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

Giovenzana, Anna; Vecchio, Federica; Cugnata, Federica; Nonis, Alessandro; Mandelli, Alessandra; Stabilini, Angela; Mazzi, Benedetta; Pellegrin, Maurizio De; Laurenzi, Andrea; Bonfanti, Riccardo; Battaglia, Manuela; Bosi, Emanuele; Petrelli, Alessandra

doi:10.1007/s00592-021-01819-2

Cited by 5 publications

(5 citation statements)

References 33 publications

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“…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 ). Further evidence for the importance of pancreatic enzymes comes from a recent Mendelian Randomisation study to identify circulating proteins influencing type 1 diabetes susceptibility, which showed that increased levels of serum chymotrypsinogen was associated with a decreased risk of T1D ( 62 ).…”

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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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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“…However, heterogeneity in T1D onset as well as response to therapies calls for a better understanding of pathophysiology and additional markers of risk. Exocrine atrophy precedes the onset of detectable islet autoimmunity in some subjects [ 5 , 6 , 18 , 30 ], signifying that measures of exocrine pancreas size and function could be beneficial early biomarkers. If exocrine loss occurs before the onset of islet autoantibodies, markers of exocrine pancreas size or function could be useful to predict early T1D risk.…”

Section: Using Exocrine Biomarkers In Disease Prediction and Monitoringmentioning

confidence: 99%

Type 1 Diabetes: A Disorder of the Exocrine and Endocrine Pancreas

Bruggeman,

Schatz

2023

J Cell Immunol

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Type 1 diabetes has historically been described as an endocrine (β-cell) specific autoimmune disease. However, a substantial reduction (20-50%) in pancreas organ size and subclinical to symptomatic exocrine pancreatic insufficiency are present at diagnosis and may begin even prior to the development of islet autoimmunity. The mechanisms of exocrine loss in type 1 diabetes are not well understood, but leading hypotheses include developmental defects, β-cell loss resulting in exocrine atrophy, or autoimmune or inflammatory destruction of exocrine cells. Inflammatory changes including acute and chronic pancreatitis, exocrine T cell infiltration and classical complement activation, and serum exocrine autoantibodies within type 1 diabetes individuals suggest that an autoimmune or inflammatory process may contribute to exocrine pancreatic dysfunction. Exocrine pancreas atrophy primarily occurs prior to the onset of clinical disease. Indeed, recent work implicates exocrine-specific alterations in gene and protein expression as key in type 1 diabetes development. Measures of exocrine size and function could be useful additions in the prediction of disease onset and in identifying potential therapeutic responders to disease therapies, however, this is an underdeveloped area of research. Additionally, exocrine pancreatic insufficiency is underdiagnosed in individuals with type 1 diabetes and individualized treatment protocols are lacking. Much work remains to be done in this area, but we can definitively say that type 1 diabetes is a disorder of both the exocrine and endocrine pancreas likely from the start.

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“…It has been postulated that patients with T1D exhibit exocrine pancreas dysfunction secondary to a lack of insulin and dysregulation of endocrine function. 13,14 Imaging studies have reported a correlation of the T1 signal intensity ratio (SIR) specifically with pancreatic exocrine dysfunction measured by the endoscopic pancreatic function tests. 15,16 Noda et al 17 reported that pancreatic T1 relaxation time is significantly increased with pre-DM individuals and moderately correlates with HbA1c (glycated hemoglobin), suggesting that T1 has the potential of being an imaging biomarker for DM.…”

Section: Background and Rationalementioning

confidence: 99%

“…We will measure the pancreatic fat signal using MRI, and we expect the fat fraction to be higher in the new-onset DM group compared with the control group. It has been postulated that patients with T1D exhibit exocrine pancreas dysfunction secondary to a lack of insulin and dysregulation of endocrine function 13,14 . Imaging studies have reported a correlation of the T1 signal intensity ratio (SIR) specifically with pancreatic exocrine dysfunction measured by the endoscopic pancreatic function tests 15,16 .…”

Section: Background and Rationalementioning

confidence: 99%

Design and Rationale for the Use of Magnetic Resonance Imaging Biomarkers to Predict Diabetes After Acute Pancreatitis in the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study

Tirkes¹,

Chinchilli²,

Bağcı³

et al. 2022

Pancreas

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This core component of the Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM) study will examine the hypothesis that advanced magnetic resonance imaging (MRI) techniques can reflect underlying pathophysiologic changes and provide imaging biomarkers that predict diabetes mellitus (DM) after acute pancreatitis (AP). A subset of participants in the DREAM study will enroll and undergo serial MRI examinations using a specific research protocol. The aim of the study is to differentiate at-risk individuals from those who remain euglycemic by identifying parenchymal features after AP. Performing longitudinal MRI will enable us to observe and understand the natural history of post-AP DM. We will compare MRI parameters obtained by interrogating tissue properties in euglycemic, prediabetic, and incident diabetes subjects and correlate them with metabolic, genetic, and immunological phenotypes. Differentiating imaging parameters will be combined to develop a quantitative composite risk score. This composite risk score will potentially have the ability to monitor the risk of DM in clinical practice or trials. We will use artificial intelligence, specifically deep learning, algorithms to optimize the predictive ability of MRI. In addition to the research MRI, the DREAM study will also correlate clinical computed tomography and MRI scans with DM development.

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

Cited by 5 publications

References 33 publications

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

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

Type 1 Diabetes: A Disorder of the Exocrine and Endocrine Pancreas

Design and Rationale for the Use of Magnetic Resonance Imaging Biomarkers to Predict Diabetes After Acute Pancreatitis in the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study

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