Abnormal glucose tolerance and insulin secretion in pancreas-specific Tcf7l2-null mice

Aims/hypothesis 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 select...

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Bibliographic Details
Published in:	Diabetologia Vol. 55; no. 10; pp. 2667 - 2676
Main Authors:	da Silva Xavier, G., Mondragon, A., Sun, G., Chen, L., McGinty, J. A., French, P. M., Rutter, G. A.
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer-Verlag 01-10-2012 Springer Springer Nature B.V
Subjects:	Animals Apoptosis Biological and medical sciences Cell growth Cells, Cultured Diabetes Diabetes. Impaired glucose tolerance Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance Gene expression Genomes Glucagon Glucagon - blood Glucagon-Like Peptide 1 - blood Glucagon-Like Peptide 1 - pharmacology Glucose Glucose - metabolism Glucose Tolerance Test Homeostasis Homeostasis - physiology Human Physiology Insulin Insulin - metabolism Insulin Secretion Insulin-Secreting Cells - cytology Insulin-Secreting Cells - drug effects Insulin-Secreting Cells - physiology Internal Medicine Islets of Langerhans - cytology Islets of Langerhans - drug effects Islets of Langerhans - metabolism Lymphocytes Medical sciences Medicine Medicine & Public Health Metabolic Diseases Mice Mice, Knockout Pancreas Pancreas - cytology Pancreas - drug effects Pancreas - metabolism Peptides Physiology Proinsulin - blood Transcription Factor 7-Like 2 Protein - deficiency Transcription Factor 7-Like 2 Protein - genetics Transcription Factor 7-Like 2 Protein - metabolism Glucose tolerance GLP-1 GWAS Beta cell mass Knockout mouse Pancreas Insulin Endocrinopathy Pancreatic hormone Secretion Diabetes mellitus Langerhans islet Rodentia Tolerance Glucose Vertebrata Mammalia Mouse Animal β Cell Mutation Impaired glucose tolerance Endocrine pancreas
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Summary:	Aims/hypothesis 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/interpretation 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0012-186X 1432-0428
DOI:	10.1007/s00125-012-2600-7