An adequate number of beta cells are required for production of a sufficient amount of insulin to maintain normoglycemia. Enhancing beta cell proliferation or regeneration can be an effective means to treat type 2 diabetes (T2D). Mutations in the multiple endocrine neoplasia type 1 gene (Men1), which encodes the nuclear protein menin, usually result in benign hyperplasia in several endocrine organs, such as pancreatic islets, but do not affect other organs, such as the liver. One of our long-term goals is to understand how menin regulates beta cell proliferation. Though it is attractive to tap into repressing menin to enhance beta cell regeneration and ameliorate diabetes, this was once thought problematic or unfeasible for fear of the potential tumorigenic effect from menin inhibition. However, recent and rapid research progress has altered this view. Menin is physiologically repressed to increase beta cell proliferation and prevent gestational diabetes. Our recent findings suggest that menin interplays with glucagon-like peptide 1 (GLP-1) signaling pathway, which promotes beta cell regeneration, to regulate gene transcription. For instance, menin suppresses, but GLP-1 increases cyclin A expression, linking menin to GLP-1 signaling. Menin interacts with PRMT5, a histone arginine methytransferase that represses gene transcription. Notably, Men1 excision not only renders mice resistant to streptozotocin (STZ)-induced hyperglycemia, but also ameliorates pre-existing hyperglycemia in STZ-induced diabetic mice. Our new results since the last submission also demonstrate that acute Men1 excision normalized pre-existing glucose intolerance in high-fat diet-fed mice. These findings strongly suggest that repressing menin can be a novel means to enhance beta cell regeneration and ameliorate diabetes. It is hypothesized that menin normally suppresses beta cell proliferation through repressing transcription of cell cycle regulators, such as GLP-1-induced cyclin A, in concert with epigenetic regulator PRMT5, and that Men1 inhibition leads to beta cell regeneration and amelioration of type 2 diabetes. Thus, in this proposal, how menin represses transcription of cell cycle-regulating genes, such as GLP-1-induced cyclin A, will be investigated. Second, the mechanisms underlying the interplay between menin and the GLP-1 pathway in controlling cyclin A transcription and beta cell proliferation will be elucidated. Third, the impact of Men1 inhibition on ameliorating T2D will be examined in T2D mouse models. These studies will likely unravel novel mechanisms in control of beta cell proliferation by the interplay between menin and the GLP-1 pathway through epigenetic regulation of gene transcription. The proposed studies may pave the way to developing novel and menin pathway-based strategies to treat T2D.

Public Health Relevance

There are over 20 million patients with diagnosed or undiagnosed type 2 diabetes in the United States of America;in these patients there is an inadequate number of beta cells to control blood glucose. Our proposed studies likely unravel a new pathway, the menin pathway, in controlling beta cell proliferation, and this pathway could be modulated to ameliorate type 2 diabetes. These studies will likely pave the way to develop the next generation of new drugs to treat this widespread disease.

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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University of Pennsylvania
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Gurung, Buddha; Muhammad, Abdul Bari; Hua, Xianxin (2014) Menin is required for optimal processing of the microRNA let-7a. J Biol Chem 289:9902-8
Matkar, Smita; Katona, Bryson W; Hua, Xianxin (2014) Harnessing the hidden antitumor power of the MLL-AF4 oncogene to fight leukemia. Cancer Cell 25:411-3
Feng, Zi-Jie; Gurung, Buddha; Jin, Guang-Hui et al. (2013) SUMO modification of menin. Am J Cancer Res 3:96-106
Gurung, Buddha; Feng, Zijie; Iwamoto, Daniel V et al. (2013) Menin epigenetically represses Hedgehog signaling in MEN1 tumor syndrome. Cancer Res 73:2650-8
Thiel, Austin T; Feng, Zijie; Pant, Dhruv K et al. (2013) The trithorax protein partner menin acts in tandem with EZH2 to suppress C/EBP? and differentiation in MLL-AF9 leukemia. Haematologica 98:918-27
Gurung, Buddha; Feng, Zijie; Hua, Xianxin (2013) Menin directly represses Gli1 expression independent of canonical Hedgehog signaling. Mol Cancer Res 11:1215-22
Gurung, Buddha; Hua, Xianxin (2013) Menin/PRMT5/hedgehog signaling: a potential target for the treatment of multiple endocrine neoplasia type 1 tumors. Epigenomics 5:469-71
Matkar, Smita; Thiel, Austin; Hua, Xianxin (2013) Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem Sci 38:394-402
Huang, Jing; Gurung, Buddha; Wan, Bingbing et al. (2012) The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature 482:542-6
Matkar, Smita S; Durham, Amy; Brice, Angela et al. (2011) Systemic activation of K-ras rapidly induces gastric hyperplasia and metaplasia in mice. Am J Cancer Res 1:432-445

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