Type 1 Diabetes (T1D), also known as Juvenile Diabetes, is a disease that results from a highly specific, autoimmune destruction of the insulin-producing ?-cells of the pancreas. To date, T1D is the most common chronic disease in children and adolescents. For this reason, much effort is placed on finding strategies to replenish ss-cells. Currently, Joslin Diabetes Center is conducting a study known as the 50-Year Medalist Study that consists of studying a rare and exclusive group of T1D patients, the """"""""Medalists"""""""", who have endured this disease for 50 years or more. Recent studies have found that a small cohort of these patients can still produce C-peptide hormone, an indicator of endogenous insulin production, after a meal despite the extreme duration of their disease. Furthermore, postmortem examination of C-peptide positive patient pancreases revealed that they contained a significant proportion of residual ? -cells. However, the reason for the survival or source of ? - cells in these patients remains unknown. From these observations, I hypothesize that the residual ? -cell population observed in C-peptide positive Medalists is due to an increased resistance of ? -cells to microenvironmental stress and/or cytotoxic insults. Also, it is possible that this resistance may be present at earlier ? -cell progenitor stages, dela the onset of T1D and/or allow the survival of ? -cell populations in some patients. In order to address this question, I propose here an exciting project that will take advantage of the exclusive access to Medalists'skin samples at Joslin Diabetes Center to generate patient-specific induced pluripotent stem cells (iPSCs) and further differentiate them toward the ?-cell lineage. An examination of the differences between these cells'gene and protein signatures as well as an assessment of their susceptibility to various cytotoxic insults throughout their development will then be performed. Ultimately, the proposed experiments will provide a better understanding of the mechanisms that enhance ? -cell survival in the context of extreme-duration T1D.

Public Health Relevance

The aim of this project is to derive induced pluripotent stem cells from skin biopsies from patients with long-standing type 1 diabetes (Joslin Medalist patients) and differentiate these cells toward the ? -cell lineage. Previous observations have found that a small cohort of these patients possess functional ? -cells despite the extreme duration of their disease. These cells will then be exposed to different conditions, such as inflammatory cytokines and elevated glucose levels that are known to induce cellular stress with the intention of elucidating mechanisms that allow ?-cell survival in the face of such cytotoxic stimuli.

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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Mcbryde, Kevin D
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Harvard Medical School
Schools of Medicine
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Teo, Adrian Kee Keong; Lau, Hwee Hui; Valdez, Ivan Achel et al. (2016) Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia. Stem Cell Reports 6:357-67
Valdez, Ivan Achel; Dirice, Ercument; Gupta, Manoj K et al. (2016) Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation. Cell Rep 15:460-470
Valdez, Ivan A; Teo, Adrian K K; Kulkarni, Rohit N (2015) Cellular stress drives pancreatic plasticity. Sci Transl Med 7:273ps2
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