Sustained expression of the transcription factor GLIS3 is required for normal beta cell function in adults.
Bottom Line: Genome-wide association studies identified GLIS3 as a susceptibility locus for type 1 and type 2 diabetes.GLIS3 controls beta cell proliferation in response to high-fat feeding at least partly by regulating Ccnd2 transcription.We conclude that normal Glis3 expression is required for pancreatic beta cell function and mass maintenance during adulthood, which impairment leads to diabetes in adults.
Affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Diabetes and Endocrinology Research Center, Baylor College of Medicine, Houston, TX, USA.Show MeSH
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Mentions: Eight weeks after treatment, the ratio of pancreas weight to body weight was similar (Fig 4E) between vehicle and TAM-treated Glis3fl/fl/Pdx1CreERT+ mice. Histological examination of the pancreas revealed a markedly reduced islet density in the TAM-treated Glis3fl/fl/Pdx1CreERT+ mice; the residual islets were small and severely disorganized (Fig 5A and B). In agreement with the markedly reduced insulin mRNA, immunostaining showed a near total absence of insulin-positive cells among the residual islets as compared to vehicle-treated mice (Fig 5C and D). We next investigated the expression of other mature beta cell markers GLUT2 (Pang et al, 1994; Thorens et al, 1990), PDX1 (Jonsson et al, 1994; Offield et al, 1996; Ohlsson et al, 1993) and NKX6-1 (Jensen et al, 1996; Oster et al, 1998; Rudnick et al, 1994) by immunostaining and found that all three mature beta cell marker-expressing cells were markedly decreased in the islets of TAM-treated Glis3fl/fl/Pdx1CreERT+ mice, as compared to vehicle-treated controls (Fig 5E–H, Supporting Information Fig S3). To determine if increased apoptosis contributed to beta cells loss, we performed terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay and immunostaining of cleaved caspase-3, a marker of apoptosis, and found that the number of TUNEL+ islet cells (Fig 5I) and cleaved caspase-3-positive cells (Supporting Information Fig S4), was greatly increased in the Glis3fl/fl/Pdx1CreERT+ mice 8 weeks after TAM treatment as compared to the vehicle-treated mice.
Affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Diabetes and Endocrinology Research Center, Baylor College of Medicine, Houston, TX, USA.