title: Increased vimentin in human α- and β-cells in type 2 diabetes.
abstract: Type 2 diabetes (T2DM) is associated with pancreatic islet dysfunction. Loss of β-cell identity has been implicated via dedifferentiation or conversion to other pancreatic endocrine cell types. How these transitions contribute to the onset and progression of T2DMin vivois unknown. The aims of this study were to determine the degree of epithelial-to-mesenchymal transition occurring in α and β cellsin vivoand to relate this to diabetes-associated (patho)physiological conditions. The proportion of islet cells expressing the mesenchymal marker vimentin was determined by immunohistochemistry and quantitative morphometry in specimens of pancreas from human donors with T2DM (n= 28) and without diabetes (ND,n= 38) and in non-human primates at different stages of the diabetic syndrome: normoglycaemic (ND,n= 4), obese, hyperinsulinaemic (HI,n= 4) and hyperglycaemic (DM,n= 8). Vimentin co-localised more frequently with glucagon (α-cells) than with insulin (β-cells) in the human ND group (1.43% total α-cells, 0.98% total β-cells, median;P< 0.05); these proportions were higher in T2DM than ND (median 4.53% α-, 2.53% β-cells;P< 0.05). Vimentin-positive β-cells were not apoptotic, had reduced expression of Nkx6.1 and Pdx1, and were not associated with islet amyloidosis or with bihormonal expression (insulin + glucagon). In non-human primates, vimentin-positive β-cell proportion was larger in the diabetic than the ND group (6.85 vs 0.50%, medians respectively,P< 0.05), but was similar in ND and HI groups. In conclusion, islet cell expression of vimentin indicates a degree of plasticity and dedifferentiation with potential loss of cellular identity in diabetes. This could contribute to α- and β-cell dysfunction in T2DM.
authors.affiliation: Department of Internal MedicineLeiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Maaike M
authors.initials: MM
authors.lastname: Roefs
authors.affiliation: Department of Internal MedicineLeiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Françoise
authors.initials: F
authors.lastname: Carlotti
authors.affiliation: Oxford Centre for DiabetesEndocrinology and Metabolism (OCDEM), Oxford, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Jones
authors.affiliation: Oxford Centre for DiabetesEndocrinology and Metabolism (OCDEM), Oxford, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Wills
authors.affiliation: Oxford Centre for DiabetesEndocrinology and Metabolism (OCDEM), Oxford, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hamilton
authors.affiliation: Department of Internal MedicineLeiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Verschoor
authors.affiliation: Department of Internal MedicineLeiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Joanna M Williams
authors.initials: JMW
authors.lastname: Durkin
authors.affiliation: Department of Internal MedicineLeiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Garcia-Perez
authors.affiliation: Department of PhysiologyAnatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Melissa F
authors.initials: MF
authors.lastname: Brereton
authors.affiliation: Oxford Centre for DiabetesEndocrinology and Metabolism (OCDEM), Oxford, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: McCulloch
authors.affiliation: Department of Internal MedicineLeiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Marten A
authors.initials: MA
authors.lastname: Engelse
authors.affiliation: Oxford Centre for DiabetesEndocrinology and Metabolism (OCDEM), Oxford, UK.|Nuffield Department of Surgical SciencesJohn Radcliffe Hospital, Oxford, UK.
authors.forename: Paul R V
authors.initials: PRV
authors.lastname: Johnson
authors.affiliation: Departments of Internal Medicine and PediatricsMorsani College of Medicine, University of South Florida, Tampa, Florida, USA.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Hansen
authors.affiliation: Medical SciencesUniversity of Aberdeen, Aberdeen, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Docherty
authors.affiliation: Department of Internal MedicineLeiden University Medical Center (LUMC), Leiden, the Netherlands.|Hubrecht InstituteUtrecht, the Netherlands.
authors.forename: Eelco J P
authors.initials: EJP
authors.lastname: de Koning
authors.affiliation: Oxford Centre for DiabetesEndocrinology and Metabolism (OCDEM), Oxford, UK anne.clark@drl.ox.ac.uk.
authors.forename: Anne
authors.initials: A
authors.lastname: Clark
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism / Q000662:veterinary; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008252:Macaca fascicularis; D008253:Macaca mulatta; D014746:Vimentin / Q000378:metabolism*
chemical_list: D014746:Vimentin
keywords: EMT; amyloid; dedifferentiation; glucagon; insulin; islet; non-human primate