Project Abstract The Chronic Pancreatitis Diabetes Pancreatic Cancer (CPDPC) research consortium is advancing care for patients with exocrine disease, particularly focused on the overlap of these three conditions through a series of multicenter collaborative clinically-focused research studies. The University of Minnesota (UMN) offers both the clinical expertise and the academic environment to contribute substantially and innovatively to the CPDCP. The UMN provides state of the art clinical care for pancreatitis and pancreatic cancer, and receives patient referrals for endoscopic and surgical management of complex acute pancreatitis and chronic pancreatitis (CP) from across the U.S. Dr. Bellin and Beilman (Co-PIs) will add expertise on chronic pancreatitis-related diabetes mellitus (CP-DM) and pancreatic surgery to the current consortium membership. Together Bellin and Beilman have established ongoing collaborations with multiple lead investigators within the CPDCP, highlighting the ability of this team to integrate seamlessly into the existing CPDCP Clinical Centers. Through engagement as a sub-site for Ohio State and INSPPIRE within the current consortium structure, UMN has already contributed to ancillary studies development, manuscripts, and enrollment of participants in the CPDPC developed INSPPIRE and DETECT protocols. In summary, UMN has documented its ability to contribute to the CPDCP goals and will add value as a recognized Clinical Center. As a Clinical Center within the CPDPC, we will enroll adults and children with pancreatitis into the existing CPDPC studies including PROCEED, INSPPIRE, and DETECT (AIM 1). We will also participate in working groups, development of protocols and standard operating procedures, and proposal of new ancillary studies. We propose to build upon the current CPDCP efforts to define mechanisms of CP-DM by studying the pathophysiology and mechanisms of glucose dysregulation and CP-DM after pancreatic surgery. Pancreatic surgery including surgical drainage, Whipple procedure, or total pancreatectomy with islet autotransplant fundamentally alters the pancreatic-intestinal anatomy and may have different endocrine mechanisms by which hyperglycemia or hypoglycemia develop; since ~20% of patients with CP may have eventually surgery, it is important to understand disease in this subgroup of patients, in order to properly screen for, treat, and ultimately prevent CP-DM. For AIM 2 we will enroll patients with CP who have had surgery (n=75 per surgical group) and an endoscopic CP and healthy control groups to test insulin, pancreatic polypeptide (PP), and incretin hormone secretion and insulin sensitivity by mixed meal tolerance and frequent sample intravenous glucose tolerance testing to differentiate mechanisms of dysglycemia in these groups. For AIM 3, non-diabetic patients will be re- studied 12-18 months later to determine risk factors for progressive defects in glycemic regulation. In addition, we will assess novel exploratory biomarkers (not routinely studied in CP-DM) including markers of beta cell death, genetic risk factors, and beta cell autoantibodies.

Project Narrative Chronic pancreatitis is a painful and debilitating disease with few medical treatment options. Patients often require pancreatic surgery for relief of pain, but pancreatic surgery may increase the risk for blood glucose abnormalities and diabetes mellitus. At the University of Minnesota, we will enroll patients in multiple clinical research studies in the Chronic Pancreatitis Diabetes Pancreatic Cancer (CPDPC) Consortium and will develop new clinical studies that better define how different pancreatic surgeries impact diabetes risk.