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.
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.
|Kawamori, Dan; Shirakawa, Jun; Liew, Chong Wee et al. (2017) GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in ?IRKO mice. Diabetologia 60:1442-1453|
|Sakaguchi, Masaji; Fujisaka, Shiho; Cai, Weikang et al. (2017) Adipocyte Dynamics and Reversible Metabolic Syndrome in Mice with an Inducible Adipocyte-Specific Deletion of the Insulin Receptor. Cell Metab 25:448-462|
|Dirice, Ercument; Ng, Raymond W S; Martinez, Rachael et al. (2017) Isoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetes. J Biol Chem 292:17598-17608|
|Shirakawa, Jun; Fernandez, Megan; Takatani, Tomozumi et al. (2017) Insulin Signaling Regulates the FoxM1/PLK1/CENP-A Pathway to Promote Adaptive Pancreatic ? Cell Proliferation. Cell Metab 25:868-882.e5|
|Patti, Mary-Elizabeth; Goldfine, Allison B; Hu, Jiang et al. (2017) Heterogeneity of proliferative markers in pancreatic ?-cells of patients with severe hypoglycemia following Roux-en-Y gastric bypass. Acta Diabetol 54:737-747|
|Boucher, Jeremie; Softic, Samir; El Ouaamari, Abdelfattah et al. (2016) Differential Roles of Insulin and IGF-1 Receptors in Adipose Tissue Development and Function. Diabetes 65:2201-13|
|Ghanem, Simona S; Heinrich, Garrett; Lester, Sumona G et al. (2016) Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2). J Biol Chem 291:980-8|
|Takatani, Tomozumi; Shirakawa, Jun; Roe, Michael W et al. (2016) IRS1 deficiency protects ?-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation. Sci Rep 6:28177|
|Singhal, Garima; Fisher, Ffolliott Martin; Chee, Melissa J et al. (2016) Fibroblast Growth Factor 21 (FGF21) Protects against High Fat Diet Induced Inflammation and Islet Hyperplasia in Pancreas. PLoS One 11:e0148252|
|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|
Showing the most recent 10 out of 99 publications