The role of Glis3 in the development of functional pancreatic beta-cells and diabetes

Wednesday, October 26, 2011 — Poster Session III
10:00 a.m. – Noon	Natcher Conference Center	NIEHS	ENDOC-7

* FARE Award Winner

Authors

• K Lichti-Kaiser
• HS Kang
• AM Jetten

Abstract

Gli-similar (GLIS)3 has been associated with neonatal, type-1, and type-2 diabetes. Glis3 KO mice die within one week from neonatal diabetes due to a dramatic loss of insulin-secreting beta-cells. Glis3 regulates insulin gene expression in mature beta-cells, indicating that Glis3 plays a role in both the development and function of pancreatic beta-cells. We have generated two pancreas-specific Glis3 KO mouse models. Glis3 fx/fx mice were crossed with mice expressing cre-recombinase under the control of the Pdx or Insulin gene promoters, expressed at early and late time-points during pancreas development. Pdx(Glis3) KO mice develop delayed-onset diabetes at two-three months of age as evidenced by hyperglycemia, hypoinsulinemia, and loss of white adipose tissue, whereas Ins(Glis3) KO mice do not develop overt diabetes. Insulin expression was decreased at two months, but not at two weeks, of age in Pdx(Glis3) KO mice. The expression of other pancreatic hormones and transcription factors important for endocrine cell development was not different than that of WT littermates, indicating that there is not a significant loss of beta-cells in the Pdx(Glis3) KO mice. Our study shows that Glis3 has multiple critical functions in the pancreas and that Glis3 may provide a new therapeutic target to intervene in diabetes.

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