Endocrine Abstracts

Diabetes mellitus is one of the greatest health crises of our time. In response to diabetic stress, pancreatic beta-cells undergo a set of profound phenotypical alterations, including dedifferentiation, polyploidisation and hypertrophy, and apoptosis. Although we know that thyroid hormone (TH) signalling controls these phenomena in response to various injuries, little is known about its role in the pathobiology of diabetic pancreas. The aim of this study was to investigate the role of TH signalling in the pathogenesis of diabetes in Zucker diabetic fatty (ZDF) rats and in in vitro human model of glucose-induced injury. Results showed that diabetic stress induces beta-cell apoptosis, decrease in the expression of mature beta-cell markers (PDX1, NKX6.1, insulin) and simultaneous increase in glucagon expression and the number of bihormonal cells. Interestingly, treatment with T3 reversed these alterations by increasing the insulin secreting area and normalising the expression of PDX1 and NKX6.1. Moreover histological and imaging analysis showed that T3 treatment ameliorated the structure and organisation of pancreatic islets and prevents beta-cell polyploidization. To assess whether TH signalling plays a role in pathological changes in human pancreatic beta-cells, we exposed purified human beta-cells to high concentrations of glucose and evaluated phenotypic changes. Results from immunofluorescence analysis showed that high glucose injury concurrently induced an increase in glucagon-positive cells and a decrease in insulin-positive cell numbers, further confirming that the high concentration of glucose induces the transdifferentiation of beta- into alpha-cells. Importantly, we also observed a significant reduction in the number of cells after high glucose injury, compared to control cells and an increase in cell area. Remarkably, treatment with T3 significantly increased intracellular insulin content and decreased the number of transdifferentiating cells, restored cell numbers to the control level, and markedly reduced the pancreatic beta-cell area. Conversely, the inhibition of T3 binding to TRα1 with desbutyl-dronedarone – before adding T3 to glucose-stressed cells – completely abrogated the beneficial effects of T3, and largely enhanced further transdifferentiation of beta-cells into alpha-cells. This implies that the unliganded TRα1 may trigger opposite actions with respect to the liganded receptor in the diabetic pancreas. All together these data indicate that TH signalling plays a crucial role in diabetes-induced beta-cell pathological growth, dedifferentiation and transdifferentiation.