PROJECT SUMMARY / ABSTRACT Pancreatogenic diabetes, or type 3c diabetes (T3cDM), is a known complication of acute pancreatitis (AP). Recent data suggest that T3cDM occurs more commonly than previously recognized and exhibits a spectrum of defects including features that overlap aspects of both type 1 and type 2 diabetes. At present, the extent to which immune activation, β cell dysfunction, and insulin resistance occur following AP and the genetic, metabolic and imaging correlates of these phenotypes have not been characterized. To address these knowledge gaps, we have assembled a multidisciplinary team with expertise in pancreatitis and exocrine pathophysiology, diabetes, β cell biology, diabetes genetics, and pancreatic imaging at the Indiana University School of Medicine. The IU Clinical Center will work with other members of the Type 1 Diabetes in Acute Pancreatitis Consortium to test the hypothesis that T3cDM encompasses a heterogeneous combination of metabolic and potentially immunologic phenotypes that are determined by distinct underlying pathophysiologies. We propose the following specific aims (SA) to meet the goals of this RFA. SA #1: To perform an observational study of robustly characterized adults with AP in order to address knowledge gaps in the natural history and incidence of autoantibody-positive diabetes (AAb+), impaired glucose tolerance (IGT)/impaired fasting glucose (IFG), and diabetes occurring subsequent to AP. Enrolled participants will be longitudinally characterized with emphasis on identifying genetic, immunological, metabolic, and clinical risk factors for the development of AAb+, IGT/IFG, or T3cDM. We will use state-of-the-art immunologic phenotyping and measurements of pancreatic β cell function to define the physiologic basis for metabolic dysregulation in T3cDM after AP. In tandem, a biorepository will be developed for undertaking translational, mechanistic and biomarker investigations and ancillary studies. SA#2: The Imaging Morphology of Pancreas in Diabetic Patients following Acute Pancreatitis (IMMINENT) study aims to utilize novel quantitative magnetic resonance imaging techniques as a non-invasive biomarker to identify patients at risk for the development of post-AP T3cDM. This longitudinal study will evaluate pancreatic parenchymal morphologic and pathophysiologic changes following AP in AAb+, euglycemic, IGT and DM individuals. Imaging phenotypes will be correlated with the metabolic, genetic and immunological phenotypes established in SA#1. SA#3: To perform a nested case control study using state-of-the-art techniques to define the underlying pathophysiology of endocrine and exocrine function in the subgroup of AAb+ individuals with AP-associated metabolic dysfunction relative to those who remain normoglycemic. We will undertake detailed metabolic phenotyping to evaluate islet cell responses (i.e. β and alpha cell function) in parallel with arginine-augmented hyperglycemic clamp methodology to measure functional β cell mass, and endoscopic assessment to define the relationship between impaired exocrine and endocrine function in AAb+ T3cDM. We will utilize 25 individuals with AAb+ and IGT or T3cDM and compare findings to results in 25 normoglycemic individuals with negative autoantibodies from SA#1.

PROJECT NARRATIVE While diabetes is a known complication of acute pancreatitis (AP), a full understanding of the underlying etiology of this disorder is lacking. To address this gap in knowledge, we have assembled a multidisciplinary team at Indiana University, with expertise in exocrine pancreas pathophysiology, diabetes, β cell biology, genetics, and pancreatic imaging. As part of the newly formed Type 1 Diabetes in Acute Pancreatitis Consortium, members of the Indiana University Clinical Center will collaborate with other consortium members to undertake studies focused on the comprehensive clinical, epidemiological, biological and imaging characterization of diabetes occurring after AP.