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

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 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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Non-Invasive Assessment of Metabolic Adaptation in Paediatric Patients Suffering from Type 1 Diabetes Mellitus

Journal of Clinical Medicine ◽

10.3390/jcm8111797 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1797 ◽

Cited By ~ 4

Author(s):

Phillip Trefz ◽

Sibylle C. Schmidt ◽

Pritam Sukul ◽

Jochen K. Schubert ◽

Wolfram Miekisch ◽

...

Keyword(s):

Type 1 Diabetes ◽

Food Intake ◽

Leptin Receptor ◽

Point Of Care ◽

Clinical Importance ◽

Breath Analysis ◽

Individual Variability ◽

Metabolic Adaptation ◽

Exhaled Breath

An analysis of exhaled volatile organic compounds (VOC) may deliver systemic information quicker than available invasive techniques. Metabolic aberrations in pediatric type 1 diabetes (T1DM) are of high clinical importance and could be addressed via breathomics. Real-time breath analysis was combined with continuous glucose monitoring (CGM) and blood tests in children suffering from T1DM and age-matched healthy controls in a highly standardized setting. CGM and breath-resolved VOC analysis were performed every 5 minutes for 9 hours and blood was sampled at pre-defined time points. Per participant (n = 44) food intake and physical activity were identical and a total of 22 blood samples and 93 minutes of breath samples were investigated. The inter-individual variability of glucose, insulin, glucagon, leptin, and soluble leptin receptor relative to food intake differed distinctly between patients and controls. In T1DM patients, the exhaled amounts of acetone, 2-propanol, and pentanal correlated to glucose concentrations. Of note, the strength of these correlations strongly depended on the interval between food intake and breath sampling. Our data suggests that metabolic adaptation through postprandial hyperglycemia and related oxidative stress is immediately reflected in exhaled breath VOC concentrations. Clinical translations of our findings may enable point-of-care applicability of online breath analysis towards personalized medicine.

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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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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