Pathophysiology, Epidemiology, and Prevention of Pancreatogenic Diabetes

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 DESCRIPTION (provided by applicant): 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.