Limits...
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.

Show MeSH

Related in: MedlinePlus

Impairment of beta cell mass expansion in Glis3+/− mice with HFD feedingA,B. Representative images of insulin immunostaining (A) and Ins+ cell area (***p = 0.00016 versus Glis3+/+ CD; ###p = 0.00013 versus Glis3+/+ HFD) (B) in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks. Scale bar, 100 µm.C,D. Islet density (**p = 0.009 versus Glis3+/+ CD; ##p = 0.003 versus Glis3+/+ HFD) (C) and mean beta cell size (*p = 0.014 versus Glis3+/+ CD; #p = 0.027 versus Glis3+/+ HFD) (D) in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks.E. Relative mRNA expression of Ins1, Ins2 and Pdx1 (*p < 0.05, **p < 0.01, versus Glis3+/+ CD. ##p < 0.01, ###p < 0.001 versus Glis3+/+ HFD) in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks.F–H. Islet insulin content (F) (***p = 0.0002 versus Glis3+/+ CD; ###p = 0.00008 versus Glis3+/+ HFD), glucose-stimulated insulin secretion (GSIS) (G) and GSIS normalized to islet insulin content (H) in isolated islets of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks.I,J. TUNEL+ beta cell (I) and PCNA+ beta cell (J) (*p = 0.024 versus Glis3+/+ CD; #p = 0.02 versus Glis3+/+ HFD), normalized to total beta cell number, in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks. Results were analyzed by student's t-test and presented as the mean ± standard error (S.E.).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3569656&req=5

fig02: Impairment of beta cell mass expansion in Glis3+/− mice with HFD feedingA,B. Representative images of insulin immunostaining (A) and Ins+ cell area (***p = 0.00016 versus Glis3+/+ CD; ###p = 0.00013 versus Glis3+/+ HFD) (B) in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks. Scale bar, 100 µm.C,D. Islet density (**p = 0.009 versus Glis3+/+ CD; ##p = 0.003 versus Glis3+/+ HFD) (C) and mean beta cell size (*p = 0.014 versus Glis3+/+ CD; #p = 0.027 versus Glis3+/+ HFD) (D) in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks.E. Relative mRNA expression of Ins1, Ins2 and Pdx1 (*p < 0.05, **p < 0.01, versus Glis3+/+ CD. ##p < 0.01, ###p < 0.001 versus Glis3+/+ HFD) in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks.F–H. Islet insulin content (F) (***p = 0.0002 versus Glis3+/+ CD; ###p = 0.00008 versus Glis3+/+ HFD), glucose-stimulated insulin secretion (GSIS) (G) and GSIS normalized to islet insulin content (H) in isolated islets of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks.I,J. TUNEL+ beta cell (I) and PCNA+ beta cell (J) (*p = 0.024 versus Glis3+/+ CD; #p = 0.02 versus Glis3+/+ HFD), normalized to total beta cell number, in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks. Results were analyzed by student's t-test and presented as the mean ± standard error (S.E.).

Mentions: Adult type 2 diabetes may be associated with failure of beta cell expansion (Ackermann & Gannon, 2007; Sachdeva & Stoffers, 2009; Weir & Bonner-Weir, 2004). To determine whether Glis3 is required for beta cell expansion in response to HFD feeding, we examined pancreatic insulin positive cell area (indicating beta cell mass) in Glis3+/− and Glis3+/+ mice fed a CD or HFD for 20 weeks. In Glis3+/+ mice, HFD induced >2.6-fold increase in beta cell mass compared to CD-fed mice, whereas Glis3+/− mice on HFD or CD failed to show any difference in beta cell mass (Fig 2A and B). Whilst both islet density (Fig 2C) and the size of individual beta cells (Fig 2D, indicating hypertrophy) increased in Glis3+/+ mice with HFD feeding, these parameters remained unchanged in Glis3+/− mice. As expected, the mRNA expression of pancreatic mature beta cell markers, such as Ins1, Ins2 and Pdx1 (Fig 2E), and islet immunoreactive insulin content (Fig 2F) were drastically reduced in the HFD-fed Glis3+/− mice compared with Glis3+/+ mice. Therefore, Glis3 is required for normal compensatory beta cell mass expansion in response to HFD feeding.


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)

Impairment of beta cell mass expansion in Glis3+/− mice with HFD feedingA,B. Representative images of insulin immunostaining (A) and Ins+ cell area (***p = 0.00016 versus Glis3+/+ CD; ###p = 0.00013 versus Glis3+/+ HFD) (B) in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks. Scale bar, 100 µm.C,D. Islet density (**p = 0.009 versus Glis3+/+ CD; ##p = 0.003 versus Glis3+/+ HFD) (C) and mean beta cell size (*p = 0.014 versus Glis3+/+ CD; #p = 0.027 versus Glis3+/+ HFD) (D) in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks.E. Relative mRNA expression of Ins1, Ins2 and Pdx1 (*p < 0.05, **p < 0.01, versus Glis3+/+ CD. ##p < 0.01, ###p < 0.001 versus Glis3+/+ HFD) in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks.F–H. Islet insulin content (F) (***p = 0.0002 versus Glis3+/+ CD; ###p = 0.00008 versus Glis3+/+ HFD), glucose-stimulated insulin secretion (GSIS) (G) and GSIS normalized to islet insulin content (H) in isolated islets of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks.I,J. TUNEL+ beta cell (I) and PCNA+ beta cell (J) (*p = 0.024 versus Glis3+/+ CD; #p = 0.02 versus Glis3+/+ HFD), normalized to total beta cell number, in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks. Results were analyzed by student's t-test and presented as the mean ± standard error (S.E.).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569656&req=5

fig02: Impairment of beta cell mass expansion in Glis3+/− mice with HFD feedingA,B. Representative images of insulin immunostaining (A) and Ins+ cell area (***p = 0.00016 versus Glis3+/+ CD; ###p = 0.00013 versus Glis3+/+ HFD) (B) in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks. Scale bar, 100 µm.C,D. Islet density (**p = 0.009 versus Glis3+/+ CD; ##p = 0.003 versus Glis3+/+ HFD) (C) and mean beta cell size (*p = 0.014 versus Glis3+/+ CD; #p = 0.027 versus Glis3+/+ HFD) (D) in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks.E. Relative mRNA expression of Ins1, Ins2 and Pdx1 (*p < 0.05, **p < 0.01, versus Glis3+/+ CD. ##p < 0.01, ###p < 0.001 versus Glis3+/+ HFD) in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks.F–H. Islet insulin content (F) (***p = 0.0002 versus Glis3+/+ CD; ###p = 0.00008 versus Glis3+/+ HFD), glucose-stimulated insulin secretion (GSIS) (G) and GSIS normalized to islet insulin content (H) in isolated islets of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks.I,J. TUNEL+ beta cell (I) and PCNA+ beta cell (J) (*p = 0.024 versus Glis3+/+ CD; #p = 0.02 versus Glis3+/+ HFD), normalized to total beta cell number, in the pancreas of Glis3+/+ and Glis3+/− mice fed with a CD or HFD for 20 weeks. Results were analyzed by student's t-test and presented as the mean ± standard error (S.E.).
Mentions: Adult type 2 diabetes may be associated with failure of beta cell expansion (Ackermann & Gannon, 2007; Sachdeva & Stoffers, 2009; Weir & Bonner-Weir, 2004). To determine whether Glis3 is required for beta cell expansion in response to HFD feeding, we examined pancreatic insulin positive cell area (indicating beta cell mass) in Glis3+/− and Glis3+/+ mice fed a CD or HFD for 20 weeks. In Glis3+/+ mice, HFD induced >2.6-fold increase in beta cell mass compared to CD-fed mice, whereas Glis3+/− mice on HFD or CD failed to show any difference in beta cell mass (Fig 2A and B). Whilst both islet density (Fig 2C) and the size of individual beta cells (Fig 2D, indicating hypertrophy) increased in Glis3+/+ mice with HFD feeding, these parameters remained unchanged in Glis3+/− mice. As expected, the mRNA expression of pancreatic mature beta cell markers, such as Ins1, Ins2 and Pdx1 (Fig 2E), and islet immunoreactive insulin content (Fig 2F) were drastically reduced in the HFD-fed Glis3+/− mice compared with Glis3+/+ mice. Therefore, Glis3 is required for normal compensatory beta cell mass expansion in response to HFD feeding.

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