Role of IGF-1 and insulin receptors beta-cell survival

Joslin Diabetes Center, Boston MA

Investigators

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Abstract

PROJECT SUMMARY 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 an autoimmune disease, thought to be triggered by genetic or environmental factors in early childhood, which results in antibody-mediated destruction of insulin producing pancreatic β-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 β-cells. The latter question has emerged to be important in this field that requires attention. This application is focused on addressing the specific question of how beta cells are able to compensate for the ambient insulin resistance by enhancing secretion and/or increased cell numbers in some individuals but not others. We especially address this question in the context of growth factors and proteins in their signalling pathways that are important for regulating β-cell proliferation, apoptosis and secretory function. Our studies are driven by the work accomplished in the previous cycle where we identified m6A as an important RNA modification with the ability to determine mammalian beta cell mass and secretory function. During these studies we observed a link with mRNA modification and beta cell compensation in response to insulin resistance. Our preliminary data identified a novel protein with the ability to regulate glucose sensing and modulate beta cell proliferation and viability. We now seek to interrogate the direct relevance of this protein in mammalian beta cells to identify the signatures that might provide important clues to processes that contribute to beta cell compensation and maintenance of normoglycemia. In this proposal we will: 1) Characterize and phenotype a novel mouse model with a beta-cell specific knockout of the chromatin- regulating protein in the context of glucose homeostasis and islet function; 2) determine the mechanism of action of the protein in the context of insulin signaling and Rho-kinase pathways in regulating human β-cell mass, viability and secretory function; and 3) explore the relevance of the m6A RNA demethylase by phenotyping a beta-cell specific knockout of Alkbh5 to study its impact on beta cell secretory function and growth. All studies will include key experiments in human islets and beta cells to establish translational relevance.