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Why Does Nkx6.1 Fail to Increase Functional Beta‐cell Mass in Aged Islets?
Author(s) -
Crabtree Jacqueline,
Littlefield Connor,
Tessem Jeffery Sivert
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.05831
Subject(s) - beta cell , islet , beta (programming language) , insulin , diabetes mellitus , transcription factor , medicine , endocrinology , secretion , transplantation , biology , microbiology and biotechnology , gene , genetics , computer science , programming language
Diabetes Mellitus is a major health problem across the world. The number of people diagnosed is predicted to reach 642 million by 2040. The major forms of diabetes mellitus, type 1 and type 2, have the shared characteristics of hyperglycemia, impaired insulin production, and decreased beta‐cell mass. A possible cure for diabetes mellitus is transplantation of the beta‐cell containing islets of Langerhans. A major constraint to greater use of islet transplantation is the relative scarcity of transplant ready islets. Understanding that molecular pathways that result in increased beta‐cell proliferation could be used to increasing the number of transplant ready islets. We have shown that the beta‐cell transcription factor Nkx6.1 is sufficient to enhance glucose stimulated insulin secretion and induce beta‐cell proliferation in primary rat islets. However, Nkx6.1 overexpression in aged rat islets is unable to drive expression of key target genes that result in increased glucose stimulated insulin secretion and proliferation. This dichotomy is extremely important, given that most islet donors are beyond adolescence. Therefore, understanding why aged beta‐cells are refractory to these Nkx6.1 mediated signals is essential. We hypothesize that Nkx6.1 is unable to drive expression of genes necessary for beta‐cell proliferation and insulin secretion in aged islets due to lack of accessibility to chromatin due to changes in Nkx6.1 binding partner expression. Here we present data demonstrating the difference in Nkx6.1 promoter localization and binding partners as a process of aging. These data begin to describe age dependent changes that leave the aged beta‐cell refractory to proliferative signals.