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 T2DM is unknown. The aims of this study were to determine the degree of epithelial-to-mesenchymal transition occurring in α and β cells and 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 ( = 28) and without diabetes (ND, = 38) and in non-human primates at different stages of the diabetic syndrome: normoglycaemic (ND, = 4), obese, hyperinsulinaemic (HI, = 4) and hyperglycaemic (DM, = 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; < 0.05); these proportions were higher in T2DM than ND (median 4.53% α-, 2.53% β-cells; < 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, < 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.

Islet Identity in Transplantation Procedures: The Intersection of Cellular Maturity and Function

“…And, in recently diagnosed pancreas samples with T2DM, β-cells showed evidence of α-cell colocalization, as well as the presence of the mesenchymal marker vimentin, indicating both β-cell dedifferentiation and reprogramming to other cell lineages [117]. The presence of vimentin in the endocrine cells of patients with T2DM has been similarly shown by others, demonstrating a higher expression in α-cells than β-cells, and relative to ND-control donor samples [118]. These vimentin-positive β-cells were not apoptotic, and had reduced expression of Nkx6.1 and Pdx1.…”

Beta-Cell Dedifferentiation in Type 2 Diabetes: Concise Review

“…For example, detection of glucagon expression in insulin‐positive cells could reflect abnormal activation of glucagon in β cells, or conversely activation of insulin expression in α cells, as part of a compensatory mechanism aimed at increasing the number of insulin‐producing cells. Similarly, expression of the mesenchymal marker vimentin in T2D pancreas insulin‐positive cells may reflect cell dedifferentiation, resembling epithelial‐mesenchymal transition (EMT) observed in β cells cultured from normal human islets, which manifest proliferation associated with dedifferentiation . Given that brief and reversible EMT occurs in islet progenitor cells in the pancreatic ductal epithelium, as part of normal islet development , vimentin expression in T2D β cells may reflect dedifferentiation to a progenitor‐like state.…”

Variability in endocrine cell identity in patients with chronic pancreatitis undergoing islet autotransplantation

“…Pancreatectomy and islet autotransplantation (PIAT) is a treatment for this disease.Endocrine dedifferentiation is an incompletely understood process, with emerging evidence that β-cells are not only lost by apoptosis in response to chronic hyperglycemia, but they also dedifferentiate, which contributes to subsequent endocrine failure. 1 Endocrinecell dedifferentiation in type 2 diabetes is characterized by β-cells coexpressing insulin and other endocrine hormones, 1-3 losing expression of islet-specific markers MAFA, 4 or urocortin3 (UCN3), 5 and in some cases reverting to a progenitor-like state, presenting as the gain of mesenchymal protein vimentin, 3,6 or the loss of hormone-positive status relative to the pan-endocrine marker synaptophysin. 1,2 There are no previous reports of similar changes in β-and α-cell phenotype in CP.…”