Diabetes results from a reduction in the functional mass of pancreatic ?-cells. In type 1 diabetes reduction in ?-cell mass results from autoimmune attack while in type 2 diabetes ?-cell mass is not sufficient to secrete the amount of insulin required to meet the demand. The generation of glucose-responsive ?-cells from stem/progenitor cells for cell-based therapy for both types of diabetes and the functional enhancement of ?-cell in type 2 diabetes could provide significant improvement in current therapeutic approaches. Since our identification of RIPE3b1 as MafA, evidence has been accumulating to support the role of Maf factors (MafA, MafB and c-Maf) in regulating the specification of insulin+ cells, and in their subsequent maturation and function. We suggest that better understanding of their roles in regulation of these processes will contribute to the development of therapies for both forms of diabetes. In this proposal we will test the hypothesis that in vivo modulation of MafA function in pancreatic ?-cells regulates their maturation and function, which will improve ?-cell dysfunction and ameliorate diabetes. We will also examine the hypothesis that in vivo insulin+ cells are specified via two alternate pathways (MafB dependent and MafB independent), and that insulin+ cells derived from both pathways are """"""""true"""""""" glucose-responsive ?-cells. To characterize the role of Maf factors in regulating specification, maturation and function of ?-cells, we propose Two Specific Aims.
Aim 1 will examine that MafB and cMaf, but not MafA, regulates specification of insulin+ cells from alternate pathways. We will characterize the requirements for specification of insulin+ cells from both pathways and test whether insulin+ cells from MafB-independent pathway represent true glucose responsive ?-cell.
Aim 2 will characterize the ability of enhancing MafA expression on delaying/preventing development of diabetes. We will examine the mechanisms for the development of diabetes in ?-cells with impaired MafA function. We will also test whether enhancing MafA can enhance maturation of ?-cells. Thus, this research will have significant impact on our ability to generate glucose-responsive insulin-producing cells for the cell-based therapy of diabetes and provide knowledge that may lead to the development of new therapies to overcome ?-cell dysfunction.

Public Health Relevance

The limited availability of donor pancreases to meet the demand for islet transplantation underscores the critical need for developing a reliable source of glucose-responsive ?- cells. Most current approaches to convert embryonic stem cells, pancreatic progenitor cells or other differentiated cell types to ?-cells result in the generation of cells with significantly reduced insulin content and/or inability secrete insulin in response to changes in glucose concentrations. Our limited knowledge of the precise pathways involved in the specification of insulin+ cells and their subsequent maturation to glucose- responsive cells makes it difficult to realize the full potential of stem/precursor cells. However, we have strong evidence that the transcription factors MafB and cMaf turns-on insulin expression and MafA can induce the genes necessary for functional maturation of the ? cells. We suggest that better understanding of the roles of Maf factors in regulation of these processes will contribute to the development of therapies for both forms of diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Sato, Sheryl M
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Joslin Diabetes Center
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El Khattabi, Ilham; Sharma, Arun (2015) Proper activation of MafA is required for optimal differentiation and maturation of pancreatic ?-cells. Best Pract Res Clin Endocrinol Metab 29:821-31
Nishimura, Wataru; Kapoor, Archana; El Khattabi, Ilham et al. (2015) Compensatory Response by Late Embryonic Tubular Epithelium to the Reduction in Pancreatic Progenitors. PLoS One 10:e0142286
Nomoto, Hiroshi; Kondo, Takuma; Miyoshi, Hideaki et al. (2015) Inhibition of Small Maf Function in Pancreatic ?-Cells Improves Glucose Tolerance Through the Enhancement of Insulin Gene Transcription and Insulin Secretion. Endocrinology 156:3570-80
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El Khattabi, Ilham; Sharma, Arun (2013) Preventing p38 MAPK-mediated MafA degradation ameliorates ?-cell dysfunction under oxidative stress. Mol Endocrinol 27:1078-90
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Juhl, Kirstine; Bonner-Weir, Susan; Sharma, Arun (2010) Regenerating pancreatic beta-cells: plasticity of adult pancreatic cells and the feasibility of in-vivo neogenesis. Curr Opin Organ Transplant 15:79-85
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