U.S.

Diabetes Care 2021 Jun 23. Epub 2021 Jun 23.

PEDEGO Research Unit, Department of Pediatrics, University of Oulu and Oulu University Hospital, Oulu, Finland.

Objective: To combine prospective cohort studies, by including HLA harmonization, and estimate risk of islet autoimmunity and progression to clinical diabetes.

Research Design And Methods: For prospective cohorts in Finland, Germany, Sweden, and the U.S., 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes have been followed. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years.

Results: In the infant-toddler cohort, 1,413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two, or three autoantibodies at seroconversion: 45% (95% CI 40-52), 85% (78-90), and 92% (85-97), respectively. Among those with a single autoantibody, status 2 years after seroconversion predicted diabetes risk: 12% (10-25) if reverting to autoantibody negative, 30% (20-40) if retaining a single autoantibody, and 82% (80-95) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single-autoantibody status. Their 15-year diabetes incidence for higher- versus lower-risk genotypes was 40% (28-50) vs. 12% (5-38). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies, ranging from 20% per year to 6% per year in children developing multipositivity in ≤2 years or >7.4 years, respectively.

Conclusions: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining a single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc20-1836DOI Listing
June 2021

Novel autoantibodies to the β-cell surface epitopes of ZnT8 in patients progressing to type-1 diabetes.

J Autoimmun 2021 Aug 12;122:102677. Epub 2021 Jun 12.

Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address:

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by autoimmune destruction of insulin-producing β-cells in pancreatic islets. Seroconversions to islet autoantibodies (IAbs) precede the disease onset by many years, but the role of humoral autoimmunity in the disease initiation and progression are unclear. In the present study, we identified a new IAb directed to the extracellular epitopes of ZnT8 (ZnT8ec) in newly diagnosed patients with T1D, and demonstrated immunofluorescence staining of the surface of human β-cells by autoantibodies to ZnT8ec (ZnT8ecA). With the assay specificity set on 99th percentile of 336 healthy controls, the ZnT8ecA positivity rate was 23.6% (74/313) in patients with T1D. Moreover, 30 children in a longitudinal follow up of clinical T1D development were selected for sequential expression of four major IAbs (IAA, GADA, IA-2A and ZnT8icA). Among them, 10 children were ZnT8ecA positive. Remarkably, ZnT8ecA was the earliest IAb to appear in all 10 children. The identification of ZnT8ec as a cell surface target of humoral autoimmunity in the earliest phase of IAb responses opens a new avenue of investigation into the role of IAbs in the development of β-cell autoimmunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaut.2021.102677DOI Listing
August 2021

Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes.

Nat Genet 2021 Jul 14;53(7):962-971. Epub 2021 Jun 14.

Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.

We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4 effector T cells. Using chromatin-accessibility profiling of CD4 T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-021-00880-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273124PMC
July 2021

Predicting Type 1 Diabetes Onset using Novel Survival Analysis with Biomarker Ontology.

AMIA Annu Symp Proc 2020 25;2020:727-736. Epub 2021 Jan 25.

IBM Research, NY, USA.

Type 1 diabetes (T1D) is a chronic autoimmune disease that affects about 1 in 300 children and up to 1 in 100 adults during their life-time. Improvements in early prediction of T1D onset may help prevent diagnosis for diabetic ketoacidosis, a serious complication often associated with a missed or delayed T1D diagnosis. In addition to genetic factors, progression to T1D is strongly associated with immunologic factors that can be measured during clinical visits. We developed a T1D-specific ontology that captures the dynamic patterns of these biomarkers and used it together with a survival model, RankSvx, proposed in our prior work. We applied this approach to a T1D dataset harmonized from three birth cohort studies from the United States, Finland, and Sweden. Results show that the dynamic biomarker patterns captured in the proposed ontology are able to improve prediction performance (in concordance index) by 5.3%, 3.3%, 2.8%, and 1.0% over baseline for 3, 6, 9, and 12 month duration windows, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075541PMC
June 2021

The oxylipin profile is associated with development of type 1 diabetes: the Diabetes Autoimmunity Study in the Young (DAISY).

Diabetologia 2021 Aug 24;64(8):1785-1794. Epub 2021 Apr 24.

University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Aims/hypothesis: Oxylipins are lipid mediators derived from polyunsaturated fatty acids. Some oxylipins are proinflammatory (e.g. those derived from arachidonic acid [ARA]), others are pro-resolving of inflammation (e.g. those derived from α-linolenic acid [ALA], docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) and others may be both (e.g. those derived from linoleic acid [LA]). The goal of this study was to examine whether oxylipins are associated with incident type 1 diabetes.

Methods: We conducted a nested case-control analysis in the Diabetes Autoimmunity Study in the Young (DAISY), a prospective cohort study of children at risk of type 1 diabetes. Plasma levels of 14 ARA-derived oxylipins, ten LA-derived oxylipins, six ALA-derived oxylipins, four DHA-derived oxylipins and two EPA-related oxylipins were measured by ultra-HPLC-MS/MS at multiple timepoints related to autoantibody seroconversion in 72 type 1 diabetes cases and 71 control participants, which were frequency matched on age at autoantibody seroconversion (of the case), ethnicity and sample availability. Linear mixed models were used to obtain an age-adjusted mean of each oxylipin prior to type 1 diabetes. Age-adjusted mean oxylipins were tested for association with type 1 diabetes using logistic regression, adjusting for the high risk HLA genotype HLA-DR3/4,DQB1*0302. We also performed principal component analysis of the oxylipins and tested principal components (PCs) for association with type 1 diabetes. Finally, to investigate potential critical timepoints, we examined the association of oxylipins measured before and after autoantibody seroconversion (of the cases) using PCs of the oxylipins at those visits.

Results: The ARA-related oxylipin 5-HETE was associated with increased type 1 diabetes risk. Five LA-related oxylipins, two ALA-related oxylipins and one DHA-related oxylipin were associated with decreased type 1 diabetes risk. A profile of elevated LA- and ALA-related oxylipins (PC1) was associated with decreased type 1 diabetes risk (OR 0.61; 95% CI 0.40, 0.94). A profile of elevated ARA-related oxylipins (PC2) was associated with increased diabetes risk (OR 1.53; 95% CI 1.03, 2.29). A critical timepoint analysis showed type 1 diabetes was associated with a high ARA-related oxylipin profile at post-autoantibody-seroconversion but not pre-seroconversion.

Conclusions/interpretation: The protective association of higher LA- and ALA-related oxylipins demonstrates the importance of both inflammation promotion and resolution in type 1 diabetes. Proinflammatory ARA-related oxylipins may play an important role once the autoimmune process has begun.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-021-05457-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249332PMC
August 2021

Phospholipid Levels at Seroconversion Are Associated With Resolution of Persistent Islet Autoimmunity: The Diabetes Autoimmunity Study in the Young.

Diabetes 2021 Apr 16. Epub 2021 Apr 16.

Department of Epidemiology, Colorado School of Public Health, Aurora, CO

Reversion of islet autoimmunity (IA) may point to mechanisms that prevent IA progression. We followed 199 individuals who developed IA during the Diabetes Autoimmunity Study in the Young. Untargeted metabolomics was performed in serum samples following IA. Cox proportional hazards models were used to test whether the metabolites (2,487) predicted IA reversion: two or more consecutive visits negative for all autoantibodies. We conducted a principal components analysis (PCA) of the top metabolites; |hazard ratio (HR) >1.25| and nominal < 0.01. Phosphatidylcholine (16:0_18:1(9Z)) was the strongest individual metabolite (HR per 1 SD 2.16, false discovery rate (FDR)-adjusted = 0.0037). Enrichment analysis identified four clusters (FDR < 0.10) characterized by an overabundance of sphingomyelin (d40:0), phosphatidylcholine (16:0_18:1(9Z)), phosphatidylcholine (30:0), and l-decanoylcarnitine. Overall, 63 metabolites met the criteria for inclusion in the PCA. PC1 (HR 1.4, < 0.0001), PC2 (HR 0.85, = 0.0185), and PC4 (HR 1.28, = 0.0103) were associated with IA reversion. Given the potential influence of diet on the metabolome, we investigated whether nutrients were correlated with PCs. We identified 20 nutrients that were correlated with the PCs ( < 0.05). Total sugar intake was the top nutrient. Overall, we identified an association between phosphatidylcholine, sphingomyelin, and carnitine levels and reversion of IA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db20-1251DOI Listing
April 2021

Associations of breastfeeding with childhood autoimmunity, allergies, and overweight: The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Am J Clin Nutr 2021 Jul;114(1):134-142

Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany; and Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, and Forschergruppe Diabetes eV, Neuherberg, Germany.

Background: Breastfeeding has beneficial effects on numerous health outcomes.

Objectives: We investigated whether breastfeeding duration is associated with the development of early childhood autoimmunity, allergies, or obesity in a multinational prospective birth cohort.

Methods: Infants with genetic susceptibility for type 1 diabetes (n = 8676) were followed for the development of autoantibodies to islet autoantigens or transglutaminase, allergies, and for anthropometric measurements to a median age of 8.3 y (IQR: 2.8-10.2 y). Information on breastfeeding was collected at 3 mo of age and prospectively thereafter. A propensity score for longer breastfeeding was calculated from the variables that were likely to influence any or exclusive breastfeeding. The risks of developing autoimmunity or allergy were assessed using Cox proportional hazards models, and the risk of obesity at 5.5 y of age was assessed using logistic regression with adjustment by the propensity score.

Results: Breastfeeding duration was not associated with a lower risk of either islet or transglutaminase autoimmunity (any breastfeeding >6 mo, adjusted HR: 1.07; 95% CI: 0.96, 1.19; exclusive breastfeeding >3 mo, adjusted HR: 1.03; 95% CI: 0.92, 1.15). Exclusive breastfeeding >3 mo was associated with a decreased risk of seasonal allergic rhinitis (adjusted HR: 0.70; 95% CI: 0.53, 0.92; P < 0.01). Any breastfeeding >6 mo and exclusive breastfeeding >3 mo were associated with decreased risk of obesity (adjusted OR: 0.62; 95% CI: 0.47, 0.81; P < 0.001; and adjusted OR: 0.68; 95% CI: 0.47, 0.95; P < 0.05, respectively).

Conclusions: Longer breastfeeding was not associated with a lower risk of childhood (islet or transglutaminase) autoimmunity in genetically at-risk children but was associated with decreased risk of seasonal allergic rhinitis and obesity at 5.5 y of age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcn/nqab065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246624PMC
July 2021

Transcriptional networks in at-risk individuals identify signatures of type 1 diabetes progression.

Sci Transl Med 2021 03;13(587)

Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge CB2 0AW, UK.

Type 1 diabetes (T1D) is a disease of insulin deficiency that results from autoimmune destruction of pancreatic islet β cells. The exact cause of T1D remains unknown, although asymptomatic islet autoimmunity lasting from weeks to years before diagnosis raises the possibility of intervention before the onset of clinical disease. The number, type, and titer of islet autoantibodies are associated with long-term disease risk but do not cause disease, and robust early predictors of individual progression to T1D onset remain elusive. The Environmental Determinants of Diabetes in the Young (TEDDY) consortium is a prospective cohort study aiming to determine genetic and environmental interactions causing T1D. Here, we analyzed longitudinal blood transcriptomes of 2013 samples from 400 individuals in the TEDDY study before both T1D and islet autoimmunity. We identified and interpreted age-associated gene expression changes in healthy infancy and age-independent changes tracking with progression to both T1D and islet autoimmunity, beginning before other evidence of islet autoimmunity was present. We combined multivariate longitudinal data in a Bayesian joint model to predict individual risk of T1D onset and validated the association of a natural killer cell signature with progression and the model's predictive performance on an additional 356 samples from 56 individuals in the independent Type 1 Diabetes Prediction and Prevention study. Together, our results indicate that T1D is characterized by early and longitudinal changes in gene expression, informing the immunopathology of disease progression and facilitating prediction of its course.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.abd5666DOI Listing
March 2021

Maternal food consumption during late pregnancy and offspring risk of islet autoimmunity and type 1 diabetes.

Diabetologia 2021 Jul 30;64(7):1604-1612. Epub 2021 Mar 30.

Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA.

Aims/hypothesis: We aimed to investigate the association between maternal consumption of gluten-containing foods and other selected foods during late pregnancy and offspring risk of islet autoimmunity (IA) and type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Methods: The TEDDY study recruited children at high genetic risk for type 1 diabetes at birth, and prospectively follows them for the development of IA and type 1 diabetes (n = 8556). A questionnaire on the mother's diet in late pregnancy was completed by 3-4 months postpartum. The maternal daily intake was estimated from a food frequency questionnaire for eight food groups: gluten-containing foods, non-gluten cereals, fresh milk, sour milk, cheese products, soy products, lean/medium-fat fish and fatty fish. For each food, we described the distribution of maternal intake among the four participating countries in the TEDDY study and tested the association of tertile of maternal food consumption with risk of IA and type 1 diabetes using forward selection time-to-event Cox regression.

Results: By 28 February 2019, 791 cases of IA and 328 cases of type 1 diabetes developed in TEDDY. There was no association between maternal late-pregnancy consumption of gluten-containing foods or any of the other selected foods and risk of IA, type 1 diabetes, insulin autoantibody-first IA or GAD autoantibody-first IA (all p ≥ 0.01). Maternal gluten-containing food consumption in late pregnancy was higher in Sweden (242 g/day), Germany (247 g/day) and Finland (221 g/day) than in the USA (199 g/day) (pairwise p < 0.05).

Conclusions/interpretation: Maternal food consumption during late pregnancy was not associated with offspring risk for IA or type 1 diabetes.

Trial Registration: ClinicalTrials.gov NCT00279318.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-021-05446-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187332PMC
July 2021

An Age-Related Exponential Decline in the Risk of Multiple Islet Autoantibody Seroconversion During Childhood.

Diabetes Care 2021 Feb 24. Epub 2021 Feb 24.

National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD.

Objective: Islet autoimmunity develops before clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for presymptomatic type 1 diabetes.

Research Design And Methods: The Environmental Determinants of Diabetes in the Young study prospectively monitored 8,556 genetically at-risk children at 3- to 6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models.

Results: The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% CI 3.8-4.7) at 7.5 months of age and declined to 1.1% (95% CI 0.8-1.3) at a landmark age of 6.25 years ( < 0.0001). Risk decline was slight or absent in single insulin and GAD autoantibody phenotypes. The influence of sex, , and other susceptibility genes on risk subsided with increasing age and was abrogated by age 6 years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5-7 years of age.

Conclusions: The risk of developing islet autoimmunity declines exponentially with age, and the influence of major genetic factors on this risk is limited to the first few years of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc20-2122DOI Listing
February 2021

Children's erythrocyte fatty acids are associated with the risk of islet autoimmunity.

Sci Rep 2021 Feb 11;11(1):3627. Epub 2021 Feb 11.

Health and Well-Being Promotion Unit, Public Health and Welfare Department, Finnish Institute for Health and Welfare, P.O. Box 30, 00271, Helsinki, Finland.

Our aim was to investigate the associations between erythrocyte fatty acids and the risk of islet autoimmunity in children. The Environmental Determinants of Diabetes in the Young Study (TEDDY) is a longitudinal cohort study of children at high genetic risk for type 1 diabetes (n = 8676) born between 2004 and 2010 in the U.S., Finland, Sweden, and Germany. A nested case-control design comprised 398 cases with islet autoimmunity and 1178 sero-negative controls matched for clinical site, family history, and gender. Fatty acids composition was measured in erythrocytes collected at the age of 3, 6, and 12 months and then annually up to 6 years of age. Conditional logistic regression models were adjusted for HLA risk genotype, ancestry, and weight z-score. Higher eicosapentaenoic and docosapentaenoic acid (n - 3 polyunsaturated fatty acids) levels during infancy and conjugated linoleic acid after infancy were associated with a lower risk of islet autoimmunity. Furthermore, higher levels of some even-chain saturated (SFA) and monounsaturated fatty acids (MUFA) were associated with increased risk. Fatty acid status in early life may signal the risk for islet autoimmunity, especially n - 3 fatty acids may be protective, while increased levels of some SFAs and MUFAs may precede islet autoimmunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-82200-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878879PMC
February 2021

Prevalence of SARS-CoV-2 Antibodies in Children and Adults with Type 1 Diabetes.

Diabetes Technol Ther 2021 07 25;23(7):517-521. Epub 2021 Feb 25.

Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

As diabetes is a risk factor for severe symptoms, hospitalization, and death with COVID-19 disease, we aimed to assess the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in children and adults with and without type 1 diabetes in Colorado during 2020. We developed a highly sensitive and specific test for antibodies against SARS-CoV-2 and measured the antibodies in children and adults with new-onset ( = 129) and established type 1 diabetes ( = 94) seen for routine diabetes care at our center between January and October 2020. The antibodies were also measured in 562 children and 102 adults from the general population of Colorado. The prevalence of SARS-CoV-2 antibodies in persons with new-onset type 1 diabetes (0.8%; 95% confidence interval 0.1%-4.2%) or those with established disease (4.3%; 1.7%-10.4%) did not differ from that in the general population children (2.8%; 1.8%-4.6%) or adults (3.9%; 1.5%-9.7%). In a subset of individuals with positive antibodies ( = 31), antibodies remained positive for up to 9 months, although the levels decreased starting 3 months after the infection ( = 0.007). From January to October 2020, the prevalence of SARS-CoV-2 antibodies were not different in children and adults with and without type 1 diabetes in Colorado. We found no evidence for increased prevalence of COVID-19 infections among youth with newly diagnosed type 1 diabetes. (COMIRB Protocol 20-1007).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/dia.2020.0609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252893PMC
July 2021

T-cell responses to hybrid insulin peptides prior to type 1 diabetes development.

Proc Natl Acad Sci U S A 2021 02;118(6)

Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO 80045

T-cell responses to posttranslationally modified self-antigens are associated with many autoimmune disorders. In type 1 diabetes, hybrid insulin peptides (HIPs) are implicated in the T-cell-mediated destruction of insulin-producing β-cells within pancreatic islets. The natural history of the disease is such that it allows for the study of T-cell reactivity prior to the onset of clinical symptoms. We hypothesized that CD4 T-cell responses to posttranslationally modified islet peptides precedes diabetes onset. In a cohort of genetically at-risk individuals, we measured longitudinal T-cell responses to native insulin and hybrid insulin peptides. Both proinflammatory (interferon-γ) and antiinflammatory (interluekin-10) cytokine responses to HIPs were more robust than those to native peptides, and the ratio of such responses oscillated between pro- and antiinflammatory over time. However, individuals who developed islet autoantibodies or progressed to clinical type 1 diabetes had predominantly inflammatory T-cell responses to HIPs. Additionally, several HIP T-cell responses correlated to worsening measurements of blood glucose, highlighting the relevance of T-cell responses to posttranslationally modified peptides prior to autoimmune disease development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2019129118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017940PMC
February 2021

Large-Scale Screening in General Population Children for Celiac Disease with a Multiplex Electrochemiluminescence (ECL) Assay.

J Immunol Res 2020 24;2020:8897656. Epub 2020 Dec 24.

Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA.

Background: Autoimmunity Screening for Kids (ASK) study was launched to screen general population children for type 1 diabetes (T1D) and celiac disease (CD).

Methods: A total of 23,319 children from general population were screened. A high throughput multiplex electrochemiluminescence (ECL) assay to screen multiautoantibodies in a single well was applied, parallel with a standard radiobinding assay (RBA). All children with any positive autoantibodies in screening were revisited within one month for confirmation and followed every 6 months.

Results: Among 23,319 children, 2.6% (606/23,319) of children were tested positive for TGA. Multiplex ECL assay detected more TGA (584/23,319) in the initial screening than RBA (490/23,319, = 0.004) and was able to detect TGA earlier than RBA in a subset of children by 0.8 to 34.8 months. Prevalence of TGA by either ECL or RBA in children with islet autoantibodies was found significantly higher than overall prevalence in general population screened.

Conclusions: A multiplex ECL assay was more sensitive than standard RBA by identifying more TGA positivity and detecting TGA earlier in general population screening. It also provides a high efficient tool with its unique advantage of multiplexing measurements to screen for multiple autoimmune diseases simultaneously in general population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/8897656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775136PMC
December 2020

First-appearing islet autoantibodies for type 1 diabetes in young children: maternal life events during pregnancy and the child's genetic risk.

Diabetologia 2021 Mar 6;64(3):591-602. Epub 2021 Jan 6.

Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmo, Sweden.

Aims/hypothesis: Psychological stress has long been considered a possible trigger of type 1 diabetes, although prospective studies examining the link between psychological stress or life events during pregnancy and the child's type 1 diabetes risk are rare. The objective of this study was to examine the association between life events during pregnancy and first-appearing islet autoantibodies (IA) in young children, conditioned by the child's type 1 diabetes-related genetic risk.

Methods: The IA status of 7317 genetically at-risk The Environmental Determinants of Diabetes in the Young (TEDDY) participants was assessed every 3 months from 3 months to 4 years, and bi-annually thereafter. Reports of major life events during pregnancy were collected at study inception when the child was 3 months of age and placed into one of six categories. Life events during pregnancy were examined for association with first-appearing insulin (IAA) (N = 222) or GAD (GADA) (N = 209) autoantibodies in the child until 6 years of age using proportional hazard models. Relative excess risk due to interaction (RERI) by the child's HLA-DR and SNP profile was estimated.

Results: Overall, 65% of mothers reported a life event during pregnancy; disease/injury (25%), serious interpersonal (28%) and job-related (25%) life events were most common. The association of life events during pregnancy differed between IAA and GADA as the first-appearing autoantibody. Serious interpersonal life events correlated with increased risk of GADA-first only in HLA-DR3 children with the BACH2-T allele (HR 2.28, p < 0.0001), an additive interaction (RERI 1.87, p = 0.0004). Job-related life events were also associated with increased risk of GADA-first among HLA-DR3/4 children (HR 1.53, p = 0.04) independent of serious interpersonal life events (HR 1.90, p = 0.002), an additive interaction (RERI 1.19, p = 0.004). Job-related life events correlated with reduced risk of IAA-first (HR 0.55, p = 0.004), particularly in children with the BTNL2-GG allele (HR 0.48; 95% CI 0.31, 0.76).

Conclusions/interpretation: Specific life events during pregnancy are differentially related to IAA vs GADA as first-appearing IA and interact with different HLA and non-HLA genetic factors, supporting the concept of different endotypes underlying type 1 diabetes. However, the mechanisms underlying these associations remain to be discovered. Life events may be markers for other yet-to-be-identified factors important to the development of first-appearing IA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-020-05344-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880544PMC
March 2021

Incidence and predictors of type 1 diabetes among younger adults aged 20-45 years: The diabetes in young adults (DiYA) study.

Diabetes Res Clin Pract 2021 Jan 15;171:108624. Epub 2020 Dec 15.

Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612, USA.

Aims: To estimate incidence of type 1 diabetes (T1D) and to develop a T1D prediction model among young adults.

Methods: Adults 20-45 years newly-diagnosed with diabetes in 2017 were identified within Kaiser Permanente's healthcare systems in California and invited for diabetes autoantibody (DAA) testing. Multiple imputation was conducted to assign missing DAA status. The primary outcome for incidence rates (IR) and the prediction model was T1D defined by ≥1 positive DAA.

Results: Among 2,347,989 persons at risk, 7862 developed diabetes, 2063 had DAA measured, and 166 (8.0%) had ≥1 positive DAA. T1D IR (95% CI) per 100,000 person-years was 15.2 (10.2-20.1) for ages 20-29 and 38.2 (28.6-47.8) for ages 30-44 years. The age-standardized IRs were 32.5 (22.2-42.8) for men and 27.2 (21.0-34.5) for women. The age/sex-standardized IRs were 30.1 (23.5-36.8) overall; 41.4 (25.3-57.5) for Hispanics, 37.0 (11.6-62.4) for Blacks, 21.4 (14.3-28.6) for non-Hispanic Whites, and 19.4 (8.5-30.2) for Asians. Predictors of T1D among cases included female sex, younger age, lower BMI, insulin use and having T1D based on diagnostic codes.

Conclusions: T1D may account for up to 8% of incident diabetes cases among young adults. Follow-up is needed to establish the clinical course of patients with one DAA at diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.diabres.2020.108624DOI Listing
January 2021

Parent and Pediatrician Preferences for Type 1 Diabetes Screening in the U.S.

Diabetes Care 2021 Feb 10;44(2):332-339. Epub 2020 Dec 10.

RTI Health Solutions, Research Triangle Park, NC.

Objective: The purpose of this study was to use a discrete-choice experiment methodology to understand the relative importance of the attributes of screening tests for type 1 diabetes among parents and pediatricians in the U.S.

Research Design And Methods: Online surveys presented hypothetical screening test profiles from which respondents chose their preferred test profile. Survey attributes were based on likely screening test options and included the mode of administration, where and when the test was conducted, the type of education and monitoring available to lower the risk of diabetic ketoacidosis (DKA), and whether a treatment was available that would delay onset of insulin dependence. Data were analyzed using random-parameters logit models.

Results: Parents placed the highest relative importance on monitoring programs that could reduce the risk of DKA to 1%, followed by treatment to delay onset of insulin dependence by 1 or 2 years, and, finally, avoiding a $50 out-of-pocket cost. Pediatricians placed equal importance on monitoring programs that reduced a patient's risk of DKA to 1% and on avoiding a $50 out-of-pocket cost for the screening test, followed by the option of a treatment to delay the onset of insulin dependence. The mode of administration and location and timing of the screening were much less important to parents and pediatricians.

Conclusions: Parents and pediatricians preferred screening tests that were accompanied by education and monitoring plans to reduce the risk of DKA, had available treatment to delay type 1 diabetes, and had lower out-of-pocket costs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc20-0927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818333PMC
February 2021

Novel genetic risk factors influence progression of islet autoimmunity to type 1 diabetes.

Sci Rep 2020 11 5;10(1):19193. Epub 2020 Nov 5.

Center for Public Health Genomics, University of Virginia, PO Box 800717, Charlottesville, VA, 22908, USA.

Type 1 diabetes arises from the autoimmune destruction of insulin-producing beta-cells of the pancreas, resulting in dependence on exogenously administered insulin to maintain glucose homeostasis. In this study, our aim was to identify genetic risk factors that contribute to progression from islet autoimmunity to clinical type 1 diabetes. We analyzed 6.8 million variants derived from whole genome sequencing of 160 islet autoantibody positive subjects, including 87 who had progressed to type 1 diabetes. The Cox proportional-hazard model for survival analysis was used to identify genetic variants associated with progression. We identified one novel region, 20p12.1 (TASP1; genome-wide P < 5 × 10) and three regions, 1q21.3 (MRPS21-PRPF3), 2p25.2 (NRIR), 3q22.1 (COL6A6), with suggestive evidence of association (P < 8.5 × 10) with progression from islet autoimmunity to type 1 diabetes. Once islet autoimmunity is initiated, functional mapping identified two critical pathways, response to viral infections and interferon signaling, as contributing to disease progression. These results provide evidence that genetic pathways involved in progression from islet autoimmunity differ from those pathways identified once disease has been established. These results support the need for further investigation of genetic risk factors that modulate initiation and progression of subclinical disease to inform efforts in development of novel strategies for prediction and intervention of type 1 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-75690-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645414PMC
November 2020

Prediction of the development of islet autoantibodies through integration of environmental, genetic, and metabolic markers.

J Diabetes 2021 Feb 16;13(2):143-153. Epub 2020 Aug 16.

Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Background: The Environmental Determinants of the Diabetes in the Young (TEDDY) study has prospectively followed, from birth, children at increased genetic risk of type 1 diabetes. TEDDY has collected heterogenous data longitudinally to gain insights into the environmental and biological mechanisms driving the progression to persistent islet autoantibodies.

Methods: We developed a machine learning model to predict imminent transition to the development of persistent islet autoantibodies based on time-varying metabolomics data integrated with time-invariant risk factors (eg, gestational age). The machine learning was initiated with 221 potential features (85 genetic, 5 environmental, 131 metabolomic) and an ensemble-based feature evaluation was utilized to identify a small set of predictive features that can be interrogated to better understand the pathogenesis leading up to persistent islet autoimmunity.

Results: The final integrative machine learning model included 42 disparate features, returning a cross-validated receiver operating characteristic area under the curve (AUC) of 0.74 and an AUC of ~0.65 on an independent validation dataset. The model identified a principal set of 20 time-invariant markers, including 18 genetic markers (16 single nucleotide polymorphisms [SNPs] and two HLA-DR genotypes) and two demographic markers (gestational age and exposure to a prebiotic formula). Integration with the metabolome identified 22 supplemental metabolites and lipids, including adipic acid and ceramide d42:0, that predicted development of islet autoantibodies.

Conclusions: The majority (86%) of metabolites that predicted development of islet autoantibodies belonged to three pathways: lipid oxidation, phospholipase A2 signaling, and pentose phosphate, suggesting that these metabolic processes may play a role in triggering islet autoimmunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1753-0407.13093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818425PMC
February 2021

Plasma Metabolome and Circulating Vitamins Stratified Onset Age of an Initial Islet Autoantibody and Progression to Type 1 Diabetes: The TEDDY Study.

Diabetes 2021 01 26;70(1):282-292. Epub 2020 Oct 26.

Health Informatics Institute, University of South Florida, Tampa, FL.

Children's plasma metabolome, especially lipidome, reflects gene regulation and dietary exposures, heralding the development of islet autoantibodies (IA) and type 1 diabetes (T1D). The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 newborns by screening of HLA-DR-DQ genotypes at six clinical centers in four countries, profiled metabolome, and measured concentrations of ascorbic acid, 25-hydroxyvitamin D [25(OH)D], and erythrocyte membrane fatty acids following birth until IA seroconversion under a nested case-control design. We grouped children having an initial autoantibody only against insulin (IAA-first) or GAD (GADA-first) by unsupervised clustering of temporal lipidome, identifying a subgroup of children having early onset of each initial autoantibody, i.e., IAA-first by 12 months and GADA-first by 21 months, consistent with population-wide early seroconversion age. Differential analysis showed that infants having reduced plasma ascorbic acid and cholesterol experienced IAA-first earlier, while early onset of GADA-first was preceded by reduced sphingomyelins at infancy. Plasma 25(OH)D prior to either autoantibody was lower in T1D progressors compared with nonprogressors, with simultaneous lower diglycerides, lysophosphatidylcholines, triglycerides, and alanine before GADA-first. Plasma ascorbic acid and 25(OH)D at infancy were lower in HLA-DR3/DR4 children among IA case subjects but not in matched control subjects, implying gene expression dysregulation of circulating vitamins as latent signals for IA or T1D progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db20-0696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876562PMC
January 2021

Factors Associated With the Decline of C-Peptide in a Cohort of Young Children Diagnosed With Type 1 Diabetes.

J Clin Endocrinol Metab 2021 Mar;106(3):e1380-e1388

Department of Clinical Sciences, Lund University CRC, Skåne University Hospital, Malmö, Sweden.

Context: Understanding factors involved in the rate of C-peptide decline is needed to tailor therapies for type 1 diabetes (T1D).

Objective: Evaluate factors associated with rate of C-peptide decline after a T1D diagnosis in young children.

Design: Observational study.

Setting: Academic centers.

Participants: A total of 57 participants from the Environmental Determinants of Diabetes in the Young (TEDDY) study who were enrolled at 3 months of age and followed until T1D, and 56 age-matched children diagnosed with T1D in the community.

Intervention: A mixed meal tolerance test was used to measure the area under the curve (AUC) C-peptide at 1, 3, 6, 12, and 24 months postdiagnosis.

Outcome: Factors associated with rate of C-peptide decline during the first 2 years postdiagnosis were evaluated using mixed effects models, adjusting for age at diagnosis and baseline C-peptide.

Results: Adjusted slopes of AUC C-peptide decline did not differ between TEDDY subjects and community controls (P = 0.21), although the former had higher C-peptide baseline levels. In univariate analyses combining both groups (n = 113), younger age, higher weight and body mass index z-scores, female sex, an increased number increased number of islet autoantibodies, and IA-2A or ZnT8A positivity at baseline were associated with a higher rate of C-peptide loss. Younger age, female sex, and higher weight z-score remained significant in multivariate analysis (all P < 0.02). At 3 months after diagnosis, higher HbA1c became an additional independent factor associated with a higher rate of C-peptide decline (P < 0.01).

Conclusion: Younger age at diagnosis, female sex, higher weight z-score, and HbA1c were associated with a higher rate of C-peptide decline after T1D diagnosis in young children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244121PMC
March 2021

Childhood growth prior to screen-detected celiac disease: prospective follow-up of an at-risk birth cohort.

Scand J Gastroenterol 2020 Nov 17;55(11):1284-1290. Epub 2020 Sep 17.

Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden.

Objectives: To determine the association between childhood growth prior to the development of celiac disease (CD) and CD autoimmunity (CDA) identified by periodic serological screening.

Study Design: The Diabetes Autoimmunity Study in the Young cohort includes 1979 genetically at-risk children from Denver, Colorado, with annual growth measurements from age nine months until ten years. Between 1993 and February 2019, 120 children developed CDA defined by persistent positive tissue transglutaminase autoantibodies (TGA); among these, 71 met our criteria for CD based on histopathological findings or high TGA levels. Age- and sex-specific -scores of weight, body mass index (BMI), and height prior to seroconversion were derived using US reference charts as standards. Joint modeling of serial growth measurements was used to estimate adjusted hazard ratios (aHRs) accounting for celiac-associated human leukocyte antigens, early-life feeding practices, and socio-demographics.

Results: In the first 10 years of life, there were no significant associations between the child's current weight, BMI and height and the risk of screening-detected CDA or CD, neither was the weight nor BMI velocity associated with CDA or CD as identified by screening (all aHRs approximated 1). Increased height velocity was associated with later CD, but not CDA, development (aHR per 0.01- score/year, 1.28; 95% confidence interval [CI] 1.18-1.38 and 1.03; 0.97-1.09, respectively).

Conclusions: In the first 10 years of life, from prospectively collected serial growth measurements, we found no evidence of impaired childhood growth before CD and CDA development as identified through early and periodic screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00365521.2020.1821087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646943PMC
November 2020

A combined risk score enhances prediction of type 1 diabetes among susceptible children.

Nat Med 2020 08 7;26(8):1247-1255. Epub 2020 Aug 7.

Pacific Northwest Research Institute, Seattle, WA, USA.

Type 1 diabetes (T1D)-an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency-often begins early in life when islet autoantibody appearance signals high risk. However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common and is most severe in the very young, in whom it can be life threatening and difficult to treat. Autoantibody surveillance programs effectively prevent most ketoacidosis but require frequent evaluations whose expense limits public health adoption. Prevention therapies applied before onset, when greater islet mass remains, have rarely been feasible because individuals at greatest risk of impending T1D are difficult to identify. To remedy this, we sought accurate, cost-effective estimation of future T1D risk by developing a combined risk score incorporating both fixed and variable factors (genetic, clinical and immunological) in 7,798 high-risk children followed closely from birth for 9.3 years. Compared with autoantibodies alone, the combined model dramatically improves T1D prediction at ≥2 years of age over horizons up to 8 years of age (area under the receiver operating characteristic curve ≥ 0.9), doubles the estimated efficiency of population-based newborn screening to prevent ketoacidosis, and enables individualized risk estimates for better prevention trial selection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-020-0930-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556983PMC
August 2020

Relative Hypoxia and Early Diabetic Kidney Disease in Type 1 Diabetes.

Diabetes 2020 12 31;69(12):2700-2708. Epub 2020 Jul 31.

Section of Endocrinology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO

The objective of this study was to compare the ratio of renal oxygen availability (RO) to glomerular filtration rate (GFR), a measure of relative renal hypoxia, in adolescents with and without type 1 diabetes (T1D) and relate the ratio to albuminuria, renal plasma flow (RPF), fat mass, and insulin sensitivity (). RO was estimated by blood oxygen level-dependent MRI; fat mass was estimated by DXA; GFR and RPF were estimated by iohexol and -aminohippurate clearance; albuminuria was estimated by urine albumin-to-creatinine ratio (UACR); and was estimated from steady-state glucose infusion rate/insulin (mg/kg/min) by hyperglycemic clamp in 50 adolescents with T1D (age 16.1 ± 3.0 years, HbA 8.6 ± 1.2%) and 20 control patients of similar BMI (age 16.1 ± 2.9 years, HbA 5.2 ± 0.2%). The RO:GFR (ms/mL/min) was calculated as RO (T2*, ms) divided by GFR (mL/min). Whole-kidney RO:GFR was 25% lower in adolescents with T1D versus control patients ( < 0.0001). In adolescents with T1D, lower whole-kidney RO:GFR was associated with higher UACR ( = -0.31, = 0.03), RPF ( = -0.52, = 0.0009), and fat mass ( = -0.33, = 0.02). Lower medullary RO:GFR was associated with lower ( = 0.31, = 0.03). In conclusion, adolescents with T1D exhibited relative renal hypoxia that was associated with albuminuria and with increased RPF, fat mass, and insulin resistance. These data suggest a potential role of renal hypoxia in the development of diabetic kidney disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db20-0457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679770PMC
December 2020

Predictors of oxylipins in a healthy pediatric population.

Pediatr Res 2021 May 29;89(6):1530-1540. Epub 2020 Jul 29.

University of Colorado Denver Anschutz Medical Campus, Denver, CO, USA.

Background: Oxylipins are formed from oxidation of omega-6 (n6) and omega-3 (n3) fatty acids (FAs). Evidence for inflammatory effects comes mostly from adults.

Methods: Oxylipins from n6 FA (27 n6-oxylipins) and n3 FA (12 n3-oxylipins) were measured through ultra-high-performance liquid chromatography-mass spectrometry (LC-MS/MS) in plasma from 111 children at risk of type 1 diabetes (age 1-17 years) studied longitudinally. Oxylipin precursor FAs (arachidonic acid, linoleic acid, alpha-linolenic acid, docosahexaenoic acid, eicosapentaenoic acid) were measured in red blood cell (RBC) membrane and plasma. Precursor FAs dietary intake was measured through food frequency questionnaire and environmental tobacco smoke (ETS) through questionnaires. Linear mixed models were used to test oxylipins with predictors.

Results: Age associated with 15 n6- and 6 n3-oxylipins; race/ethnicity associated with 3 n6- and 1 n3-oxylipins; sex associated with 2 n6-oxylipins. ETS associated with lipoxin-A4. Oxylipins associated with precursor FAs in plasma more often than RBC. RBC levels and dietary intake of precursor FAs more consistently associated with n3-oxylipins than with n6-oxylipins.

Conclusions: In healthy children, oxylipin levels change with age. Oxylipins associated with precursor FAs more often in plasma than RBC or diet, suggesting that inflammatory regulation leading to FA release into plasma may also be a determinant of oxylipin generation.

Impact: This is the first study to examine predictors of oxylipins in healthy children at risk of type 1 diabetes. In healthy children at risk of type 1 diabetes, many oxylipins change with age, and most oxylipins do not differ by sex or race/ethnicity. Environmental tobacco smoke exposure was associated with the presence of lipoxin A4. Omega-6- and omega-3-related oxylipin levels were consistently associated with their respective precursor fatty acid levels measured in the plasma. Proportionally more omega-3 compared to omega-6 oxylipins were associated with dietary intake and red blood cell membrane levels of the respective precursor fatty acid.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41390-020-1084-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855434PMC
May 2021
-->