General Information:

Id: 5,841
Diseases: Diabetes mellitus, type II - [OMIM]
Insulin resistance
Mus musculus
article
Reference: Landsman L et al.(2011) Elevated Hedgehog/Gli signaling causes beta-cell dedifferentiation in mice Proc. Natl. Acad. Sci. U.S.A. 108 [PMID: 21969560]

Interaction Information:

Comment Increased Hedgehog (Hh) signaling in adult beta-cells, induced by simultaneous expression of an activated form of the GLI2 transcription factor and the elimination of primary cilia in compound transgenic animals, results in glucose intolerance.
Formal Description
Interaction-ID: 55181

increases_activity of

in adult pancreatic beta cells
Comment Increased Hedgehog (Hh) signaling leads to impaired beta-cell function and insulin secretion, resulting in glucose intolerance in transgenic mice.
Formal Description
Interaction-ID: 55184

decreases_activity of

in adult pancreatic beta cells
Comment Increased Hedgehog (Hh) signaling leads to impaired beta-cell function and insulin secretion, resulting in glucose intolerance in transgenic mice.
Formal Description
Interaction-ID: 55185

decreases_activity of

phenotype

reduced pancreatic beta cell function

in adult pancreatic beta cells
Comment As expected from previous work showing that elevated Hedgehog (Hh) signaling protects cultured beta-cells from apoptosis, a significant increase in the expression level of the anti-apoptotic gene Bcl2 was detected.
Formal Description
Interaction-ID: 55186

increases_expression of

gene/protein

BCL2

in adult pancreatic beta cells
Drugbank entries Show/Hide entries for BCL2
Comment The expression level of Kir6.2 and Sur1, components of beta-cell K(ATP) channels required for insulin secretion, was analyzed. Transcript levels of both genes were significantly reduced in TAM-treated transgenic islets compared with control, suggesting potential secretion defects.
Formal Description
Interaction-ID: 55187

decreases_expression of

gene/protein

KCNJ11

in adult pancreatic beta cells
Drugbank entries Show/Hide entries for KCNJ11
Comment The expression level of Kir6.2 and Sur1, components of beta-cell K(ATP) channels required for insulin secretion, was analyzed. Transcript levels of both genes were significantly reduced in TAM-treated transgenic islets compared with control, suggesting potential secretion defects.
Formal Description
Interaction-ID: 55188

decreases_expression of

gene/protein

ABCC8

in adult pancreatic beta cells
Drugbank entries Show/Hide entries for ABCC8
Comment Accurate sensing of blood glucose levels is essential for beta-cell function, a process in which the Glucose Transporter 2 (Glut2) plays a key role. Analysis of Glut2 transcript and protein levels revealed a significant reduction in its expression levels in Pdx1-CreER;CLEG2;Kif3af/f transgenic mice compared with control. Immunohistochemical analysis further demonstrated dramatically perturbed Glut2 protein distribution in transgenic islets, implicating defects in glucose sensing.
Formal Description
Interaction-ID: 55189

decreases_expression of

gene/protein

SLC2A2

in adult pancreatic beta cells
Drugbank entries Show/Hide entries for SLC2A2
Comment Numerous studies have delineated the transcription factor network that guides beta-cell development and ensures proper beta-cell function by maintaining the fully differentiated state of the cells. To study whether the impaired GSIS observed in Pdx1-CreER;CLEG2;Kif3af/f mice was a result of the loss of the mature beta-cell phenotype, the authors analyzed the expression levels of such factors. Transgenic islets expressed lower levels of Pdx1, as shown by significant reduction of both transcript and protein levels compared with nontransgenic control. The analysis further revealed significant reduction in the expression of MafA, NeuroD1, Nkx6.1, and Neurogenin3 (Ngn3) in transgenic islets 4 wk after TAM treatment compared with control. Thus, elevated Hh signaling causes reduction of critical beta-cell markers, suggesting a loss of the mature beta-cell phenotype.
Formal Description
Interaction-ID: 55190

decreases_expression of

gene/protein

PDX1

in adult pancreatic beta cells
Comment Numerous studies have delineated the transcription factor network that guides beta-cell development and ensures proper beta-cell function by maintaining the fully differentiated state of the cells. To study whether the impaired GSIS observed in Pdx1-CreER;CLEG2;Kif3af/f mice was a result of the loss of the mature beta-cell phenotype, the authors analyzed the expression levels of such factors. Transgenic islets expressed lower levels of Pdx1, as shown by significant reduction of both transcript and protein levels compared with nontransgenic control. The analysis further revealed significant reduction in the expression of MafA, NeuroD1, Nkx6.1, and Neurogenin3 (Ngn3) in transgenic islets 4 wk after TAM treatment compared with control. Thus, elevated Hh signaling causes reduction of critical beta-cell markers, suggesting a loss of the mature beta-cell phenotype.
Formal Description
Interaction-ID: 55191

decreases_expression of

gene/protein

MAFA

in adult pancreatic beta cells
Comment Numerous studies have delineated the transcription factor network that guides beta-cell development and ensures proper beta-cell function by maintaining the fully differentiated state of the cells. To study whether the impaired GSIS observed in Pdx1-CreER;CLEG2;Kif3af/f mice was a result of the loss of the mature beta-cell phenotype, the authors analyzed the expression levels of such factors. Transgenic islets expressed lower levels of Pdx1, as shown by significant reduction of both transcript and protein levels compared with nontransgenic control. The analysis further revealed significant reduction in the expression of MafA, NeuroD1, Nkx6.1, and Neurogenin3 (Ngn3) in transgenic islets 4 wk after TAM treatment compared with control. Thus, elevated Hh signaling causes reduction of critical beta-cell markers, suggesting a loss of the mature beta-cell phenotype.
Formal Description
Interaction-ID: 55192

decreases_expression of

gene/protein

NEUROD1

in adult pancreatic beta cells
Comment Numerous studies have delineated the transcription factor network that guides beta-cell development and ensures proper beta-cell function by maintaining the fully differentiated state of the cells. To study whether the impaired GSIS observed in Pdx1-CreER;CLEG2;Kif3af/f mice was a result of the loss of the mature beta-cell phenotype, the authors analyzed the expression levels of such factors. Transgenic islets expressed lower levels of Pdx1, as shown by significant reduction of both transcript and protein levels compared with nontransgenic control. The analysis further revealed significant reduction in the expression of MafA, NeuroD1, Nkx6.1, and Neurogenin3 (Ngn3) in transgenic islets 4 wk after TAM treatment compared with control. Thus, elevated Hh signaling causes reduction of critical beta-cell markers, suggesting a loss of the mature beta-cell phenotype.
Formal Description
Interaction-ID: 55193

decreases_expression of

gene/protein

NKX6-1

in adult pancreatic beta cells
Comment Sox9, whose function is required in pancreas progenitor cells, is normally excluded from mature beta-cells. Sox9 transcript and protein levels were increased twofold and fourfold, respectively, in Pdx1-CreER;CLEG2;Kif3af/f transgenic islets compared with control.
Formal Description
Interaction-ID: 55194

increases_expression of

gene/protein

SOX9

in adult pancreatic beta cells
Comment Hes1, a transcription factor activated by the Notch signaling pathway, is expressed in embryonic and adult pancreata but excluded from beta-cells. Pdx1-CreER;CLEG2;Kif3af/f islets showed a twofold increase in Hes1 transcript levels compared with controls, accompanied by a profound up-regulation of the Hes1 protein.
Formal Description
Interaction-ID: 55195

increases_expression of

gene/protein

HES1

in adult pancreatic beta cells
Comment Prolonged elevation of Hedgehog (Hh) signaling in beta-cells results in development of undifferentiated pancreatic tumors.
Formal Description
Interaction-ID: 55196

increases_activity of

in adult pancreatic beta cells