This application seeks to establish a Clinical Center (CC) at Cedars-Sinai Medical Center to conduct studies on chronic pancreatitis (CP), diabetes, and pancreatic cancer (RFA-DK-14-027). Drs. Stephen Pandol and Mark Goodarzi (PDs) have assembled a team of gastroenterologists, endocrinologists, physiologists, and epidemiologists who are eager to collaborate in the Consortium in translational pancreatic research. Aside from a track record in clinical investigation and prospective follow-up studies that are the foundation for the proposed CC, our location in Los Angeles County (>9 million inhabitants) affords the Consortium research opportunities in diverse populations through our clinical partners at UCLA and other large medical centers in the region. We have also partnered with productive pancreatology colleagues from Auckland (New Zealand). The proposed studies will elucidate the mechanisms underlying glucose intolerance in CP. Pancreatogenic diabetes (i.e., Type 3c diabetes, T3cDM) develops in most individuals with CP. The risk for pancreatic cancer in patients with both pancreatitis and diabetes is increased 33-fold. Prevention of pancreatitis progression and diabetes (and thus pancreatic cancer) is a critical goal of the Consortium. The following outlines study aims that will be proposed to the Steering Committee once the Consortium is implemented:
Aim 1. Test the hypothesis that chronic pancreatitis patients with prediabetes have insulin resistance as well as impaired insulin secretion. Patients with and without CP and with and without prediabetes (4 groups) will undergo the frequently-sampled intravenous glucose tolerance test and mixed meal tolerance tests to characterize insulin resistance, insulin secretion, insulin clearance; and incretin and islet hormonal responses. In focusing on prediabetes, this Aim will identify early defects that predispose to T3cDM.
Aim 2. Test the hypothesis that pancreatic enzyme insufficiency in chronic pancreatitis leads to attenuated incretin responses and consequent deficient insulin secretion. The subjects from Aim 1 who have CP and prediabetes will be treated with 2 weeks of pancreatic enzyme supplementation (PES), followed by a repeat physiologic evaluation. It is anticipated that PES will result in augmented incretin responses to a meal, resulting in improved insulin secretion and reduction in glucose levels.
Aim 3. Test the hypothesis that metformin treatment will prevent development of diabetes in patients with acute recurrent and chronic pancreatitis. The ability of metformin to prevent Type 3c diabetes is unknown. We will conduct a diabetes prevention study of metformin versus placebo in these patients. Research in CP and pancreatic cancer research requires diverse leadership and multiple clinical sites. We have assembled experts for our CC with skills not always addressing the proposed Aims in recognition of the broad scope of experience and expertise needed to optimize the Consortium's potential. We are committed to interaction with the NIDDK/NCI, the other CCs, and the Coordination and Data Management Center.

Public Health Relevance

This is an application for the establishment of a Clinical Center (CC) at Cedars-Sinai Medical Center to conduct studies on chronic pancreatitis, diabetes, and pancreatic cancer (RFA-DK-14-027). We have developed 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. Patients with both chronic pancreatitis and diabetes have up to a 33 fold increased risk of pancreatic cancer. We propose studies to both determine the mechanisms of diabetes in the patients with chronic pancreatitis and test preventative therapies for the diabetes that will, in turn, decrease the rate of pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK108314-02
Application #
9150584
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O1)S)
Program Officer
Unalp-Arida, Aynur
Project Start
2015-09-28
Project End
2020-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
2
Fiscal Year
2016
Total Cost
$459,262
Indirect Cost
$190,336
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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Uc, Aliye; Perito, Emily R; Pohl, John F et al. (2018) INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE Cohort Study: Design and Rationale for INSPPIRE 2 From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. Pancreas 47:1222-1228
Hart, Phil A; Andersen, Dana K; Mather, Kieren J et al. (2018) Evaluation of a Mixed Meal Test for Diagnosis and Characterization of PancrEaTogEniC DiabeTes Secondary to Pancreatic Cancer and Chronic Pancreatitis: Rationale and Methodology for the DETECT Study From the Consortium for the Study of Chronic Pancreatitis Pancreas 47:1239-1243
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Serrano, Jose; Andersen, Dana K; Forsmark, Christopher E et al. (2018) Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer: From Concept to Reality. Pancreas 47:1208-1212
Forsmark, Christopher E; Andersen, Dana K; Farrar, John T et al. (2018) Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis: Summary of the Working Group on Drug Development and Trials in Chronic Pancreatitis at the National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas 47:1200-1207
Fisher, William E; Cruz-Monserrate, Zobeida; McElhany, Amy L et al. (2018) Standard Operating Procedures for Biospecimen Collection, Processing, and Storage: From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. Pancreas 47:1213-1221
Birtolo, Chiara; Pham, Hung; Morvaridi, Susan et al. (2017) Cadherin-11 Is a Cell Surface Marker Up-Regulated in Activated Pancreatic Stellate Cells and Is Involved in Pancreatic Cancer Cell Migration. Am J Pathol 187:146-155
Lew, Daniel; Afghani, Elham; Pandol, Stephen (2017) Chronic Pancreatitis: Current Status and Challenges for Prevention and Treatment. Dig Dis Sci 62:1702-1712

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