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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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Tcf7l2 deletion impairs glucose and GLP1-stimulated insulin secretion from isolated islets. (A) Plasma insulin following intraperitoneal injection of glucose from 20-week-old mice that had been maintained on a high fat diet was measured as described in Materials and Methods. (B) Real-time quantitative PCR analysis was performed on islets from 20-weeks-old mice that had been maintained on a normal chow diet. n = 7–10 mice; *P ≤ 0.05. (C and D) Insulin secretion as assessed in isolated islets from 20-week old Tcf7l2fl/fl::Ins1.Cre+(red) and littermate Tcf7l2fl/fl::Ins1.Cre− (black) mice on normal chow (C) or high fat diet (D). n = 5 mice per genotype; *P ≤ 0.05; **P ≤ 0.01.
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DDU553F2: Tcf7l2 deletion impairs glucose and GLP1-stimulated insulin secretion from isolated islets. (A) Plasma insulin following intraperitoneal injection of glucose from 20-week-old mice that had been maintained on a high fat diet was measured as described in Materials and Methods. (B) Real-time quantitative PCR analysis was performed on islets from 20-weeks-old mice that had been maintained on a normal chow diet. n = 7–10 mice; *P ≤ 0.05. (C and D) Insulin secretion as assessed in isolated islets from 20-week old Tcf7l2fl/fl::Ins1.Cre+(red) and littermate Tcf7l2fl/fl::Ins1.Cre− (black) mice on normal chow (C) or high fat diet (D). n = 5 mice per genotype; *P ≤ 0.05; **P ≤ 0.01.

Mentions: To determine whether the imposition of a metabolic stress may affect the glucose intolerance observed in Tcf7l2fl/fl::Ins1.Cre+mice, animals were maintained for the indicated times on a high fat (∼60% total calories) diet. Null animals under these conditions gained weight similarly to wildtype littermates, albeit with a small increase versus controls apparent from 20 weeks (Supplementary Material, Fig. S1). While glucose intolerance was not apparent at 12 weeks (Fig. 1B), the dysglycemia observed at 16 and 20 weeks was further exaggerated compared with that apparent in animals maintained on regular chow (Fig. 1C and D). Insulin tolerance did not differ between genotypes (Fig. 1G), and fasting glucagon levels were identical (Fig. 1H). Nonetheless, in vivo insulin release prompted by IP injection of 1 g/kg glucose was markedly impaired in the mice (Fig. 2A).Figure 2.


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)

Tcf7l2 deletion impairs glucose and GLP1-stimulated insulin secretion from isolated islets. (A) Plasma insulin following intraperitoneal injection of glucose from 20-week-old mice that had been maintained on a high fat diet was measured as described in Materials and Methods. (B) Real-time quantitative PCR analysis was performed on islets from 20-weeks-old mice that had been maintained on a normal chow diet. n = 7–10 mice; *P ≤ 0.05. (C and D) Insulin secretion as assessed in isolated islets from 20-week old Tcf7l2fl/fl::Ins1.Cre+(red) and littermate Tcf7l2fl/fl::Ins1.Cre− (black) mice on normal chow (C) or high fat diet (D). n = 5 mice per genotype; *P ≤ 0.05; **P ≤ 0.01.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4321446&req=5

DDU553F2: Tcf7l2 deletion impairs glucose and GLP1-stimulated insulin secretion from isolated islets. (A) Plasma insulin following intraperitoneal injection of glucose from 20-week-old mice that had been maintained on a high fat diet was measured as described in Materials and Methods. (B) Real-time quantitative PCR analysis was performed on islets from 20-weeks-old mice that had been maintained on a normal chow diet. n = 7–10 mice; *P ≤ 0.05. (C and D) Insulin secretion as assessed in isolated islets from 20-week old Tcf7l2fl/fl::Ins1.Cre+(red) and littermate Tcf7l2fl/fl::Ins1.Cre− (black) mice on normal chow (C) or high fat diet (D). n = 5 mice per genotype; *P ≤ 0.05; **P ≤ 0.01.
Mentions: To determine whether the imposition of a metabolic stress may affect the glucose intolerance observed in Tcf7l2fl/fl::Ins1.Cre+mice, animals were maintained for the indicated times on a high fat (∼60% total calories) diet. Null animals under these conditions gained weight similarly to wildtype littermates, albeit with a small increase versus controls apparent from 20 weeks (Supplementary Material, Fig. S1). While glucose intolerance was not apparent at 12 weeks (Fig. 1B), the dysglycemia observed at 16 and 20 weeks was further exaggerated compared with that apparent in animals maintained on regular chow (Fig. 1C and D). Insulin tolerance did not differ between genotypes (Fig. 1G), and fasting glucagon levels were identical (Fig. 1H). Nonetheless, in vivo insulin release prompted by IP injection of 1 g/kg glucose was markedly impaired in the mice (Fig. 2A).Figure 2.

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