scholarly journals Circulating Metabolites in Progression to Islet Autoimmunity and Type 1 Diabetes

2018 ◽  
Author(s):  
Santosh Lamichhane ◽  
Esko Kemppainen ◽  
Kajetan Trost ◽  
Heli Siljander ◽  
Heikki Hyoty ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Study Groups ◽  
Islet Autoantibodies ◽  
Islet Autoimmunity ◽  
Islet Autoantibody ◽  
Metabolic Disturbances ◽  
Longitudinal Plasma ◽  
Sugar Derivatives ◽  
Negative Controls

Previous studies suggest that metabolic dysregulation precedes the onset of type 1 diabetes (T1D). However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. Here we analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to T1D (PT1D), who seroconverted to one islet autoantibody (Ab) but not to T1D (P1Ab), and Ab-negative controls (CTR). In early infancy, PT1D associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, as compared to CTR. Methionine remained persistently upregulated in PT1D as compared to CTR and P1Ab. Appearance of islet autoantibodies associated with decreased glutamic and aspartic acids. Our findings suggest that children who progress to T1D have a unique metabolic profile, which is however altered with the onset of islet autoantibodies. Our findings may assist in early prediction of T1D.

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

2021 ◽  
Author(s):  
Ezio Bonifacio ◽  
Andreas Weiß ◽  
Christiane Winkler ◽  
Markus Hippich ◽  
Marian J. Rewers ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Confidence Interval ◽  
Islet Autoantibodies ◽  
Islet Autoimmunity ◽  
Islet Autoantibody ◽  
Age Related ◽  
At Risk Children ◽  
Exponential Decline ◽  
Design And Methods

<b>Objective</b>. Islet autoimmunity develops prior to 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 pre-symptomatic type 1 diabetes. <p><b>Research Design and Methods</b>. The Environmental Determinants of Diabetes in the Young study prospectively followed 8,556 genetically at-risk children at 3–6-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. </p> <p><b>Results</b>. The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% confidence interval, 3.8–4.7) at 7.5 months of age and declined to 1.1% (95% confidence interval, 0.8–1.3) at a landmark age of 6.25 years (<i>P</i><0.0001). Risk decline was slight or absent in single insulin- and GAD-autoantibody phenotypes. The influence of sex, <i>HLA</i> and other susceptibility genes on risk subsided with increasing age and was abrogated by age six 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. </p> <p><b>Conclusions</b>. 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. </p>

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

2021 ◽  
Author(s):  
Ezio Bonifacio ◽  
Andreas Weiß ◽  
Christiane Winkler ◽  
Markus Hippich ◽  
Marian J. Rewers ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Confidence Interval ◽  
Islet Autoantibodies ◽  
Islet Autoimmunity ◽  
Islet Autoantibody ◽  
Age Related ◽  
At Risk Children ◽  
Exponential Decline ◽  
Design And Methods

<b>Objective</b>. Islet autoimmunity develops prior to 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 pre-symptomatic type 1 diabetes. <p><b>Research Design and Methods</b>. The Environmental Determinants of Diabetes in the Young study prospectively followed 8,556 genetically at-risk children at 3–6-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. </p> <p><b>Results</b>. The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% confidence interval, 3.8–4.7) at 7.5 months of age and declined to 1.1% (95% confidence interval, 0.8–1.3) at a landmark age of 6.25 years (<i>P</i><0.0001). Risk decline was slight or absent in single insulin- and GAD-autoantibody phenotypes. The influence of sex, <i>HLA</i> and other susceptibility genes on risk subsided with increasing age and was abrogated by age six 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. </p> <p><b>Conclusions</b>. 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. </p>

scholarly journals Cord-Blood Lipidome in Progression to Islet Autoimmunity and Type 1 Diabetes

Biomolecules ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 33 ◽  
Author(s):  
Santosh Lamichhane ◽  
Linda Ahonen ◽  
Thomas Sparholt Dyrlund ◽  
Alex M. Dickens ◽  
Heli Siljander ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cord Blood ◽  
Characteristic Curve ◽  
Newborn Infants ◽  
Study Groups ◽  
Islet Autoimmunity ◽  
Molecular Profile ◽  
Islet Autoantibody ◽  
Risk Of Progression

Previous studies suggest that children who progress to type 1 diabetes (T1D) later in life already have an altered serum lipid molecular profile at birth. Here, we compared cord blood lipidome across the three study groups: children who progressed to T1D (PT1D; n = 30), children who developed at least one islet autoantibody but did not progress to T1D during the follow-up (P1Ab; n = 33), and their age-matched controls (CTR; n = 38). We found that phospholipids, specifically sphingomyelins, were lower in T1D progressors when compared to P1Ab and the CTR. Cholesterol esters remained higher in PT1D when compared to other groups. A signature comprising five lipids was predictive of the risk of progression to T1D, with an area under the receiver operating characteristic curve (AUROC) of 0.83. Our findings provide further evidence that the lipidomic profiles of newborn infants who progress to T1D later in life are different from lipidomic profiles in P1Ab and CTR.

scholarly journals Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study

2018 ◽  
Vol 56 (9) ◽  
pp. 602-605 ◽  
Author(s):  
Andreas Beyerlein ◽  
Ezio Bonifacio ◽  
Kendra Vehik ◽  
Markus Hippich ◽  
Christiane Winkler ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Factors ◽  
Genetic Risk Score ◽  
Risk Scores ◽  
Islet Autoimmunity ◽  
Islet Autoantibody ◽  
Clinical Type

BackgroundProgression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown.MethodsIn 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression.ResultsIslet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93).ConclusionsGenetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.

scholarly journals Class II HLA Genotype Association With First-Phase Insulin Response Is Explained by Islet Autoantibodies

2017 ◽  
Vol 103 (8) ◽  
pp. 2870-2878 ◽  
Author(s):  
Maarit K Koskinen ◽  
Johanna Lempainen ◽  
Eliisa Löyttyniemi ◽  
Olli Helminen ◽  
Anne Hekkala ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Insulin Response ◽  
Class Ii ◽  
Islet Autoantibodies ◽  
Islet Autoimmunity ◽  
Intravenous Glucose ◽  
Hla Dr ◽  
Hla Genotype ◽  
First Phase Insulin Response

Abstract Context A declining first-phase insulin response (FPIR) is characteristic of the disease process leading to clinical type 1 diabetes. It is not known whether reduced FPIR depends on class II human leukocyte antigen (HLA) genotype, islet autoimmunity, or both. Objective To dissect the role of class II HLA DR-DQ genotypes and biochemical islet autoantibodies in the compromised FPIR. Design, Setting, Participants A total of 438 children with defined HLA DR-DQ genotype in the prospective Finnish Type 1 Diabetes Prediction and Prevention Study were analyzed for FPIR in a total of 1149 intravenous glucose tolerance tests and were categorized by their HLA DR-DQ genotype and the number of biochemical islet autoantibodies at the time of the first FPIR. Age-adjusted hierarchical linear mixed models were used to analyze repeated measurements of FPIR. Main Outcome Measure The associations between class II HLA DR-DQ genotype, islet autoantibody status, and FPIR. Results A strong association between the degree of risk conferred by HLA DR-DQ genotype and positivity for islet autoantibodies existed (P &lt; 0.0001). FPIR was inversely associated with the number of biochemical autoantibodies (P &lt; 0.0001) irrespective of HLA DR-DQ risk group. FPIR decreased over time in children with multiple autoantibodies and increased in children with no biochemical autoantibodies (P &lt; 0.0001 and P = 0.0013, respectively). Conclusions The class II HLA DR-DQ genotype association with FPIR was secondary to the association between HLA and islet autoimmunity. Declining FPIR was associated with positivity for multiple islet autoantibodies irrespective of class II HLA DR-DQ genotype.

scholarly journals 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.

2021 ◽  
Author(s):  
Vibha Anand ◽  
Ying Li ◽  
Bin Liu ◽  
Mohamed Ghalwash ◽  
Eileen Koski ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cohort Studies ◽  
Prospective Cohort ◽  
Diabetes Risk ◽  
Islet Autoantibodies ◽  
Islet Autoimmunity ◽  
Diabetes Incidence ◽  
Prospective Cohort Studies ◽  
Hla Dr

OBJECTIVE: To combine prospective cohort studies, by including HLA harmonization, and to estimate risk of islet autoimmunity and progression to clinical diabetes. <p>RESEARCH DESIGN AND METHODS: Prospective cohorts in Finland, Germany, Sweden and the US have followed 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years.</p> <p>RESULTS: In the infant-toddler cohort, 1413 (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 single autoantibody, their status two years after seroconversion predicted diabetes risk: 12% (10-25%) if reverting to autoantibody negative, 30% (20-40%) if retaining 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. Their 15-year diabetes incidence for higher vs. 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%/year to 6%/year in children developing multi-positivity ≤2 years or >7.4 years, respectively. </p> <p>CONCLUSIONS: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.</p>

scholarly journals Autoimmune Markers in Diabetes

2011 ◽  
Vol 57 (2) ◽  
pp. 168-175 ◽  
Author(s):  
William E Winter ◽  
Desmond A Schatz
Keyword(s):  
Type 1 Diabetes ◽  
Clinical Medicine ◽  
Islet Autoantibodies ◽  
Islet Autoantibody ◽  
Β Cells ◽  
Β Cell ◽  
Autoimmune Destruction ◽  
Clinical Tools ◽  
Autoimmune Etiology

BACKGROUND Type 1 diabetes (T1DM) results from cell-mediated autoimmune destruction of the β cells of the islets of Langerhans. Autoantibodies directed against the islets are useful clinical tools that allow the recognition and confirmation of β-cell autoimmunity. CONTENT In this review we define the term “islet autoantibody,” describe the pathogenesis of autoantibody generation, and explain the uses of islet autoantibodies in clinical medicine and in research studies that concern the interruption or prevention of T1DM. We also discuss the biology of islet autoantibodies and their rates of appearance at the time of onset of T1DM and their appearance before the development of T1DM. SUMMARY The presence of islet autoantibodies in persons with diabetes confirms an autoimmune etiology. In nondiabetic individuals, islet autoantibodies are strong predictors of the later development of T1DM.

scholarly journals Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes

2008 ◽  
Vol 205 (13) ◽  
pp. 2975-2984 ◽  
Author(s):  
Matej Orešič ◽  
Satu Simell ◽  
Marko Sysi-Aho ◽  
Kirsti Näntö-Salonen ◽  
Tuulikki Seppänen-Laakso ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glutamic Acid ◽  
Time Window ◽  
Serum Levels ◽  
Autoimmune Response ◽  
Islet Autoimmunity ◽  
Acid Decarboxylase ◽  
Late Response ◽  
Metabolic Disturbances

The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward β cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.

scholarly journals Islet Autoantibody Type-Specific Titer Thresholds Improve Stratification of Risk of Progression to Type 1 Diabetes in Children

2021 ◽  
Author(s):  
Kenney Ng ◽  
Harry Stavropoulos ◽  
Vibha Anand ◽  
Riitta Veijola ◽  
Jorma Toppari ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Familial Risk ◽  
Multivariable Analysis ◽  
Diabetes Risk ◽  
Islet Autoimmunity ◽  
Acid Decarboxylase ◽  
Islet Autoantibody ◽  
Surveillance Strategy ◽  
Risk Of Progression

OBJECTIVE: To utilize islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children. <p>RESEARCH DESIGN AND METHODS: Prospective cohort studies in Finland, Germany, Sweden and the US followed 24,662 children at increased genetic or familial risk to develop islet autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and insulinoma-associated antigen-2 (IA-2A) were harmonized for diabetes risk analyses.</p> <p>RESULTS: Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA (n=909), GADA (n=1076) or IA-2A (n=714), when stratified by quartiles of titer, ranging from 19% (GADA 1<sup>st</sup> quartile) to 60% (IA-2A 4<sup>th</sup> quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6<sup>th</sup>, 52.4<sup>th</sup> and 10.2<sup>nd</sup> percentile of children specifically positive for each of IAA, GADA and IA-2A, respectively. Using these autoantibody type-specific titer thresholds in the 1,481 children with all autoantibodies tested, the 5-year risk conferred by single (n=954) and multiple (n=527) autoantibodies could be stratified from 6% to 75% (p<0.0001). The thresholds effectively identified children with 50% or higher 5-year risk when considering age-specific autoantibody screening (57-65% positive predictive value and 56-74% sensitivity for ages 1-5 years). Multivariable analysis confirmed the significance of associations between the three autoantibody titers and diabetes risk, informing a childhood risk surveillance strategy.</p> <p>CONCLUSIONS: This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children.</p>

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

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Suna Onengut-Gumuscu ◽  
Umadevi Paila ◽  
Wei-Min Chen ◽  
Aakrosh Ratan ◽  
Zhennan Zhu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 1 Diabetes ◽  
Genetic Risk ◽  
Viral Infections ◽  
Genetic Risk Factors ◽  
Islet Autoimmunity ◽  
Islet Autoantibody ◽  
Critical Pathways ◽  
Genome Wide

Abstract 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 × 10–8) and three regions, 1q21.3 (MRPS21–PRPF3), 2p25.2 (NRIR), 3q22.1 (COL6A6), with suggestive evidence of association (P < 8.5 × 10–8) 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.

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