The number of people with diabetes worldwide is predicted to increase from 415 million in 2015 to 642 million in 2040. The health care costs of treating the disease account for 12% of the global health expenditure and continue to be a huge economic burden (IDF World Atlas 2015). Type 1 diabetes mellitus (T1DM) constitutes 10-15% of the disease burden and is thought to be triggered by genetic or environmental factors in early childhood, which results in antibody-mediated destruction of insulin producing pancreatic ?-cells causing life-threatening hyperglycemia. In contrast, type 2 diabetes mellitus (T2DM) develops later in life and results from insulin resistance in target tissues and inflammation coupled with an inadequate compensation by the ?-cells. A reduced number of functional ?-cells is a central feature of both T1D and TD2 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 RNA modifications and how they modulate ?-cell proliferation, apoptosis and secretory function. We will use recently developed sequencing approaches to characterize RNA marks (e.g. N6-methyladenosine) in human islets from patients with T2D and in the human beta cell line. We will also examine the effects of knocking down key regulators of methylation including erasers, writers and readers and create genetic mouse models lacking one or more of these regulators in ?-cells to complement the studies in ? cell lines for in vitro and ex vivo experiments. Based on Preliminary Data, we seek to continue our studies with the following Specific Aims: 1. Examine the expression of regulators of m6a methylation, undertake m6A sequencing studies in islets from male and female patients with T2 diabetes and characterize the dynamic RNA methylation changes in the EndoC-bH1 cells in response to metabolites and hormones; 2. Determine the relevance of the methyltransferases in the regulation of ER-mediated events, non-sense mediated decay and secretory responses to hormones; and 3. Interrogate effects of absence of the demethylases on alterations in cell cycle control, DNA damage and chromatin modeling.

Public Health Relevance

The mechanisms and pathways that operate during the onset and progression of type 2 diabetes (T2D) are not fully understood. We will take advantage of the recent observation that methylation marks on ribonucleic acids plays a potential regulatory role in determining the ability of cells to rapidly respond to environmental triggers by modulating the expression of key proteins. We seek to explore the dynamic modifications in RNA in islets/beta cells from models of type 2 diabetes in the long-term goal of gaining new insights into the pathophysiology of this chronic disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Joslin Diabetes Center
United States
Zip Code
Rao, Tata Nageswara; Gupta, Manoj K; Softic, Samir et al. (2018) Attenuation of PKC? enhances metabolic activity and promotes expansion of blood progenitors. EMBO J 37:
Jeong, Da Eun; Heo, Sungeun; Han, Ji Hye et al. (2018) Glucose Controls the Expression of Polypyrimidine Tract-Binding Protein 1 via the Insulin Receptor Signaling Pathway in Pancreatic ? Cells. Mol Cells 41:909-916
Kim, Chongtae; Jeong, Da Eun; Heo, Sungeun et al. (2018) Reduced expression of the RNA-binding protein HuD in pancreatic neuroendocrine tumors correlates with low p27Kip1 levels and poor prognosis. J Pathol 246:231-243
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
Ghanem, Simona S; Muturi, Harrison T; DeAngelis, Anthony M et al. (2017) Age-dependent insulin resistance in male mice with null deletion of the carcinoembryonic antigen-related cell adhesion molecule 2 gene. Diabetologia 60:1751-1760
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, J; De Jesus, D F; Kulkarni, R N (2017) Exploring inter-organ crosstalk to uncover mechanisms that regulate ?-cell function and mass. Eur J Clin Nutr 71:896-903
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
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

Showing the most recent 10 out of 107 publications