TCF7L2 rs7903146 impairs islet function and morphology in non-diabetic individuals.
OBJECTIVE
Transcription factor 7-like 2 (TCF7L2) is a Wnt-signalling-associated transcription factor. Genetic studies have clearly demonstrated that DNA polymorphisms within TCF7L2 confer the strongest known association with increased risk of type 2 diabetes. However, the impact of the TCF7L2 type-2-diabetes-associated rs7903146 T allele on biological function and morphology of human pancreatic islets is unknown.


METHODS
Paraffin sections of pancreases from 187 brain-deceased donors (HbA(1c) <6.5% [48 mmol/mol]) were used to genotype the TCF7L2 variant rs7903146 and evaluate its impact on islet morphology and alpha and beta cell subpopulations following immunostaining for glucagon and C-peptide. Following islet isolation, we investigated the correlation between TCF7L2 genotype and in vitro islet functional variables from our in-house pancreatic database.


RESULTS
TCF7L2 rs7903146 (T/T) was associated with reduced basal and glucose-stimulated insulin secretion in isolated human islets, and reduced islet density in whole pancreas. Morphological analysis demonstrated islet size was increased in T/T carriers. Furthermore, rs7903146 was associated with an increased glucagon/C-peptide ratio, especially in bigger islets.


CONCLUSIONS
The TCF7L2 variant rs7903146 risk allele is associated with impaired insulin secretion, reduction of total islet number and quantitative as well as qualitative morphological changes in human islets. Understanding how the TCF7L2 genotype modulates its activity and how TCF7L2 impacts the islet morphology may aid the design of new therapeutic approaches for the treatment of type 2 diabetes.
Université Lille Nord de France, Lille, France.|Faculty of Medicine, Inserm UMR859, Biotherapies for Diabetes, 1 Place de Verdun, 59000, Lille, France.|CNRS UMR 8199, Institut de Biologie de Lille, 1 Rue du Professeur Calmette, 59021, Lille Cedex, France.
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Le Bacquer
Université Lille Nord de France, Lille, France. jkerr-conte@univ-lille2.fr.|Faculty of Medicine, Inserm UMR859, Biotherapies for Diabetes, 1 Place de Verdun, 59000, Lille, France. jkerr-conte@univ-lille2.fr.
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Kerr-Conte
Université Lille Nord de France, Lille, France.|Faculty of Medicine, Inserm UMR859, Biotherapies for Diabetes, 1 Place de Verdun, 59000, Lille, France.
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Gargani
Université Lille Nord de France, Lille, France.|Faculty of Medicine, Inserm UMR859, Biotherapies for Diabetes, 1 Place de Verdun, 59000, Lille, France.
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Delalleau
Université Lille Nord de France, Lille, France.|CNRS UMR 8199, Institut de Biologie de Lille, 1 Rue du Professeur Calmette, 59021, Lille Cedex, France.
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Huyvaert
Université Lille Nord de France, Lille, France.|Faculty of Medicine, Inserm UMR859, Biotherapies for Diabetes, 1 Place de Verdun, 59000, Lille, France.
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Gmyr
Université Lille Nord de France, Lille, France.|CNRS UMR 8199, Institut de Biologie de Lille, 1 Rue du Professeur Calmette, 59021, Lille Cedex, France.|Imperial College London, London, UK.
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Froguel
Université Lille Nord de France, Lille, France. Bernadette.neve@good.ibl.fr.|CNRS UMR 8199, Institut de Biologie de Lille, 1 Rue du Professeur Calmette, 59021, Lille Cedex, France. Bernadette.neve@good.ibl.fr.
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Neve
Université Lille Nord de France, Lille, France.|Faculty of Medicine, Inserm UMR859, Biotherapies for Diabetes, 1 Place de Verdun, 59000, Lille, France.|Department of Endocrine Surgery, Centre Hospitalier Universitaire de Lille, Lille, France.
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Pattou
D000483:Alleles; D002478:Cells, Cultured; D005838:Genotype; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*
D007328:Insulin; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D005934:Glucagon; D005947:Glucose