Pioglitazone Therapy for Endocrine and Exocrine Disease in Alcoholic Pancreatitis

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DESCRIPTION (provided by applicant): As a member of the GI Division and Diabetes Center, my research focuses on endocrine and exocrine pancreatic diseases, with interest in the relationship between diabetes mellitus or insulin resistance and reduced pancreatic exocrine secretion and/or chronic pancreatitis (CP). We intend to translate data from rodent studies to humans by evaluating the therapeutic effect of PPAR-3 agonists on endocrine function & exocrine function & structure of CP. In collaboration with the Dr. M.A. Anderson and the clinical GI pancreas group, and Dr. W.H. Herman, Director of the Diabetes Research Center, data from this study will be used to compete for extramural funding to carry out a larger, multi- centered study (and lead toward a pancreas program project) In health, insulin potentiates postprandial and secretagogue stimulated pancreatic exocrine secretion by ~5-fold. In disease, pancreatic endocrine and exocrine disorders frequently coexist in presumed primary endocrine or exocrine disorders; insulin resistance and 2-cell dysfunction occur in CP and impaired exocrine pancreatic secretion occurs with insulinopenia and insulin resistance. In patients with mild- moderate CP, the relationship between exocrine and endocrine dysfunction is under- investigated, but the majority develop insulin resistance. Of therapeutic importance, it is established that insulin sensitizing PPAR-3 agonists ameliorate inflammation and fibrosis and even abort established CP in rat models. Further, we showed that an established model of insulin resistance (endothelial NO synthase (eNOS) gene deleted mice) has a 50% reduction in pancreatic exocrine secretion evoked by CCK and that treatment with a PPAR-3 agonist restores insulin sensitivity and exocrine pancreatic secretion. Findings in eNOS (-/-) mice are relevant to CP because the major risk factors for CP are alcohol and smoking, and both uncouple eNOS from NO production. Hence, with coexisting endocrine and exocrine pancreas disorders, successful treatment of one disorder may require treatment of both. Our first hypothesis is that endocrine and exocrine dysfunction are reversible in patients with mild-moderate alcoholic CP. Secondly, we hypothesize that pioglitazone, by improving endocrine dysfunction, will improve pancreatic exocrine function and structure and quality of life and reduce pain. To begin to test these hypotheses we will perform a prospective, randomized controlled study in patients with mild-moderate alcoholic CP to determine whether pioglitazone vs. placebo improves 1) pancreatic endocrine function by oral glucose tolerance testing, 2) pancreatic exocrine secretion & structure and 3) health related quality of life. PROJECT NARRATIVE CP is a progressive clinical disease involving endocrine and exocrine pancreas dysfunction and causing debilitating abdominal pain. "Benign" pancreatic diseases, including CP, affect 5-24 million in the U.S. and cost up to $2.5 billion annually. The triggers, thresholds, immunologic response and cellular mechanisms of CP are unclear and therapies remain unproven. This study may provide insight into endocrine & exocrine pancreas interactions found in diabetes mellitus, insulin resistance and CP and clarify whether therapies for insulin resistance can reverse the natural history of CP and delay/abort diabetes, malabsorption, calcification and pain.