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Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass.

Mitchell RK, Mondragon A, Chen L, Mcginty JA, French PM, Ferrer J, Thorens B, Hodson DJ, Rutter GA, Da Silva Xavier G - Hum. Mol. Genet. (2014)

Bottom Line: Single nucleotide polymorphisms in the T-cell factor 7-like 2 (TCF7L2) gene, associated with T2D by genome-wide association studies, lead to impaired β cell function.Tcfl2(fl/fl)::Ins1Cre islets displayed defective glucose- and GLP-1-stimulated insulin secretion and the expression of both the Ins2 (∼20%) and Glp1r (∼40%) genes were significantly reduced.These data demonstrate that Tcf7l2 plays a cell autonomous role in the control of β cell function and mass, serving as an important regulator of gene expression and islet cell coordination.

View Article: PubMed Central - PubMed

Affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine.

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Impact of Tcf7l2 deletion on β and α cell mass. (A) Representative 3D images from OPT (see Material and Methods) of Tcf7l2fl/fl::Ins1.Cre+ and Tcf7l2fl/fl::Ins1.Cre− pancreata labelled with anti-insulin and anti-glucagon primary antibodies, and revealed using AlexaFluor 568 and 680, respectively. Right hand-most panels are overlaid with the autofluorescence signal revealing the pancreatic ductal system. Quantification of β (B), α (C) and (D) β/α cell mass from Tcf7l2fl/fl::Ins1.Cre+(red) and Tcf7l2fl/fl::Ins1.Cre− (black) knockout mice pancreata from 20-week-old mice that had been maintained on high fat diet. Quantification was conducted using Volocity software (Invitrogen), N = 4 mice per genotype.
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DDU553F4: Impact of Tcf7l2 deletion on β and α cell mass. (A) Representative 3D images from OPT (see Material and Methods) of Tcf7l2fl/fl::Ins1.Cre+ and Tcf7l2fl/fl::Ins1.Cre− pancreata labelled with anti-insulin and anti-glucagon primary antibodies, and revealed using AlexaFluor 568 and 680, respectively. Right hand-most panels are overlaid with the autofluorescence signal revealing the pancreatic ductal system. Quantification of β (B), α (C) and (D) β/α cell mass from Tcf7l2fl/fl::Ins1.Cre+(red) and Tcf7l2fl/fl::Ins1.Cre− (black) knockout mice pancreata from 20-week-old mice that had been maintained on high fat diet. Quantification was conducted using Volocity software (Invitrogen), N = 4 mice per genotype.

Mentions: To determine whether alterations in β (or α) cell mass also might contribute to impaired insulin production in vivo after Tcf7l2 elimination, pancreata from 20-week-old Tcf7l2fl/fl::Ins1.Cre+mice that had been maintained on a HFD for 12 weeks were stained for insulin and glucagon, respectively, and analyzed by optical projection tomography (OPT). Cre+ islets displayed a markedly (31.7%, P < 0.05; n = 4 mice per genotype) decreased β cell mass, but normal α-cell mass, compared with littermate controls (Fig. 4), resulting in an overall decrease in β to α cell ratio. The number of smaller insulin-stained islets was particularly sharply decreased in TCF7L2fl/fl::Ins1.Cre+ mouse islets (Fig. 4B).Figure 4.


Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass.

Mitchell RK, Mondragon A, Chen L, Mcginty JA, French PM, Ferrer J, Thorens B, Hodson DJ, Rutter GA, Da Silva Xavier G - Hum. Mol. Genet. (2014)

Impact of Tcf7l2 deletion on β and α cell mass. (A) Representative 3D images from OPT (see Material and Methods) of Tcf7l2fl/fl::Ins1.Cre+ and Tcf7l2fl/fl::Ins1.Cre− pancreata labelled with anti-insulin and anti-glucagon primary antibodies, and revealed using AlexaFluor 568 and 680, respectively. Right hand-most panels are overlaid with the autofluorescence signal revealing the pancreatic ductal system. Quantification of β (B), α (C) and (D) β/α cell mass from Tcf7l2fl/fl::Ins1.Cre+(red) and Tcf7l2fl/fl::Ins1.Cre− (black) knockout mice pancreata from 20-week-old mice that had been maintained on high fat diet. Quantification was conducted using Volocity software (Invitrogen), N = 4 mice per genotype.
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DDU553F4: Impact of Tcf7l2 deletion on β and α cell mass. (A) Representative 3D images from OPT (see Material and Methods) of Tcf7l2fl/fl::Ins1.Cre+ and Tcf7l2fl/fl::Ins1.Cre− pancreata labelled with anti-insulin and anti-glucagon primary antibodies, and revealed using AlexaFluor 568 and 680, respectively. Right hand-most panels are overlaid with the autofluorescence signal revealing the pancreatic ductal system. Quantification of β (B), α (C) and (D) β/α cell mass from Tcf7l2fl/fl::Ins1.Cre+(red) and Tcf7l2fl/fl::Ins1.Cre− (black) knockout mice pancreata from 20-week-old mice that had been maintained on high fat diet. Quantification was conducted using Volocity software (Invitrogen), N = 4 mice per genotype.
Mentions: To determine whether alterations in β (or α) cell mass also might contribute to impaired insulin production in vivo after Tcf7l2 elimination, pancreata from 20-week-old Tcf7l2fl/fl::Ins1.Cre+mice that had been maintained on a HFD for 12 weeks were stained for insulin and glucagon, respectively, and analyzed by optical projection tomography (OPT). Cre+ islets displayed a markedly (31.7%, P < 0.05; n = 4 mice per genotype) decreased β cell mass, but normal α-cell mass, compared with littermate controls (Fig. 4), resulting in an overall decrease in β to α cell ratio. The number of smaller insulin-stained islets was particularly sharply decreased in TCF7L2fl/fl::Ins1.Cre+ mouse islets (Fig. 4B).Figure 4.

Bottom Line: Single nucleotide polymorphisms in the T-cell factor 7-like 2 (TCF7L2) gene, associated with T2D by genome-wide association studies, lead to impaired β cell function.Tcfl2(fl/fl)::Ins1Cre islets displayed defective glucose- and GLP-1-stimulated insulin secretion and the expression of both the Ins2 (∼20%) and Glp1r (∼40%) genes were significantly reduced.These data demonstrate that Tcf7l2 plays a cell autonomous role in the control of β cell function and mass, serving as an important regulator of gene expression and islet cell coordination.

View Article: PubMed Central - PubMed

Affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine.

Show MeSH
Related in: MedlinePlus