Diabetes mellitus is a disease of disordered regulation of blood sugar, affecting over eight percent of people in the United States. In diabetes, the insulin-producing beta cells of the pancreatic islets are unable to properly maintain normal blood glucose levels because of either insufficient beta cell number or insufficient beta cell function. Treating diabetes by replacing islets has been proposed as a therapeutic strategy, but transplantable material is limited. Understanding how to produce functional beta cells from alternate sources could bypass this limitation and enable islet replacement therapies. Current methods for in vitro generation of beta cells produce cells that express insulin, but that resembles fetal or neonatal beta cells with limited glucose-regulating capacity. This project will investigate the physiological and molecular signals that normally induce islets to transition from an immature less-functional state to a mature cell type capable of effective blood glucose regulation. To achieve this, we will first test whether mimicking normal glucose-induced cell depolarization by experimentally inducing scheduled electrical activity in cultured islets is sufficient to convert immature postnatal beta cells into mature and fully functional beta cells. Electrical activity will be controlled by expressing optogenetic proteins specifically in beta cell, which will produce an electrical current across the cell membrane when cells are exposed to a specific wavelength of light. Second, we will test whether activating the Calcineurin/NFAT signaling pathway, which senses cellular calcium levels and normally controls beta cell proliferation and function, is sufficient to promote maturation of cultured immature islets. These studies will reveal cellular and molecular stimuli that control how islets normally acquire functio during development, and will inform efforts at generating new functional beta cells from renewable sources.

Public Health Relevance

Diabetes is a disease of dysregulated blood sugar affecting millions of people in the United States, for which current therapies are insufficient. Treatment of diabetes by beta cell transplantation has been proposed, but transplantable material is limited and efficient methods for generation of functional beta cells are lacking. This study will investigate the cellular and molecular signals that direct beta cells to acquire function. The results from this study will be relevant to efforts at producing functional beta cells from renewable sources for transplant-based therapies for diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZDK1)
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Castle, Arthur
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Stanford University
Anatomy/Cell Biology
Schools of Medicine
United States
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Pauerstein, Philip T; Tellez, Krissie; Willmarth, Kirk B et al. (2017) A radial axis defined by semaphorin-to-neuropilin signaling controls pancreatic islet morphogenesis. Development 144:3744-3754
Pauerstein, Philip T; Park, Keon Min; Peiris, Heshan S et al. (2016) Research Resource: Genetic Labeling of Human Islet Alpha Cells. Mol Endocrinol 30:248-53
Pauerstein, Philip T; Sugiyama, Takuya; Stanley, Susan E et al. (2015) Dissecting Human Gene Functions Regulating Islet Development With Targeted Gene Transduction. Diabetes 64:3037-49