Reactivity to N-Terminally Truncated GAD65(96–585) Identifies GAD Autoantibodies That Are More Closely Associated With Diabetes Progression in Relatives of Patients With Type 1 Diabetes

Objective: To assess the progression of type 1 diabetes using time to peak glucose or C-peptide during oral glucose tolerance tests (OGTTs) in autoantibody positive (Ab+) relatives of people with type 1 diabetes. Methods: We examined 2-hour OGTTs of participants in the Diabetes Prevention Trial Type 1 (DPT-1) and TrialNet Pathway to Prevention (PTP) studies. We included 706 DPT-1 participants (Mean±SD age: 13.84±9.53 years; BMI-Z-Score: 0.33±1.07; 56.1% male) and 3,720 PTP participants (age: 16.01±12.33 Years, BMI-Z-Score 0.66±1.3; 49.7% male). Log-rank testing and Cox regression analyses with adjustments (age, sex, race, BMI Z-Score, HOMA-IR and peak Glucose/C-peptide levels, respectively) were performed. Results: In each of DPT-1 and PTP, higher 5-year diabetes progression risk was seen in those with time to peak glucose >30 min and time to peak C-peptide >60 min (p<0.001 for all groups), before and after adjustments. In models examining strength of association with diabetes development, associations were greater for time to peak C-peptide versus peak C-peptide value (DPT-1: X2 = 25.76 vs. X2 = 8.62 and PTP: X2 = 149.19 vs. X2 = 79.98; all p<0.001). Changes in the percentage of individuals with delayed glucose and/or C-peptide peaks were noted over time. Conclusions: In two independent at risk populations, we show that those with delayed OGTT peak times for glucose or C-peptide are at higher risk of diabetes development within 5 years, independent of peak levels. Moreover, time to peak C-peptide appears more predictive than the peak level, suggesting its potential use as a specific biomarker for diabetes progression.

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Novel Leptin Receptor Mutation in NOD/LtJ Mice Suppresses Type 1 Diabetes Progression: I. Pathophysiological Analysis

Diabetes ◽

10.2337/diabetes.54.9.2525 ◽

2005 ◽

Vol 54 (9) ◽

pp. 2525-2532 ◽

Cited By ~ 21

Author(s):

C.-H. Lee ◽

P. C. Reifsnyder ◽

J. K. Naggert ◽

C. Wasserfall ◽

M. A. Atkinson ◽

...

Keyword(s):

Type 1 Diabetes ◽

Leptin Receptor ◽

Diabetes Progression

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Novel epitope begets a novel pathway in type 1 diabetes progression

Journal of Clinical Investigation ◽

10.1172/jci37125 ◽

2008 ◽

Author(s):

Jeffrey A. Frelinger

Keyword(s):

Type 1 Diabetes ◽

Diabetes Progression

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Type 1 diabetes progression is associated with loss of CD3+CD56+ regulatory T cells that control CD8+ T-cell effector functions

Nature Metabolism ◽

10.1038/s42255-020-0173-1 ◽

2020 ◽

Vol 2 (2) ◽

pp. 142-152 ◽

Cited By ~ 2

Author(s):

Giuseppe Terrazzano ◽

Sara Bruzzaniti ◽

Valentina Rubino ◽

Marianna Santopaolo ◽

Anna Teresa Palatucci ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

Regulatory T Cells ◽

Cd8 T Cell ◽

Effector Functions ◽

Diabetes Progression ◽

Cell Effector

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Young adult onset type 2 diabetes versus type 1 diabetes: Progression to and survival on renal replacement therapy

Journal of Diabetes and its Complications ◽

10.1016/j.jdiacomp.2021.108023 ◽

2021 ◽

pp. 108023

Author(s):

Timothy L. Middleton ◽

Steven Chadban ◽

Lynda Molyneaux ◽

Mario D'Souza ◽

Maria I. Constantino ◽

...

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Renal Replacement Therapy ◽

Young Adult ◽

Replacement Therapy ◽

Adult Onset ◽

Onset Type ◽

Diabetes Progression

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IFN Regulatory Factors 4 and 8 Expression in the NOD Mouse

Clinical and Developmental Immunology ◽

10.1155/2011/374859 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Gilles Besin ◽

Simon Gaudreau ◽

Émilie Dumont-Blanchette ◽

Michael Ménard ◽

Chantal Guindi ◽

...

Keyword(s):

Gene Expression ◽

Bone Marrow ◽

Type 1 Diabetes ◽

Nod Mice ◽

Nod Mouse ◽

Dc Functions ◽

Gm Csf ◽

Diabetes Progression ◽

Islet Inflammation

Dendritic cells (DCs) contribute to islet inflammation and its progression to diabetes in NOD mouse model and human. DCs play a crucial role in the presentation of autoantigen and activation of diabetogenic T cells, and IRF4 and IRF8 are crucial genes involved in the development of DCs. We have therefore investigated the expression of these genes in splenic DCs during diabetes progression in NOD mice. We found that IRF4 expression was upregulated in splenocytes and in splenic CD11c+DCs of NOD mice as compared to BALB/c mice. In contrast, IRF8 gene expression was higher in splenocytes of NOD mice whereas its expression was similar in splenic CD11c+DCs of NOD and BALB/c mice. Importantly, levels of IRF4 and IRF8 expression were lower in tolerogenic bone marrow derived DCs (BMDCs) generated with GM-CSF as compared to immunogenic BMDCs generated with GM-CSF and IL-4. Analysis of splenic DCs subsets indicated that high expression of IRF4 was associated with increased levels of CD4+CD8α−IRF4+CD11c+DCs but not CD4−CD8α+IRF8+CD11c+DCs in NOD mice. Our results showed that IRF4 expression was up-regulated in NOD mice and correlated with the increased levels of CD4+CD8α−DCs, suggesting that IRF4 may be involved in abnormal DC functions in type 1 diabetes in NOD mice.

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Antigenic Determinants to GAD Autoantibodies in Patients With Type 1 Diabetes With and Without Autoimmune Thyroid Disease

Annals of the New York Academy of Sciences ◽

10.1196/annals.1375.033 ◽

2006 ◽

Vol 1079 (1) ◽

pp. 213-219 ◽

Cited By ~ 4

Author(s):

H. PARK ◽

L. YU ◽

T. KIM ◽

B. CHO ◽

J. KANG ◽

...

Keyword(s):

Type 1 Diabetes ◽

Thyroid Disease ◽

Autoimmune Thyroid Disease ◽

Antigenic Determinants ◽

Autoimmune Thyroid ◽

Gad Autoantibodies

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Time to Peak Glucose and Peak C-Peptide During the Progression to Type 1 Diabetes in the Diabetes Prevention Trial and TrialNet Cohorts

10.2337/figshare.14974563 ◽

2021 ◽

Author(s):

Michael G Voss ◽

David D Cuthbertson ◽

Mario M Cleves ◽

Ping Xu ◽

Carmella Evans-Molina ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetes Prevention ◽

Prevention Trial ◽

Oral Glucose ◽

Z Score ◽

C Peptide ◽

Time To Peak ◽

Diabetes Progression ◽

Diabetes Development

Objective: To assess the progression of type 1 diabetes using time to peak glucose or C-peptide during oral glucose tolerance tests (OGTTs) in autoantibody positive (Ab+) relatives of people with type 1 diabetes. Methods: We examined 2-hour OGTTs of participants in the Diabetes Prevention Trial Type 1 (DPT-1) and TrialNet Pathway to Prevention (PTP) studies. We included 706 DPT-1 participants (Mean±SD age: 13.84±9.53 years; BMI-Z-Score: 0.33±1.07; 56.1% male) and 3,720 PTP participants (age: 16.01±12.33 Years, BMI-Z-Score 0.66±1.3; 49.7% male). Log-rank testing and Cox regression analyses with adjustments (age, sex, race, BMI Z-Score, HOMA-IR and peak Glucose/C-peptide levels, respectively) were performed. Results: In each of DPT-1 and PTP, higher 5-year diabetes progression risk was seen in those with time to peak glucose >30 min and time to peak C-peptide >60 min (p<0.001 for all groups), before and after adjustments. In models examining strength of association with diabetes development, associations were greater for time to peak C-peptide versus peak C-peptide value (DPT-1: X2 = 25.76 vs. X2 = 8.62 and PTP: X2 = 149.19 vs. X2 = 79.98; all p<0.001). Changes in the percentage of individuals with delayed glucose and/or C-peptide peaks were noted over time. Conclusions: In two independent at risk populations, we show that those with delayed OGTT peak times for glucose or C-peptide are at higher risk of diabetes development within 5 years, independent of peak levels. Moreover, time to peak C-peptide appears more predictive than the peak level, suggesting its potential use as a specific biomarker for diabetes progression.

Download Full-text