Chronic pancreatitis (CP) is a progressive disease, often leading to loss of exocrine and endocrine function and debilitating abdominal pain. It is unknown why some individuals progress and develop complications, including pancreatogenic diabetes (PDM) and/or pancreas cancer (PDAC). In this consortium, investigators propose to conduct well-powered studies of risk factors, environmental influences, and proof-of-concept studies to move the field forward, particularly those factors that increase the risk of PDM and PDAC. We propose the following specific aims (SA) to meet the goals of RFA-DK-14-027. SA #1: To define the natural history of pediatric and adult patients with an established diagnosis of CP or acute recurrent pancreatitis, we propose a prospective observational cohort study. We will place emphasis on identifying risk factors and phenotypes for those patients who develop PDM and/or PDAC. Biological specimens will be obtained to facilitate the study of possible biomarkers which might facilitate early disease diagnosis and management. SA #2: The pathogenesis of PDM and the interactions of non-endocrine pancreatic disease with islet dysfunction are not well understood. We will use measurements of islet function (oral glucose tolerance tests, arginine- augmented hyperglycemic clamps) in cross-sectional and prospective studies to define the prevalence and physiologic basis for metabolic dysregulation and diabetes in CP. We will also prospectively ascertain changes in islet function and transition to overt PDM, and correlate changes in metabolic status with changes in pancreatic inflammation and function. SA #3: To evaluate the diagnostic efficacy of Magnetic Resonance (MR) imaging in the non-invasive evaluation of suspected early CP, we propose a prospective study comparing CP patients to a control population with normal pancreatic exocrine function. A reduced T1-weighted MR signal, reduced diffusion and decreased duodenal fluid volume in response to secretin stimulation may suggest CP. SA #4: Galectin-3 (Gal-3) is a carbohydrate-binding protein which appears to be involved in fibrogenesis and tissue remodeling in CP. A Gal-3 inhibitor appears to be safe and shows potential for reducing organ fibrosis in humans. To determine the safety and efficacy of a Gal-3 inhibitor, we propose a randomized placebo- controlled trial in 66 CP patients. Improvement in post-therapy duodenal fluid bicarbonate level will be the primary efficacy endpoint. We anticipate that this drug will reverse fibrosis, as manifested by improvement in duodenal bicarbonate level. Additional endpoints including MRI/MRCP appearance, Gal-3 level, quality of life, abdominal pain scores and ?-cell function will also be assessed.

Public Health Relevance

Chronic pancreatitis (CP) is a progressive, unrelenting disease, often leading to loss of exocrine and endocrine function and debilitating abdominal pain, resulting in significant healthcare costs. It is unknown why some individuals progress to severe disease and develop serious complications, including diabetes and/or pancreas cancer. In this consortium, investigators from several institutions propose to conduct well-powered studies of risk factors, environmental influences, and proof-of-concept studies to move the field forward, particularly those factors that increase the risk of diabetes and malignancy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK108323-03
Application #
9352328
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Unalp-Arida, Aynur
Project Start
2015-09-28
Project End
2020-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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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
Tirkes, Temel (2018) Chronic Pancreatitis: What the Clinician Wants to Know from MR Imaging. Magn Reson Imaging Clin N Am 26:451-461
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Pendharkar, Sayali A; Drury, Marie; Walia, Monika et al. (2017) Gastrin-Releasing Peptide and Glucose Metabolism Following Pancreatitis. Gastroenterology Res 10:224-234
Korc, Murray; Jeon, Christie Y; Edderkaoui, Mouad et al. (2017) Tobacco and alcohol as risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol 31:529-536

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