A paucity of functional ?-cells is a central feature of type 1 and type 2 diabetes and an urgent question in islet biology relates to plasticity of ?-cell mass in the long-term goal of developing strategies to treat both forms of the disease. This application is focused on the role of growth factors, especially insulin and IGF-I receptors and proteins in their signaling pathway, in regulation of ?-cell proliferation, apoptosis and secretory function. We use unique genetic mouse models lacking one or more proteins in the insulin/IGF-I signaling pathway in ?-cells and complement with studies in ? cell lines and primary islets derived from the knockouts for in vitro and ex vivo experiments. Based on Preliminary Data we seek to continue our studies with the following Specific Aims:
Aim 1 : Determine the role of insulin/IGF-I signaling in proinsulin processing and test the hypothesis that an intact insulin/IRS-2 pathway is essential for appropriate proinsulin processing.
Aim 2 : Define the alterations in endoplasmic reticulum (ER) stress in ? cells lacking proteins in the insulin signaling pathway and test the hypothesis that the insulin/IRS-2 pathway is essential to limit ER stress in ? cells: Our preliminary data indicates a direct role for the insulin receptor and IRS-2, but not IRS-1, in ER stress responses in ? cells. We plan to dissect the mechanisms and pathways that underlie enhanced ER stress in the context of insulin/IRS-2 signaling with a focus on IRE-1a and contrast the findings with the pathways mediated by IRS-1.
Aim 3 : Dissect the mechanisms that link the insulin/IGF-I signaling with proteins involved in the ?-cell growth response to insulin resistance: Our preliminary data using in vivo approaches builds on previous work and indicates critical roles for cycling D2 and Px-1 in the compensatory islet growth response to insulin resistance. We will focus on these two proteins and explore their link with FoxO1 to dissect the mechanisms that underlie the proliferation responses especially in the context of differences between insulin and IGF-1 signaling. Together we believe these studies will provide novel insights into the role of growth factors in the regulation of ?-cell proliferation and apoptosis.

Public Health Relevance

This project is aimed at understanding the mechanism(s) that underlie the proliferation and survival of beta cells with a focus on the insulin and insulin-like growth factor pathways. Using genetically engineered mouse models and primary islets and beta cell lines derived from the knockout mice we will focus on identifying the pathways that promote beta cell regeneration with the long-term goal of developing therapeutic approaches to counter the loss of beta cells in both type 1 and type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067536-09
Application #
8502639
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
2004-03-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$320,150
Indirect Cost
$121,915
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Kilic, Gamze; Alvarez-Mercado, Ana I; Zarrouki, Bader et al. (2014) The islet estrogen receptor-? is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes. PLoS One 9:e87941
Hatanaka, Masayuki; Maier, Bernhard; Sims, Emily K et al. (2014) Palmitate induces mRNA translation and increases ER protein load in islet ?-cells via activation of the mammalian target of rapamycin pathway. Diabetes 63:3404-15
Dirice, Ercument; Kahraman, Sevim; Jiang, Wenyu et al. (2014) Soluble factors secreted by T cells promote *-cell proliferation. Diabetes 63:188-202
Liew, Chong Wee; Assmann, Anke; Templin, Andrew T et al. (2014) Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic ? cells. Proc Natl Acad Sci U S A 111:E2319-28
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Mezza, Teresa; Muscogiuri, Giovanna; Sorice, Gian Pio et al. (2014) Insulin resistance alters islet morphology in nondiabetic humans. Diabetes 63:994-1007
Teo, Adrian Kee Keong; Valdez, Ivan Achel; Dirice, Ercument et al. (2014) Comparable generation of activin-induced definitive endoderm via additive Wnt or BMP signaling in absence of serum. Stem Cell Reports 3:5-14
Negahdar, Maria; Aukrust, Ingvild; Molnes, Janne et al. (2014) GCK-MODY diabetes as a protein misfolding disease: the mutation R275C promotes protein misfolding, self-association and cellular degradation. Mol Cell Endocrinol 382:55-65
Raeder, Helge; McAllister, Fiona E; Tjora, Erling et al. (2014) Carboxyl-ester lipase maturity-onset diabetes of the young is associated with development of pancreatic cysts and upregulated MAPK signaling in secretin-stimulated duodenal fluid. Diabetes 63:259-69

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