Exocrine pancreas function is impaired in adult relatives of patients with type 1 diabetes

Abstract Aims Alterations of the exocrine pancreas have been reported in type 1 diabetes, but their contribution to the pathogenesis of the disease is poorly understood. Here, we investigated markers of exocrine pancreas dysfunction in individuals at-risk of developing type 1 diabetes. Methods Serum P-amylase and lipase levels were assessed in samples obtained from healthy controls, patients with new onset type 1 diabetes, relatives participating to the TrialNet Pathway to Prevention who were, at blood collection, autoantibody negative or positive for a single autoantibody (low-risk individuals), and positive for multiple autoantibodies (high-risk individuals). Linear mixed models were adopted to estimate variation of pancreatic enzymes among the groups and to evaluate the influence of high-risk HLA genotypes and residual beta cell function on exocrine pancreas function. Results In adults, but not children, reduced levels of P-amylase and lipase were shown in at-risk individuals, including (for P-amylase levels only) those at low-risk, and in T1Dnew. Furthermore, while high-risk HLA genotypes negatively affected P-amylase levels in autoantibody negative adult individuals, fasting C-peptide levels did not correlate with pancreatic enzyme levels. Conclusions Exocrine pancreas dysfunction precedes the onset of type 1 diabetes in adult at-risk individuals and may be unrelated to fasting C-peptide levels.

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The Prediction of Type 1 Diabetes in discordant and concordant families: 16 years of follow-up. Focus on the future

Diabetes Mellitus ◽

10.14341/dm2014383-89 ◽

2014 ◽

Vol 17 (3) ◽

pp. 83-89

Author(s):

Elena Vital'evna Titovich ◽

Tamara Leonidovna Kuraeva ◽

Olga Nikolaevna Ivanova ◽

Svetlana Mikhailovna Stepanova ◽

Valentina Alexandrovna Peterkova ◽

...

Keyword(s):

Type 1 Diabetes ◽

High Risk ◽

Low Risk ◽

Research Centre ◽

Sick People ◽

Immunological Markers ◽

Forecasting Methods ◽

Hla Genotypes

For 40 years, research continues to improve the forecasting methods and the development of effective and safe methods of preventing type 1 diabetes mellitus (T1DM). Аim. Prediction of the early preclinical stage of T1DM. Materials and methods. We studied the predisposing and protective haplotypes (HLA-DRB1, gene DQ) together with immunological markers (ICA, GADA, IAA) in 224 discordant/concordant families. Results. At the Endocrinology Research Centre, population and family risks of the development of T1DM in Russia were calculated on the basis of population genetic approaches. The analysis of the prevalence of HLA genotypes among T1DM patients revealed that the high-risk haplotypes in the structure of genotype(s) DQ2 and/or DQ8 in combination with the others were 78%: of these genotypes DQ2/DQ8, DQ2/DQ2, and DQ8/DQ8 accounted for 35%; DQ2/X* and DQ8/X* accounted for 43%; and the low-risk genotype Х*/Х* accounted for 22%. The genotype Х/Х consisted of weaker predisposing haplotypes that were specific to the Russian population in combination with neutral haplotypes or those consisting of neutral haplotypes only. The analysis of patients with T1DM genotypes revealed that high-risk genotypes (DQ2/DQ8) were more common in ill children up to the age of 5 (33% of cases) than in T1DM children over 10 years (23%) (p=0.05). Conversely, the low-risk genotypes were significantly less likely to be found in children with manifestations of diabetes up to 5 years than in sick people over 10 years [5% and 13%, respectively (p

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Country-specific birth weight and length in type 1 diabetes high-risk HLA genotypes in combination with prenatal characteristics

Journal of Perinatology ◽

10.1038/jp.2011.26 ◽

2011 ◽

Vol 31 (12) ◽

pp. 764-769 ◽

Cited By ~ 6

Author(s):

Y Sterner ◽

◽

C Törn ◽

H-S Lee ◽

H Larsson ◽

...

Keyword(s):

Type 1 Diabetes ◽

Birth Weight ◽

High Risk ◽

Hla Genotypes ◽

Country Specific

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589-P: Effect of Oral Insulin (OI) on Combined Glucose and C-Peptide Endpoints in Individuals at High-Risk for Type 1 Diabetes (T1D)

Diabetes ◽

10.2337/db21-589-p ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 589-P

Author(s):

LAURA M. JACOBSEN ◽

DAVID D. CUTHBERTSON ◽

EMILY K. SIMS ◽

HEBA M. ISMAIL ◽

LINDA DIMEGLIO ◽

...

Keyword(s):

Type 1 Diabetes ◽

High Risk ◽

Oral Insulin ◽

C Peptide

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C-Peptide Response and HLA Genotypes in Subjects With Recent-Onset Type 1 Diabetes After Immunotherapy With DiaPep277

Diabetes ◽

10.2337/db10-0560 ◽

2011 ◽

Vol 60 (11) ◽

pp. 3067-3072 ◽

Cited By ~ 34

Author(s):

Raffaella Buzzetti ◽

Simona Cernea ◽

Antonio Petrone ◽

Marco Capizzi ◽

Marialuisa Spoletini ◽

...

Keyword(s):

Type 1 Diabetes ◽

C Peptide ◽

Recent Onset ◽

Onset Type ◽

Hla Genotypes

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Circulating β cell‐specific CD8 + T cells restricted by high‐risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes

Clinical & Experimental Immunology ◽

10.1111/cei.13391 ◽

2019 ◽

Vol 199 (3) ◽

pp. 263-277 ◽

Cited By ~ 5

Author(s):

L. Yeo ◽

I. Pujol‐Autonell ◽

R. Baptista ◽

M. Eichmann ◽

D. Kronenberg‐Versteeg ◽

...

Keyword(s):

At Risk ◽

T Cells ◽

Type 1 Diabetes ◽

High Risk ◽

Cd8 T Cells ◽

Hla Class I ◽

Class I ◽

Β Cell ◽

Hla Class I Molecules

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Parallel Multi-Omics in High-Risk Subjects for the Identification of Integrated Biomarker Signatures of Type 1 Diabetes

Biomolecules ◽

10.3390/biom11030383 ◽

2021 ◽

Vol 11 (3) ◽

pp. 383

Author(s):

Oscar Alcazar ◽

Luis F. Hernandez ◽

Ernesto S. Nakayasu ◽

Carrie D. Nicora ◽

Charles Ansong ◽

...

Keyword(s):

At Risk ◽

Type 1 Diabetes ◽

High Risk ◽

Clinical Symptoms ◽

Human Subjects ◽

Cell Loss ◽

Comprehensive Picture ◽

And Migration ◽

Biomarker Signature

Background: Biomarkers are crucial for detecting early type-1 diabetes (T1D) and preventing significant β-cell loss before the onset of clinical symptoms. Here, we present proof-of-concept studies to demonstrate the potential for identifying integrated biomarker signature(s) of T1D using parallel multi-omics. Methods: Blood from human subjects at high risk for T1D (and healthy controls; n = 4 + 4) was subjected to parallel unlabeled proteomics, metabolomics, lipidomics, and transcriptomics. The integrated dataset was analyzed using Ingenuity Pathway Analysis (IPA) software for disturbances in the at-risk subjects compared to controls. Results: The final quadra-omics dataset contained 2292 proteins, 328 miRNAs, 75 metabolites, and 41 lipids that were detected in all samples without exception. Disease/function enrichment analyses consistently indicated increased activation, proliferation, and migration of CD4 T-lymphocytes and macrophages. Integrated molecular network predictions highlighted central involvement and activation of NF-κB, TGF-β, VEGF, arachidonic acid, and arginase, and inhibition of miRNA Let-7a-5p. IPA-predicted candidate biomarkers were used to construct a putative integrated signature containing several miRNAs and metabolite/lipid features in the at-risk subjects. Conclusions: Preliminary parallel quadra-omics provided a comprehensive picture of disturbances in high-risk T1D subjects and highlighted the potential for identifying associated integrated biomarker signatures. With further development and validation in larger cohorts, parallel multi-omics could ultimately facilitate the classification of T1D progressors from non-progressors.

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T Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes

10.2337/figshare.14186459.v1 ◽

2021 ◽

Author(s):

Josephine M. Forbes ◽

Domenica A. McCarthy ◽

Andrew J. Kassianos ◽

Tracey Baskerville ◽

Amelia J. Fotheringham ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

High Risk ◽

Kidney Disease ◽

Kidney Injury ◽

Glycemic Variability ◽

Low Risk ◽

Kidney Injury Molecule 1

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of kidney disease (DKD). In Type 1 diabetes, increased uACR (urinary albumin-creatinine ratio) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule- 1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes [n=100; 20.0±2.8 yrs; M:F-54:46, HbA1C-66.1(12.3) mmol/mol; diabetes duration-10.7±5.2 yrs; BMI-24.5(5.3) kg.m-2] and 10 year historical uACR, HbA1C and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared to streptozotocin diabetes in Apolipoprotein E-/- mice. Kidney biopsies were used to examine infiltration of KIM-1 expressing T cells in DKD and compared with other chronic kidney disease. Individuals at high risk for DKD had persistent elevations in uACR (uACRAUC0-10yrs, 29.7±8.8 vs 4.5±0.5; P<0.01 vs low risk) and early kidney dysfunction including ~8.3ml.min-1.1.73m-2 higher estimated glomerular filtration rates (eGFRSCHWARTZ; Padj <0.031 vs low risk) and plasma KIM-1 concentrations (~15% higher vs low risk; P<0.034). High risk individuals had greater glycemic variability and increased peripheral blood T cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high risk youth with diabetes showed elevated collagen IV and SGLT2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8+ T cell production of KIM-1.

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The Deterrence of Rapid Metabolic Decline within 3 Months after Teplizumab Treatment in Individuals at High Risk for Type 1 Diabetes

10.2337/figshare.16640455.v1 ◽

2021 ◽

Author(s):

Emily K. Sims ◽

David Cuthbertson ◽

Kevan C. Herold ◽

Jay M. Sosenko

Keyword(s):

Type 1 Diabetes ◽

High Risk ◽

Oral Glucose ◽

Response Curves ◽

C Peptide ◽

Cell Decline ◽

Glucose Tolerance Tests ◽

Prevention Trials ◽

Mean Glucose

Endpoints that provide an early identification of treatment effects are needed to implement type 1 diabetes prevention trials more efficiently. To this end, we assessed whether metabolic endpoints can be used to detect a teplizumab effect on rapid β-cell decline within 3 months after treatment in high-risk individuals in the TrialNet teplizumab trial. Glucose and C-peptide response curves (GCRCs) were constructed by plotting mean glucose and C-peptide values from 2-hour oral glucose tolerance tests on a 2-dimensional grid. Groups were compared visually for changes in GCRC shape and movement. GCRC changes reflected marked metabolic deterioration in the placebo group within 3 months of randomization. By 6 months, GCRCs resembled typical GCRCs at diagnosis. In contrast, GCRC changes in the teplizumab group suggested metabolic improvement. Quantitative comparisons, including two novel metabolic endpoints that indicate GCRC changes, the Within Quadrant Endpoint (WQE) and the Ordinal Directional Endpoint (ODE), were consistent with visual impressions of an appreciable treatment effect at 3 and 6-month timepoints. In conclusion, an analytic approach combining visual evidence with novel endpoints, demonstrated that Teplizumab delays rapid metabolic decline, and improves the metabolic state within 3 months after treatment; this effect extends for at least 6 months.

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