This application describes a robust Southern California-based Clinical Center for participation in the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC). Proposed protocols address the metabolic mechanisms and the genetic, protein, and imaging signature of patients with acute pancreatitis (AP) and recurrent acute pancreatitis (RAP) who are at high risk for future development of diabetes. AP is the most common cause of pancreatogenic diabetes. While meta-analyses have revealed an incidence rate of 23% for diabetes arising after AP, they have not shed light on the type of diabetes that develops, which may comprise autoimmune or idiopathic type 1 diabetes (T1DM), type 2 diabetes (T2DM), or a unique diabetes pathobiology. A detailed understanding of diabetes developing after AP will yield great benefit by facilitating novel approaches to predict, prevent, and treat this form of diabetes. The following aims are proposed to address these goals:
Specific Aim 1. Recruit a cohort of non-diabetic patients with a recent episode of AP or RAP and prospectively characterize their islet autoimmunity and glucose/insulin homeostasis using the frequently sampled intravenous glucose tolerance test and mixed meal tolerance tests performed 1 month after hospital discharge, and at 3, 6, 12, 18, and 24 months, and yearly thereafter. The goals of this aim are to (a) determine the incidence of diabetes after AP, (b) identify the types of diabetes that develop after AP, (c) identify early metabolic trajectories associated with post-AP diabetes, (d) assemble the cohort that will be the platform for Aims 2-4.
Specific Aim 2. Evaluate genetic and protein risk factors for diabetes in patients with AP or RAP.
This Aim will evaluate association of genetic risk scores for T1DM and T2DM with post AP diabetes. Thirteen candidate proteins, associated with post AP diabetes in preliminary studies, will be assessed for association with incident diabetes after AP, yielding a key set of proteins with utility not only in diabetes prediction but also targets for future preventive or therapeutic measures.
Specific Aim 3. Characterize the imaging phenotype that predicts development of diabetes after AP or RAP. Retrospective CT scans obtained during hospitalization for AP as well as CT and novel multiparametric MRI scans obtained 1 and 12 months afterward will undergo artificial intelligence analysis to identify the imaging biomarkers that signal diabetes risk.
Specific Aim 4. Develop a multi-factorial model to predict development of diabetes after AP or RAP. A wealth of data will be collected from Aims 1-3, which will be combined with clinical factors to build and validate (in independent datasets) an integrative predictive model of post AP diabetes. The goal is to create a model that can be used in clinical settings to identify those at highest risk, facilitating targeted measures to prevent diabetes. This innovative research will be conducted by an experienced team of investigators in endocrinology, gastroenterology, imaging, physiology, and epidemiology to solve a problem of great public health significance.
This is an application for the establishment of a Southern California Clinical Center to participate in the Type 1 Diabetes in Acute Pancreatitis Consortium, comprised of an expert team to carry out studies of the Consortium in Los Angeles County, the most populous and ethnically diverse county in the United States. Acute pancreatitis, one of the most frequent causes of hospitalization in the USA, greatly increases the risk of future development of diabetes, yet the type of diabetes is unclear. We propose studies to determine the metabolic mechanisms and the genetic, protein, and imaging signature of diabetes occurring after pancreatitis, which will provide the means to understand, prevent, and treat this form of diabetes.
