Molecular mechanisms underlying NHP pancreatic beta cell failure, and recovery

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DESCRIPTION (provided by applicant): Our team of experienced and productive investigators has the complementary skills, resources, and technologies to address the fundamental problem common to all diabetes: "Why do pancreatic beta cells fail?" Specifically, we will utilize the unique strengths developed at our three collaborating institutions (Oregon National Primate Research Center, Vanderbilt University, and the University of Massachusetts) to fully characterize non-human primate (NHP) islets' cellular composition, function, and gene expression profiles, using healthy donors, and donors in various specific metabolically perturbed states. In addition, and now possible for the first time, we will determine individual islet subsets' gene expression profiles using both healthy and metabolically challenged donor primates after those animals have been carefully phenotyped. While the ultimate goal is to elucidate human islet structure and function, relative to islets isolated from human and rodent donors, NHP model donors are distinctively well suited for these studies, i.e.: (1) While rodent islets differ significantly from human islets with regard to structure and function, NHP and human islets appear to be quite similar. (2) Human islets are exclusively isolated from cadaveric donors and as such the donor's pre-existing metabolic state cannot be assessed. The NHP donors are repeatedly metabolically phenotyped over time. (3) Human pancreases are subjected to variable periods of both warm- and cold-ischemia which affect islet viability, function, and gene expression. NHP pancreata are procured from surgically anesthetized donors under controlled conditions with minimal cold ischemia. Our team's studies and future work that will grow from our collaboration will enable us to identify new parameters that mark pancreatic beta cells as unhealthy, as well as novel biomarkers associated with islets displaying improved function after periods of dysfunction. Such markers can serve as potential therapeutic targets to prevent or respond to the beta cell failure that underlies both type-1 and type-2 diabetes. PUBLIC HEALTH RELEVANCE: A detailed characterization of beta cell biology will promote the rational design of therapies to abrogate the loss in pancreatic beta cell function that underlies diabetes and/or promote beta cell function recovery as occurs in many patients following bariatric surgery. Our team's efforts will utilize the relevant NHP model.