Evaluating the Immunopathogenesis of Diabetes After Acute Pancreatitis in the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study

Abstract

The association between acute pancreatitis (AP) and diabetes mellitus (DM) has long been established, with the initial descriptions of AP patients presenting with DM after a bout of AP published in the 1940s and 50s. However, the potential mechanisms involved, particularly those components related to the immune system, have not been well defined. The Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM) study is a multicenter clinical study designed to understand the frequency and phenotype of DM developing after AP. This article describes one objective of the DREAM study: to determine the immunologic mechanisms of DM after AP, including the contribution of β-cell autoimmunity. This component of the study will assess the presence of islet autoimmunity, as well as the magnitude and kinetics of the innate and adaptive immune response at enrollment and during longitudinal follow-up after 1 or more episodes of AP. Finally, DREAM will evaluate the relationship between immune features, DM development, and pancreatitis etiology and severity.

Rationale and Design for the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study

“…Additional secondary end points related to metabolic and immunological mechanisms of diabetes as well as imaging findings are discussed elsewhere. [13][14][15] STATISTICAL CONSIDERATIONS We will apply a discrete time-to-event regression analysis with interval censoring because we anticipate the occurrence of DM for most participants will be detected at the scheduled visits (eg, 3, 6, 12, 18, 24, and 36 months). We will enroll up to 1000 participants (including up to 800 without preexisting DM who will undergo longitudinal follow-up and up to 200 with preexisting DM who will only undergo baseline assessment) into the DREAM study.…”

“…Specifically, we will evaluate the readmission rate, incidence of exocrine pancreatic dysfunction (serially measured with a combination of symptoms and fecal elastase 1 levels), changes in quality of life, healthcare utilization, and the recurrence of AP and/or progression to chronic pancreatitis. Additional secondary end points related to metabolic and immunological mechanisms of diabetes as well as imaging findings are discussed elsewhere 13–15 …”

Standard Operating Procedures for Biospecimen Collection, Processing, and Storage

“…11 Finally, the Tempus tube (Applied Biosystems, Waltham, Mass) samples will be distributed for RNA transcriptome analysis as described in the immunology working group manuscript. 8 A PAXgene tube (Qiagen, Germantown, Md) will be collected once from each participant in the study for future genomic studies (Fig. 1).…”

“…However, the working groups specific to the T1DAPC brought unique insight to the biorepository. The rationale and mechanisms of obtaining these samples are described in detail elsewhere 7,8 . Specifically, the immunology working group strongly supported the use of centralized and standardized processing of PBMC 9 to minimize the variability introduced by having multiple laboratories process these samples and to standardize processing and storage.…”

Assessing the Pathophysiology of Hyperglycemia in the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study

“…For example, after recovery from mild AP, there is an increased risk of new-onset DM years later, 6 suggesting ongoing metabolic changes after AP. Conceivable mechanisms, at least in a subset of individuals, include protracted islet cell loss from ongoing inflammation and β-cell autoimmunity triggered by the AP episode 7,8 . A role for insulin resistance has also been suggested, 9 but studies have mostly relied on indirect surrogate markers of insulin resistance HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) 5,9 .…”