OR18-1 The Diabetes-associated Gene Glis3 is Required for Maintaining Beta Cell Mass and Insulin Sensitivity in Adults

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR18-Diabetes-Associated Genes & Pathways
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:15 AM
Room 304 (Moscone Center)
Yisheng Yang*1, Benny Chang2, Lina Yang1 and Lawrence C Chan3
1Baylor College of Medicine, Houston, TX, 2Baylor College of Medicine, 3Baylor Coll of Med, Houston, TX
Recent genome-wide association studies (GWAS) in adult populations identified GLIS3 as a candidate gene for type 1 diabetes (T1D), as well as a gene associated with type 2 diabetes (T2D). We showed that Glis3 robustly transactivates insulin gene transcription. With respect to T1D, during embryonic development, GLIS3 controls fetal islet differentiation by transactivating Ngn3 directly and synergistically with HNF6 and FOXA2. Glis3−/− mice die neonatally. We, therefore, examined Glis3’s function in heterozygotes. First, we found that haploinsufficiency of Glis3 rendered adult Glis3+/− mice much more prone to develop high fat diet (HFD)-induced diabetes, due to the impairment of beta cell proliferation and beta cell mass expansion during HFD feeding. Mechanistically, we found that GLIS3 controls beta cell proliferation at least partly by directly regulating Ccnd2 transcription. With respect to role of extrapancreatic Glis3 expression in T2D, we recently found that, as compared to wild-type mice, Glis3+/− mice exhibit insulin resistance on regular chow or after HFD, as evidenced by abnormal insulin tolerance test (ITT) and pyruvate tolerance test (PTT). To dissect the tissue origin of the insulin resistance, we generated Glis3fl/fl mice and intercrossed them to tissue-specific Cre mice to produce liver-specific (Albumin-Cre), muscle-specific (Mck-Cre) and adipose-specific (Ap2-Cre) Glis3 deficient mice. We found, however, that none of these mice display increased insulin resistance, whether on regular chow or HFD, as compared to wild-type controls on the same diet. We next produced myeloid specific-Glis3 deficient mice by crossing the Glis3fl/fl mice to LysM-Cre transgenic mice and were surprised to find that myeloid specific loss of Glis3 led to insulin resistance, as evidenced by abnormal ITT and PTT. Interestingly, the LysM-Cre+Glis3fl/fl mice also exhibit elevated plasma IL-6 and IL-1b. Importantly, we found that Glis3 transduction-induced GLIS3 overexpression upregulates Socs1 and Socs3 mRNA in RAW264.7 cells, indicating that Socs1 and Socs3 may be downstream targets of Glis3 in macrophages. We conclude that, apart from its capacity to transactivate the insulin gene, and its role in controlling fetal islet differentiation via Ngn3, [1] Glis3 is required for compensatory beta cell proliferation in response to HFD-induced T2D; [2] furthermore, Glis3 expression maintains normal macrophage function, which perturbation leads to macrophage activation and subsequent hepatic insulin resistance. In sum, our laboratory has identified the multi-faceted roles of Glis3 in the pancreas that control insulin production and islet differentiation, functions that impact both T1D and T2D; moreover, we found that dysfunction of Glis3-regulated genes in myeloid cells contributes to insulin resistance, an important factor in the pathogenesis of T2D.

Nothing to Disclose: YY, BC, LY, LCC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: The Diabetes and Endocrinology Research Center (P30DK079638; the Juvenile Diabetes Research Foundation (46-2010-752); the Betty Rutherford Chair for Diabetes Research from St. Luke’s Episcopal Hospital and the Charles and Barbara Close Foundation.
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