Abnormal glucose tolerance and insulin secretion in pancreas-specific Tcf7l2-null mice.
OBJECTIVE
Individuals carrying type 2 diabetes risk alleles in TCF7L2 display decreased beta cell levels of T cell factor 7 like-2 (TCF7L2) immunoreactivity, and impaired insulin secretion and beta cell sensitivity to glucagon-like peptide 1 (GLP-1). Here, we sought to determine whether selective deletion of Tcf7l2 in mouse pancreas impairs insulin release and glucose homeostasis.


METHODS
Pancreas-specific Tcf7l2-null (pTcf7l2) mice were generated by crossing mice carrying conditional knockout alleles of Tcf7l2 (Tcf7l2-flox) with mice expressing Cre recombinase under the control of the Pdx1 promoter (Pdx1.Cre). Gene expression was assessed by real-time quantitative PCR and beta cell mass by optical projection tomography. Glucose tolerance, insulin secretion from isolated islets, and plasma insulin, glucagon and GLP-1 content were assessed by standard protocols.


RESULTS
From 12 weeks of age, pTcf7l2 mice displayed decreased oral glucose tolerance vs control littermates; from 20 weeks they had glucose intolerance upon administration of glucose by the intraperitoneal route. pTcf7l2 islets displayed impaired insulin secretion in response to 17 (vs 3.0) mmol/l glucose (54.6 ± 4.6%, p < 0.01) or to 17 mmol/l glucose plus 100 nmol/l GLP-1 (44.3 ± 4.9%, p < 0.01) compared with control islets. Glp1r (42 ± 0.08%, p < 0.01) and Ins2 (15.4 ± 4.6%, p < 0.01) expression was significantly lower in pTcf7l2 islets than in controls. Maintained on a high-fat (but not on a normal) diet, pTcf7l2 mice displayed decreased expansion of pancreatic beta cell volume vs control littermates. No differences were observed in plasma insulin, proinsulin, glucagon or GLP-1 concentrations.


CONCLUSIONS
Selective deletion of Tcf7l2 in the pancreas replicates key aspects of the altered glucose homeostasis in human carriers of TCF7L2 risk alleles, indicating the direct role of this factor in controlling beta cell function.
Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, SW7 2AZ, UK. g.dasilva-xavier@imperial.ac.uk.
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da Silva Xavier
Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, SW7 2AZ, UK.
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Mondragon
Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, SW7 2AZ, UK.
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Sun
Photonics Group, Department of Physics, Imperial College London, London, UK.
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Chen
Photonics Group, Department of Physics, Imperial College London, London, UK.
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McGinty
Photonics Group, Department of Physics, Imperial College London, London, UK.
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French
Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, SW7 2AZ, UK. g.rutter@imperial.ac.uk.
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Rutter
D000818:Animals; D002478:Cells, Cultured; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011384:Proinsulin / Q000097:blood; D058118:Transcription Factor 7-Like 2 Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D007328:Insulin; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D011384:Proinsulin; D005947:Glucose