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FoxO1 gain of function in the pancreas causes glucose intolerance, polycystic pancreas, and islet hypervascularization.

Kikuchi O, Kobayashi M, Amano K, Sasaki T, Kitazumi T, Kim HJ, Lee YS, Yokota-Hashimoto H, Kitamura YI, Kitamura T - PLoS ONE (2012)

Bottom Line: FoxO1 is a downstream transcription factor of insulin/IGF-1 signaling.We found FoxO1 binds to the VEGF-A promoter and regulates VEGF-A transcription in β cells.We propose that dysregulation of FoxO1 activity in the pancreas could account for the development of diabetes and pancreatic cysts.

View Article: PubMed Central - PubMed

Affiliation: Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.

ABSTRACT
Genetic studies revealed that the ablation of insulin/IGF-1 signaling in the pancreas causes diabetes. FoxO1 is a downstream transcription factor of insulin/IGF-1 signaling. We previously reported that FoxO1 haploinsufficiency restored β cell mass and rescued diabetes in IRS2 knockout mice. However, it is still unclear whether FoxO1 dysregulation in the pancreas could be the cause of diabetes. To test this hypothesis, we generated transgenic mice overexpressing constitutively active FoxO1 specifically in the pancreas (TG). TG mice had impaired glucose tolerance and some of them indeed developed diabetes due to the reduction of β cell mass, which is associated with decreased Pdx1 and MafA in β cells. We also observed increased proliferation of pancreatic duct epithelial cells in TG mice and some mice developed a polycystic pancreas as they aged. Furthermore, TG mice exhibited islet hypervascularities due to increased VEGF-A expression in β cells. We found FoxO1 binds to the VEGF-A promoter and regulates VEGF-A transcription in β cells. We propose that dysregulation of FoxO1 activity in the pancreas could account for the development of diabetes and pancreatic cysts.

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Related in: MedlinePlus

Enhanced VEGF-A expression in β cells but not α cells in TG mice.(A) Double immunostaining of VEGF-A with insulin or glucagon in pancreatic sections from TG mice and control mice. Enhanced VEGF-A staining (red) in TG mice is completely merged with insulin staining (green to yellow) but not with glucagon staining (green). (B) Quantitative analysis of VEGF-A staining levels in the islets of TG and control mice. We measured the staining levels of VEGF-A per unit area by using NIS-Elements (Nikon) and Image-J (NIH). Six mice were analyzed for each genotype and representative images are shown.
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pone-0032249-g005: Enhanced VEGF-A expression in β cells but not α cells in TG mice.(A) Double immunostaining of VEGF-A with insulin or glucagon in pancreatic sections from TG mice and control mice. Enhanced VEGF-A staining (red) in TG mice is completely merged with insulin staining (green to yellow) but not with glucagon staining (green). (B) Quantitative analysis of VEGF-A staining levels in the islets of TG and control mice. We measured the staining levels of VEGF-A per unit area by using NIS-Elements (Nikon) and Image-J (NIH). Six mice were analyzed for each genotype and representative images are shown.

Mentions: It appeared islet capillaries were increased in TG mice based on observations from hematoxylin and eosin staining of pancreatic sections (Fig. 4A, top panels). We previously reported that PECAM1 (a marker for vascular endothelial cells) positive cells were increased in TG islets [15], and that was reconfirmed in the present study (Fig. 4A, middle panels). Interestingly, the immunoreactivity with anti-vascular endothelial growth factor-A (VEGF-A) was increased in islets of TG mice compared to control mice (Fig. 4A, bottom panels). We showed VEGF-A positive cells were β cells, but not α cells, by double staining VEGF-A with insulin or glucagon (Fig. 5). To quantify these results, we performed real-time RT-PCR and densitometry analysis, and showed that both PECAM1 and VEGF-A were significantly increased in TG islets compared to control islets (Fig. 4B and 5B), despite that the number of β cells were decreased in TG islets (Fig. 2A and B). These results indicated that forced expression of constitutively active FoxO1 increased VEGF-A expression in β cells and, thereby, increased the number of capillaries in islets.


FoxO1 gain of function in the pancreas causes glucose intolerance, polycystic pancreas, and islet hypervascularization.

Kikuchi O, Kobayashi M, Amano K, Sasaki T, Kitazumi T, Kim HJ, Lee YS, Yokota-Hashimoto H, Kitamura YI, Kitamura T - PLoS ONE (2012)

Enhanced VEGF-A expression in β cells but not α cells in TG mice.(A) Double immunostaining of VEGF-A with insulin or glucagon in pancreatic sections from TG mice and control mice. Enhanced VEGF-A staining (red) in TG mice is completely merged with insulin staining (green to yellow) but not with glucagon staining (green). (B) Quantitative analysis of VEGF-A staining levels in the islets of TG and control mice. We measured the staining levels of VEGF-A per unit area by using NIS-Elements (Nikon) and Image-J (NIH). Six mice were analyzed for each genotype and representative images are shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3285669&req=5

pone-0032249-g005: Enhanced VEGF-A expression in β cells but not α cells in TG mice.(A) Double immunostaining of VEGF-A with insulin or glucagon in pancreatic sections from TG mice and control mice. Enhanced VEGF-A staining (red) in TG mice is completely merged with insulin staining (green to yellow) but not with glucagon staining (green). (B) Quantitative analysis of VEGF-A staining levels in the islets of TG and control mice. We measured the staining levels of VEGF-A per unit area by using NIS-Elements (Nikon) and Image-J (NIH). Six mice were analyzed for each genotype and representative images are shown.
Mentions: It appeared islet capillaries were increased in TG mice based on observations from hematoxylin and eosin staining of pancreatic sections (Fig. 4A, top panels). We previously reported that PECAM1 (a marker for vascular endothelial cells) positive cells were increased in TG islets [15], and that was reconfirmed in the present study (Fig. 4A, middle panels). Interestingly, the immunoreactivity with anti-vascular endothelial growth factor-A (VEGF-A) was increased in islets of TG mice compared to control mice (Fig. 4A, bottom panels). We showed VEGF-A positive cells were β cells, but not α cells, by double staining VEGF-A with insulin or glucagon (Fig. 5). To quantify these results, we performed real-time RT-PCR and densitometry analysis, and showed that both PECAM1 and VEGF-A were significantly increased in TG islets compared to control islets (Fig. 4B and 5B), despite that the number of β cells were decreased in TG islets (Fig. 2A and B). These results indicated that forced expression of constitutively active FoxO1 increased VEGF-A expression in β cells and, thereby, increased the number of capillaries in islets.

Bottom Line: FoxO1 is a downstream transcription factor of insulin/IGF-1 signaling.We found FoxO1 binds to the VEGF-A promoter and regulates VEGF-A transcription in β cells.We propose that dysregulation of FoxO1 activity in the pancreas could account for the development of diabetes and pancreatic cysts.

View Article: PubMed Central - PubMed

Affiliation: Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.

ABSTRACT
Genetic studies revealed that the ablation of insulin/IGF-1 signaling in the pancreas causes diabetes. FoxO1 is a downstream transcription factor of insulin/IGF-1 signaling. We previously reported that FoxO1 haploinsufficiency restored β cell mass and rescued diabetes in IRS2 knockout mice. However, it is still unclear whether FoxO1 dysregulation in the pancreas could be the cause of diabetes. To test this hypothesis, we generated transgenic mice overexpressing constitutively active FoxO1 specifically in the pancreas (TG). TG mice had impaired glucose tolerance and some of them indeed developed diabetes due to the reduction of β cell mass, which is associated with decreased Pdx1 and MafA in β cells. We also observed increased proliferation of pancreatic duct epithelial cells in TG mice and some mice developed a polycystic pancreas as they aged. Furthermore, TG mice exhibited islet hypervascularities due to increased VEGF-A expression in β cells. We found FoxO1 binds to the VEGF-A promoter and regulates VEGF-A transcription in β cells. We propose that dysregulation of FoxO1 activity in the pancreas could account for the development of diabetes and pancreatic cysts.

Show MeSH
Related in: MedlinePlus