Changes in pancreatic exocrine function in young at‐risk children followed to islet autoimmunity and type 1 diabetes in the
            <scp>ENDIA</scp>
            study

Penno, Megan A. S.; Oakey, Helena; Augustine, P; Taranto, Mario; Barry, Simon C.; Colman, Peter G; Craig, Maria E.; Davis, Elizabeth A.; Giles, Lynne; Harris, Mark; Haynes, Aveni; McGorm, Kelly; Morahan, Grant; Morbey, Claire; Rawlinson, William D.; Sinnott, Richard; Soldatos, Georgia; Thomson, Rebecca L.; Vuillermin, Peter; Wentworth, John M.; Harrison, Leonard C.; Couper, Jennifer

doi:10.1111/pedi.13056

Cited by 11 publications

(15 citation statements)

References 13 publications

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“…Indeed, lipase levels were more variable compared with trypsinogen, which could be a contributing factor. Although longitudinal studies are needed to further address the ability of pancreatic exocrine enzymes to predict disease stage and progression, our data are in line with a recent report from the Environmental Determinants of Islet Autoimmunity (ENDIA) study demonstrating that fecal elastase-1 levels decline longitudinally in at-risk children who eventually diabetes.diabetesjournals.org develop islet autoimmunity and type 1 diabetes (39). Serological markers are likely of greater clinical utility given historical challenges surrounding patient compliance with fecal tests (40).…”

Section: Discussionsupporting

confidence: 88%

Exocrine Pancreatic Enzymes Are a Serological Biomarker for Type 1 Diabetes Staging and Pancreas Size

et al. 2021

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Exocrine pancreas abnormalities are increasingly recognized as features of type 1 diabetes. We previously reported reduced serum trypsinogen levels and in a separate study, smaller pancreata at and before disease onset. We hypothesized that three pancreas enzymes (amylase, lipase, and trypsinogen) might serve as serological biomarkers of pancreas volume and risk for type 1 diabetes. Amylase, lipase, and trypsinogen were measured from two independent cohorts, together comprising 800 serum samples from single-autoantibody–positive (1AAb+) and multiple-AAb+ (≥2AAb+) subjects, individuals with recent-onset or established type 1 diabetes, their AAb-negative (AAb−) first-degree relatives, and AAb− control subjects. Lipase and trypsinogen were significantly reduced in ≥2AAb+, recent-onset, and established type 1 diabetes subjects versus control subjects and 1AAb+, while amylase was reduced only in established type 1 diabetes. Logistic regression models demonstrated trypsinogen plus lipase (area under the receiver operating characteristic curve [AUROC] = 81.4%) performed equivalently to all three enzymes (AUROC = 81.4%) in categorizing ≥2AAb+ versus 1AAb+ subjects. For cohort 2 (n = 246), linear regression demonstrated lipase and trypsinogen levels could individually and collectively serve as indicators of BMI-normalized relative pancreas volume (RPVBMI, P < 0.001), previously measured by MRI. Serum lipase and trypsinogen levels together provide the most sensitive serological biomarker of RPVBMI and may improve disease staging in pretype 1 diabetes.

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Section: Discussionsupporting

confidence: 88%

Exocrine Pancreatic Enzymes Are a Serological Biomarker for Type 1 Diabetes Staging and Pancreas Size

et al. 2021

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“…Exocrine pancreas dysfunction is commonly accepted as a feature of type 1 diabetes, as evidence from multiple independent studies have shown decreased levels of pancreatic enzymes [15][16][17][18][27][28][29][30]. In this study, we demonstrate that impaired exocrine function, resulting in lower levels of circulating P-amylase and lipase, can be detected long before the onset of clinical symptoms in at-risk adult individuals, but not in children.…”

Section: Discussionsupporting

confidence: 47%

“…To strengthen these results, a validation cohort would be needed. Reduced levels of FE-1 [16], serum trypsinogen [17] and lipase [18] have been reported in children at-risk of developing type 1 diabetes. In our analysis, we have taken into account the effect of multiple parameters (such as age, sex and number of autoantibodies) on P-amylase and lipase levels.…”

Section: Discussionmentioning

confidence: 98%

“…Immune cells are abundant both in the islets and the exocrine compartment [8][9][10][11][12][13], and autoantibodies targeting exocrine pancreas-derived proteins were described in at-risk individuals as well as in patients with type 1 diabetes [14]. The reduced pancreatic mass, accompanied by immune cell infiltration, results in a subclinical exocrine functional impairment, characterized by an overall reduction of exocrine pancreatic enzymes, with trypsinogen, lipase and fecal elastase (FE-1) levels already decreased in at-risk individuals [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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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“…This suggests that pancreatic shrinkage is already ongoing in pre-diabetes. In a study of 85 children participating in the ENDIA study, levels of Fecal Elastase-1, another marker of pancreatic function, were shown to decrease over time in 28 progressors compared to non-progressors ( 60 ). A study of TrialNet participants at diagnosis and in those with islet autoantibodies showed that lower levels of circulating P-amylase and lipase (both exocrine enzymes) can be detected before the onset of clinical symptoms in at-risk adult individuals, but not in children ( 61 ).…”

Section: Monitoring Efficacy In Clinical Trialsmentioning

confidence: 99%

The importance of biomarker development for monitoring type 1 diabetes progression rate and therapeutic responsiveness

Fyvie,

Gillespie

2023

Front. Immunol.

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Type 1 diabetes (T1D) is an autoimmune condition of children and adults in which immune cells target insulin-producing pancreatic β-cells for destruction. This results in a chronic inability to regulate blood glucose levels. The natural history of T1D is well-characterized in childhood. Evidence of two or more autoantibodies to the islet antigens insulin, GAD, IA-2 or ZnT8 in early childhood is associated with high risk of developing T1D in the future. Prediction of risk is less clear in adults and, overall, the factors controlling the progression rate from multiple islet autoantibody positivity to onset of symptoms are not fully understood. An anti-CD3 antibody, teplizumab, was recently shown to delay clinical progression to T1D in high-risk individuals including adults and older children. This represents an important proof of concept for those at risk of future T1D. Given their role in risk assessment, islet autoantibodies might appear to be the most obvious biomarkers to monitor efficacy. However, monitoring islet autoantibodies in clinical trials has shown only limited effects, although antibodies to the most recently identified autoantigen, tetraspanin-7, have not yet been studied in this context. Measurements of beta cell function remain fundamental to assessing efficacy and different models have been proposed, but improved biomarkers are required for both progression studies before onset of diabetes and in therapeutic monitoring. In this mini-review, we consider some established and emerging predictive and prognostic biomarkers, including markers of pancreatic function that could be integrated with metabolic markers to generate improved strategies to measure outcomes of therapeutic intervention.

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Changes in pancreatic exocrine function in young at‐risk children followed to islet autoimmunity and type 1 diabetes in the ENDIA study

Abstract: Full title:Changes in pancreatic exocrine function in young at-risk children followed to islet autoimmunity and type 1 diabetes in the ENDIA study

Cited by 11 publications

References 13 publications

Exocrine Pancreatic Enzymes Are a Serological Biomarker for Type 1 Diabetes Staging and Pancreas Size

Exocrine Pancreatic Enzymes Are a Serological Biomarker for Type 1 Diabetes Staging and Pancreas Size

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

The importance of biomarker development for monitoring type 1 diabetes progression rate and therapeutic responsiveness

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