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Sustained expression of the transcription factor GLIS3 is required for normal beta cell function in adults.

Yang Y, Chang BH, Chan L - EMBO Mol Med (2012)

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.

View Article: PubMed Central - PubMed

Affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Diabetes and Endocrinology Research Center, Baylor College of Medicine, Houston, TX, USA.

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The expression of insulin, but not PDX1, is reduced in Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM plus insulin pellet treatmentsA–L. Representative immunostaining images and quantification of endocrine hormones such as Ins, Gcg, SS and PP in the pancreas of Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM and implanted insulin pellets (blood glucose < 300 mg/dl) or vehicle administration. Results were analyzed by student's t-test and presented as the mean ± S.E. **p < 0.00001 versus vehicle-treated mice. Scale bar, 20 µm.M–O. Representative immunostaining images and quantification of PDX1 in the pancreas of Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM and implanted insulin pellets or vehicle administration. Scale bar, 25 µm.P–R. TUNEL assay and TUNEL+ cell quantification in the pancreas of Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM and implanted insulin pellets or vehicle administration. *p = 0.019 versus vehicle-treated mice. Scale bar, 20 µm. Note: In vehicle-treated mice, only one TUNEL+ islet cell was found among more than 50 islets.
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fig06: The expression of insulin, but not PDX1, is reduced in Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM plus insulin pellet treatmentsA–L. Representative immunostaining images and quantification of endocrine hormones such as Ins, Gcg, SS and PP in the pancreas of Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM and implanted insulin pellets (blood glucose < 300 mg/dl) or vehicle administration. Results were analyzed by student's t-test and presented as the mean ± S.E. **p < 0.00001 versus vehicle-treated mice. Scale bar, 20 µm.M–O. Representative immunostaining images and quantification of PDX1 in the pancreas of Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM and implanted insulin pellets or vehicle administration. Scale bar, 25 µm.P–R. TUNEL assay and TUNEL+ cell quantification in the pancreas of Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM and implanted insulin pellets or vehicle administration. *p = 0.019 versus vehicle-treated mice. Scale bar, 20 µm. Note: In vehicle-treated mice, only one TUNEL+ islet cell was found among more than 50 islets.

Mentions: The findings in Figs 4D–I and 5 were obtained in severely hyperglycaemic TAM-treated Glis3fl/fl/Pdx1CreERT+ mice, and some of the changes observed could be the consequence of glucotoxicity (Olson et al, 1993; Poitout & Robertson, 2002, 2008; Robertson et al, 2004). To address this possibility, we implanted insulin pellets to maintain the random blood glucose level to <300 mg/dl in the TAM-treated Glis3fl/fl/Pdx1CreERT+ mice. We then performed immunofluorescence staining and observed a more than 95% reduction in insulin staining in the islets of Glis3fl/fl/Pdx1CreERT+ mice 8 weeks after TAM administration in the insulin pellet-implanted mice (Fig 6A–C) as compared to vehicle-treated mice. In contrast, the levels of glucagon, somatostatin, PP and PDX1 were comparable between the two groups (Fig 6D–O). The TUNEL+ islet cells (Fig 6P–R) and cleaved caspase-3 staining (Supporting Information Fig S4) were, however, still higher in the islets of TAM-treated and insulin pellets implanted Glis3fl/fl/Pdx1CreERT+ mice whilst no difference of PCNA staining was noted, in comparison to vehicle-treated mice.


Sustained expression of the transcription factor GLIS3 is required for normal beta cell function in adults.

Yang Y, Chang BH, Chan L - EMBO Mol Med (2012)

The expression of insulin, but not PDX1, is reduced in Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM plus insulin pellet treatmentsA–L. Representative immunostaining images and quantification of endocrine hormones such as Ins, Gcg, SS and PP in the pancreas of Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM and implanted insulin pellets (blood glucose < 300 mg/dl) or vehicle administration. Results were analyzed by student's t-test and presented as the mean ± S.E. **p < 0.00001 versus vehicle-treated mice. Scale bar, 20 µm.M–O. Representative immunostaining images and quantification of PDX1 in the pancreas of Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM and implanted insulin pellets or vehicle administration. Scale bar, 25 µm.P–R. TUNEL assay and TUNEL+ cell quantification in the pancreas of Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM and implanted insulin pellets or vehicle administration. *p = 0.019 versus vehicle-treated mice. Scale bar, 20 µm. Note: In vehicle-treated mice, only one TUNEL+ islet cell was found among more than 50 islets.
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fig06: The expression of insulin, but not PDX1, is reduced in Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM plus insulin pellet treatmentsA–L. Representative immunostaining images and quantification of endocrine hormones such as Ins, Gcg, SS and PP in the pancreas of Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM and implanted insulin pellets (blood glucose < 300 mg/dl) or vehicle administration. Results were analyzed by student's t-test and presented as the mean ± S.E. **p < 0.00001 versus vehicle-treated mice. Scale bar, 20 µm.M–O. Representative immunostaining images and quantification of PDX1 in the pancreas of Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM and implanted insulin pellets or vehicle administration. Scale bar, 25 µm.P–R. TUNEL assay and TUNEL+ cell quantification in the pancreas of Glis3fl/fl/Pdx1CreERT+ mice eight weeks after TAM and implanted insulin pellets or vehicle administration. *p = 0.019 versus vehicle-treated mice. Scale bar, 20 µm. Note: In vehicle-treated mice, only one TUNEL+ islet cell was found among more than 50 islets.
Mentions: The findings in Figs 4D–I and 5 were obtained in severely hyperglycaemic TAM-treated Glis3fl/fl/Pdx1CreERT+ mice, and some of the changes observed could be the consequence of glucotoxicity (Olson et al, 1993; Poitout & Robertson, 2002, 2008; Robertson et al, 2004). To address this possibility, we implanted insulin pellets to maintain the random blood glucose level to <300 mg/dl in the TAM-treated Glis3fl/fl/Pdx1CreERT+ mice. We then performed immunofluorescence staining and observed a more than 95% reduction in insulin staining in the islets of Glis3fl/fl/Pdx1CreERT+ mice 8 weeks after TAM administration in the insulin pellet-implanted mice (Fig 6A–C) as compared to vehicle-treated mice. In contrast, the levels of glucagon, somatostatin, PP and PDX1 were comparable between the two groups (Fig 6D–O). The TUNEL+ islet cells (Fig 6P–R) and cleaved caspase-3 staining (Supporting Information Fig S4) were, however, still higher in the islets of TAM-treated and insulin pellets implanted Glis3fl/fl/Pdx1CreERT+ mice whilst no difference of PCNA staining was noted, in comparison to vehicle-treated mice.

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.

View Article: PubMed Central - PubMed

Affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Diabetes and Endocrinology Research Center, Baylor College of Medicine, Houston, TX, USA.

Show MeSH
Related in: MedlinePlus