The lactogenic hormones, prolactin (PRL) and placental lactogen (PL), which signal through the prolactin receptor, are important for islet development, for enhancing beta cell proliferation, and for improving islet function in normal physiology as well as during pregnancy. We have developed a transgenic mouse model in which the rat insulin II promoter (RIP) drives expression of murine placental lactogen I (mPL1) cDNA in beta cells. These mice are hypoglycemic and display islet hyperplasia as a result of increased beta cell proliferation and hypertrophy. Although activation of the prolactin receptor improves survival in a number of different cell types, the effect of lactogens on beta cell survival has just begun to be examined. In this context, we have recently demonstrated that PL expression in the beta cell of RIP-mPL1 mice confers resistance to the diabetogenic and cytotoxic effects of streptozotocin in these mice, implying a protective role of mPL1 in beta cells. However, nothing is known regarding the nature, mechanism, and signaling pathways implicated in the protective effect of lactogens on beta cells. Understanding the regulation of beta cell survival is important both in normal physiology, as well as in the pathophysiology of diabetes and islet transplantation. Therefore, the main goals of the current proposal are to understand how lactogen signaling can enhance beta cell survival, to determine the relevance of this pathway in the survival of beta cells under physiological and pathophysiological conditions, and to examine whether the beneficial effects of these hormones can translate into enhanced performance in islet transplantation.
The Specific Aims of this proposal are: 1) To define the mechanisms responsible for lactogen-induced survival of beta cells. 2) To establish the physiological significance of lactogen signaling on beta cell survival. 3) To examine the role of lactogens in islet transplant outcomes. The studies in this proposal will further our understanding of the regulation of beta cell death by lactogens. The ultimate objective is to apply this knowledge to select suitable candidate genes for prolonging islet survival in future therapeutic studies in the context of islet transplantation and in the prevention and cure of diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK072264-01
Application #
6961165
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Appel, Michael C
Project Start
2005-09-15
Project End
2010-08-31
Budget Start
2005-09-15
Budget End
2006-08-31
Support Year
1
Fiscal Year
2005
Total Cost
$260,175
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Wang, Peng; Fiaschi-Taesch, Nathalie M; Vasavada, Rupangi C et al. (2015) Diabetes mellitus--advances and challenges in human ?-cell proliferation. Nat Rev Endocrinol 11:201-12
Kondegowda, Nagesha Guthalu; Fenutria, Rafael; Pollack, Ilana R et al. (2015) Osteoprotegerin and Denosumab Stimulate Human Beta Cell Proliferation through Inhibition of the Receptor Activator of NF-?B Ligand Pathway. Cell Metab 22:77-85
Demirci, Cem; Ernst, Sara; Alvarez-Perez, Juan C et al. (2012) Loss of HGF/c-Met signaling in pancreatic ?-cells leads to incomplete maternal ?-cell adaptation and gestational diabetes mellitus. Diabetes 61:1143-52
Kondegowda, N Guthalu; Mozar, A; Chin, C et al. (2012) Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinase-2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling. Diabetologia 55:1721-32
Williams, K; Abanquah, D; Joshi-Gokhale, S et al. (2011) Systemic and acute administration of parathyroid hormone-related peptide(1-36) stimulates endogenous beta cell proliferation while preserving function in adult mice. Diabetologia 54:2867-77
Guthalu Kondegowda, Nagesha; Joshi-Gokhale, Sheela; Harb, George et al. (2010) Parathyroid hormone-related protein enhances human ß-cell proliferation and function with associated induction of cyclin-dependent kinase 2 and cyclin E expression. Diabetes 59:3131-8
Zhang, Hongjie; Zhang, Jia; Pope, Christine F et al. (2010) Gestational diabetes mellitus resulting from impaired beta-cell compensation in the absence of FoxM1, a novel downstream effector of placental lactogen. Diabetes 59:143-52
Fujinaka, Yuichi; Takane, Karen; Yamashita, Hiroko et al. (2007) Lactogens promote beta cell survival through JAK2/STAT5 activation and Bcl-XL upregulation. J Biol Chem 282:30707-17
Vasavada, Rupangi C; Wang, Lin; Fujinaka, Yuichi et al. (2007) Protein kinase C-zeta activation markedly enhances beta-cell proliferation: an essential role in growth factor mediated beta-cell mitogenesis. Diabetes 56:2732-43