Epidemiological studies show that during the past three decades, there has been an alarming rate of growth in the number of type 2 diabetes patients, consequently driving the myriad diabetes-related complications and related mortality. The annual excess financial cost to society from 30 million diabetes patients and 86 million prediabetes patients is estimated to be $322 billion, a whopping 20% of the total health care spending in America with much more regarding lost revenue and associated immeasurable human suffering. Type 2 diabetes mellitus results from both increased insulin resistance and decreased insulin production. There is a failure of adaptive pancreatic ?-cell proliferation under diabetic stress, as well as increased apoptosis leading to ?-cell mass reduction. Cholecystokinin (CCK) is an incretin-like hormone produced by pancreatic ?-cells under conditions of stress and obesity. Obese mouse islets lacking CCK have decreased ?-cell mass and increased apoptosis. In pancreatic endocrine cells, we have demonstrated that CCK is both necessary and sufficient to promote ?-cell survival and to protect from cytokine-mediated ?-cell death. However, despite the accumulated observations of a pro-survival effect of CCK in various cell types and disease models, CCK receptor expression and activation in the ?-cell is mostly unknown. There is a need to understand which CCK receptor mediates the pro-survival effects in the ?-cell to develop a therapeutic that will take advantage of the positive effects of CCK in the ?-cell with a minimal amount of off-target side effects in other tissues. The long- term goal of this proposal is to identify and distinguish the functions of the CCK signaling pathways, understand how they contribute to the ?-cell protective effect in the pancreatic islet under diabetic stress, and determine the therapeutic significance of specific CCKR agonism. To that end, this proposal is aimed to test the central hypothesis that selective modulation of CCK receptor subtype-specific signaling in a beta-cell can protect ?-cell function and mass. With the completion of this project, we anticipate to better understand the therapeutic potential of selective CCK agonist which will open new avenues of developing a better tolerated, target specific, and clinically relevant drug by identifying direct roles and mechanisms by which CCK signaling promotes ?-cell survival. Finally, the completion of this project will ensure the successful progression of both research and professional career development towards the end of my doctoral training in molecular and cellular pharmacology, allowing a balanced development of qualities and experiences needed for a graduate student to make a smooth transition into the next stage of career in science where I will continue to progress towards becoming a successful, tenured professor in the field of islet biology.

Public Health Relevance

Diabetes mellitus is an unsolved clinical problem with ever-increasing prevalence in the global population. A mechanism-based therapeutic approach to diabetes prevention is necessary to address this epidemic. Identifying drug targets that can specifically promote pancreatic ?-cell survival safely and effectively will add an important new approach to the current diabetes therapies. By identifying direct roles and mechanisms by which cholecystokinin (CCK) signaling promotes ?-cell survival, the completion of the aims in this proposal will open new avenues of investigation for the development of therapies that can selectively agonize the CCK receptors to safely and efficiently improve ?-cell mass and function.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZDK1)
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Castle, Arthur
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University of Wisconsin Madison
Internal Medicine/Medicine
Schools of Medicine
United States
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