scholarly journals Monogenic Diabetes and Integrated Stress Response Genes Display Altered Gene Expression in Type 1 Diabetes

2021 ◽  
Author(s):  
Helmut Hiller ◽  
Dawn E. Beachy ◽  
Joseph J. Lebowitz ◽  
Stefanie Engler ◽  
Justin R. Mason ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Stress Response ◽  
Stress Responses ◽  
Disease Process ◽  
Monogenic Diabetes ◽  
Integrated Stress Response ◽  
Altered Expression ◽  
Increased Risk ◽  
Gene And Protein Expression

Type 1 diabetes has a multifactorial autoimmune etiology, involving environmental prompts and polygenic predisposition. We hypothesized that pancreata from individuals with and at risk for type 1 diabetes would exhibit dysregulated expression of genes associated with monogenic forms of diabetes caused by non-redundant single-gene mutations. Employing a “monogenetic transcriptomic strategy,” we measured the expression of these genes in human type 1 diabetes, autoantibody positive (autoantibody+), and control pancreas tissues using RTqPCR in accordance with the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. Gene and protein expression were visualized <i>in situ</i> using immunofluorescence, RNAScope, and confocal microscopy. Two-dozen monogenic diabetes genes showed altered expression in human pancreata from individuals with type 1 diabetes versus unaffected controls. Six of these genes also saw dysregulation in pancreata from autoantibody+ persons at increased-risk for type 1 diabetes. As a subset of these genes are related to cellular stress responses, we measured integrated stress response (ISR) genes and identified 20 with altered expression in type 1 diabetes pancreata, including three of the four eIF2a-dependent kinases. Equally intriguing, we observed significant repression of the three arms of the ISR in autoantibody+ pancreata. Collectively, these efforts suggest monogenic diabetes and ISR genes are dysregulated early in the type 1 diabetes disease process and likely contribute to the disorder’s pathogenesis.

scholarly journals Monogenic Diabetes and Integrated Stress Response Genes Display Altered Gene Expression in Type 1 Diabetes

2021 ◽  
Author(s):  
Helmut Hiller ◽  
Dawn E. Beachy ◽  
Joseph J. Lebowitz ◽  
Stefanie Engler ◽  
Justin R. Mason ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Stress Response ◽  
Stress Responses ◽  
Disease Process ◽  
Monogenic Diabetes ◽  
Integrated Stress Response ◽  
Altered Expression ◽  
Increased Risk ◽  
Gene And Protein Expression

Type 1 diabetes has a multifactorial autoimmune etiology, involving environmental prompts and polygenic predisposition. We hypothesized that pancreata from individuals with and at risk for type 1 diabetes would exhibit dysregulated expression of genes associated with monogenic forms of diabetes caused by non-redundant single-gene mutations. Employing a “monogenetic transcriptomic strategy,” we measured the expression of these genes in human type 1 diabetes, autoantibody positive (autoantibody+), and control pancreas tissues using RTqPCR in accordance with the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. Gene and protein expression were visualized <i>in situ</i> using immunofluorescence, RNAScope, and confocal microscopy. Two-dozen monogenic diabetes genes showed altered expression in human pancreata from individuals with type 1 diabetes versus unaffected controls. Six of these genes also saw dysregulation in pancreata from autoantibody+ persons at increased-risk for type 1 diabetes. As a subset of these genes are related to cellular stress responses, we measured integrated stress response (ISR) genes and identified 20 with altered expression in type 1 diabetes pancreata, including three of the four eIF2a-dependent kinases. Equally intriguing, we observed significant repression of the three arms of the ISR in autoantibody+ pancreata. Collectively, these efforts suggest monogenic diabetes and ISR genes are dysregulated early in the type 1 diabetes disease process and likely contribute to the disorder’s pathogenesis.

Monogenic Diabetes and Integrated Stress Response Genes Display Altered Gene Expression in Type 1 Diabetes

Diabetes ◽  
2021 ◽  
pp. db210070
Author(s):  
Helmut Hiller ◽  
Dawn E. Beachy ◽  
Joeseph J. Lebowitz ◽  
Stefanie Engler ◽  
Justin R. Mason ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 1 Diabetes ◽  
Stress Response ◽  
Monogenic Diabetes ◽  
Integrated Stress Response ◽  
Altered Gene Expression ◽  
Stress Response Genes ◽  
Altered Gene

scholarly journals Early epitope- and isotype-specific humoral immune responses to GAD65 in young children with genetic susceptibility to type 1 diabetes

2006 ◽  
Vol 155 (4) ◽  
pp. 633-642 ◽  
Author(s):  
Matti S Ronkainen ◽  
Sanna Hoppu ◽  
Sari Korhonen ◽  
Satu Simell ◽  
Riitta Veijola ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Young Children ◽  
Genetic Susceptibility ◽  
Humoral Immunity ◽  
Disease Process ◽  
Igg Subclasses ◽  
Acid Decarboxylase ◽  
Igg Subclass ◽  
Increased Risk

Objective: The pattern of the humoral immunity to disease-associated autoantigens may reflect the severity of the autoimmune disease process. The purpose of this study was to delineate the maturation of the humoral immunity to one of the main autoantigens in type 1 diabetes (T1D), glutamic acid decarboxylase (GAD65). Design and methods: Serum samples were obtained for the detection of epitope- and isotype-specific antibodies sequentially with short intervals from 36 young children with HLA-conferred genetic susceptibility to T1D starting from the first appearance of GAD65Ab. During prospective observation, ten children developed T1D. Antibodies were analyzed using biotinylated anti-human immunoglobulin (Ig) antibodies and chimeric GAD molecules in radio-binding assays. Results: The immune response to GAD65 started as reactivity to the middle region and spread rapidly to the C-terminal region. IgG1 antibodies dominated among the isotypes from the first appearance of GAD65Ab, while other IgG subclasses were observed to a lesser extent. IgG4 antibodies emerged clearly as the last IgG subclass. A broad initial response comprising three to four IgG subclasses and the lack of an emerging IgG4 response during follow-up was associated with increased risk for progression to clinical diabetes (P<0.05). Conclusions: The humoral response to GAD65 epitope clusters is relatively uniform in young children, whereas there is conspicuous individual variation in IgG subclass responses except for IgG1. A narrow initial IgG subclass response to GAD65 and the emergence of IgG4 antibodies were characteristic of those who remained non-diabetic over the first few years of GAD65 autoimmunity.

Immune status is associated with the mode of delivery in infants at increased risk for Type 1 Diabetes

2014 ◽  
Vol 9 (S 01) ◽  
Author(s):  
O D'Orlando ◽  
R Puff ◽  
A Henniger ◽  
S Krause ◽  
F Haupt ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Status ◽  
Mode Of Delivery ◽  
Increased Risk

Dextrose-Sulfonylurea Challenge as a Screening Test for Monogenic Diabetes in Patients Diagnosed with Type 1 Diabetes

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 310-LB
Author(s):  
AURELIA C.H. WOOD ◽  
MARIA S. REMEDI ◽  
COLIN NICHOLS ◽  
BESS A. MARSHALL
Keyword(s):  
Type 1 Diabetes ◽  
Screening Test ◽  
Monogenic Diabetes

Metabolic Markers Associated with Increased Risk for Progression from Single to Multiple Autoantibodies in Type 1 Diabetes Relatives

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 94-OR
Author(s):  
EMANUELE BOSI ◽  
SUSAN GEYER ◽  
JAY SOSENKO ◽  
DOROTHY J. BECKER ◽  
MANUELA BATTAGLIA ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Metabolic Markers ◽  
Increased Risk

836-P: Cannabis Use in Adults with Type 1 Diabetes (T1D) Is Associated with Poor Glycemic Control and Increased Risk for Diabetic Ketoacidosis (DKA)

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 836-P ◽  
Author(s):  
VIRAL N. SHAH ◽  
DANIEL D. TAYLOR ◽  
NICOLE C. FOSTER ◽  
ROY BECK ◽  
HALIS K. AKTURK ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glycemic Control ◽  
Diabetic Ketoacidosis ◽  
Cannabis Use ◽  
Poor Glycemic Control ◽  
Increased Risk

scholarly journals Coeliac disease is associated with depression in children and young adults with type 1 diabetes: results from a multicentre diabetes registry

2021 ◽  
Author(s):  
Sascha René Tittel ◽  
◽  
Désirée Dunstheimer ◽  
Dörte Hilgard ◽  
Burkhild Knauth ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Young Adults ◽  
Coeliac Disease ◽  
Diabetes Patient ◽  
Routine Care ◽  
Diabetes Registry ◽  
Increased Risk ◽  
Treatment Data ◽  
Children And Young Adults

Abstract Aims To analyse the association between coeliac disease (CD) and depression in children, adolescents, and young adults with type 1 diabetes (T1D). Methods We included 79,067 T1D patients aged 6–20 years, with at least six months of diabetes duration, and treatment data between 1995 and 2019 were documented in the diabetes patient follow-up registry. We categorized patients into four groups: T1D only (n = 73,699), T1 + CD (n = 3379), T1D + depression (n = 1877), or T1D + CD + depression (n = 112). Results CD and depression were significantly associated (adjusted OR: 1.25 [1.03–1.53]). Females were more frequent in both the depression and the CD group compared with the T1D only group. Insulin pumps were used more frequently in T1D + CD and T1D + depression compared with T1D only (both p < .001). HbA1c was higher in T1D + depression (9.0% [8.9–9.0]), T1D + CD + depression (8.9% [8.6–9.2]), both compared with T1D only (8.2% [8.2–8.2], all p < .001). We found comorbid autism, attention deficit hyperactivity disorder, anxiety, schizophrenia, and eating disorders more frequently in the T1D + CD + depression group compared with T1D only (all p < .001). Conclusions CD and depression are associated in young T1D patients. The double load of T1D and CD may lead to an increased risk for depression. Depression was associated with additional psychological and neurological comorbidities. Aside from imperative CD screening after T1D diagnosis and regular intervals, depression screening might be helpful in routine care, especially in patients with diagnosed CD.

Understanding the increased risk of infections in diabetes: innate and adaptive immune responses in type 1 diabetes

Metabolism ◽  
2021 ◽  
pp. 154795
Author(s):  
Anna W.M. Janssen ◽  
Rinke Stienstra ◽  
Martin Jaeger ◽  
Alain J. van Gool ◽  
Leo A.B. Joosten ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Responses ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Increased Risk

scholarly journals DR15-DQ6 remains dominantly protective against type 1 diabetes throughout the first five decades of life

Diabetologia ◽  
2021 ◽  
Author(s):  
Nicholas J. Thomas ◽  
John M. Dennis ◽  
Seth A. Sharp ◽  
Akaal Kaur ◽  
Shivani Misra ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Major Type ◽  
Diabetes Incidence ◽  
Diabetes Diagnosis ◽  
Risk Haplotype ◽  
Adult Onset ◽  
Uk Biobank ◽  
Onset Type ◽  
Increased Risk

Abstract Aims/hypothesis Among white European children developing type 1 diabetes, the otherwise common HLA haplotype DR15-DQ6 is rare, and highly protective. Adult-onset type 1 diabetes is now known to represent more overall cases than childhood onset, but it is not known whether DR15-DQ6 is protective in older-adult-onset type 1 diabetes. We sought to quantify DR15-DQ6 protection against type 1 diabetes as age of onset increased. Methods In two independent cohorts we assessed the proportion of type 1 diabetes cases presenting through the first 50 years of life with DR15-DQ6, compared with population controls. In the After Diabetes Diagnosis Research Support System-2 (ADDRESS-2) cohort (n = 1458) clinician-diagnosed type 1 diabetes was confirmed by positivity for one or more islet-specific autoantibodies. In UK Biobank (n = 2502), we estimated type 1 diabetes incidence rates relative to baseline HLA risk for each HLA group using Poisson regression. Analyses were restricted to white Europeans and were performed in three groups according to age at type 1 diabetes onset: 0–18 years, 19–30 years and 31–50 years. Results DR15-DQ6 was protective against type 1 diabetes through to age 50 years (OR < 1 for each age group, all p < 0.001). The following ORs for type 1 diabetes, relative to a neutral HLA genotype, were observed in ADDRESS-2: age 5–18 years OR 0.16 (95% CI 0.08, 0.31); age 19–30 years OR 0.10 (0.04, 0.23); and age 31–50 years OR 0.37 (0.21, 0.68). DR15-DQ6 also remained highly protective at all ages in UK Biobank. Without DR15-DQ6, the presence of major type 1 diabetes high-risk haplotype (either DR3-DQ2 or DR4-DQ8) was associated with increased risk of type 1 diabetes. Conclusions/interpretation HLA DR15-DQ6 confers dominant protection from type 1 diabetes across the first five decades of life. Graphical abstract

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