Date

2022-6-13

Author

FEYAT, MEHMET SEDAT

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In general, Type 2 Diabetes (T2D) is a disease characterized by impaired functioning of pancreatic beta cells and progressive insulin hormone deficiency progressively in combination with physiologically ongoing insulin resistance. In the later stages of the disease, beta cell dysfunction is defined as beta cell death and a decrease in functional cell count. It is a common clinical finding in patients with T2D that therapeutic drugs lowering insulin resistance and diet in the course of the disease treatment cause increased levels of insulin secretion in the patients and thus increased functional beta cell population. From the literature view, it has been observed that apoptotic cell death does not occur in adult mouse pancreatic beta cells exposed to obesity-sourced hyperglycemia, and these cells undergo dedifferentiation and transform into progenitor cells or other pancreatic endocrine cell types. However, maternal obesity induced human or animal pancreatic transdifferentiation in young offspring has not been studied up to date. Our proposed hypothesis was that obesity-induced hyperglycemia in the mother may cause dedifferentiation and/or transdifferentiation in offspring pancreatic beta cells.In this thesis, the effect of predisposition to diabetes pathology on the pancreas of offspring produced by the mother's cafeteria diet (CAF) was investigated via pancreatic beta cell dedifferentiation and transdifferentiation. We have obtained pancreases of 0, 20, 90 days old Wistar rat offspring whose mothers had diet-induced obesity via CAF. Later, the diabetic tendency of juvenile rats was evaluated according to the glucose-stimulated insulin release test using the islet cells isolated from the pancreas tissues of offspring. Viability rates of isolated pancreatic islet cells were analysed by appropriate viability tests (FDA / PI staining) to determine the quality of the cell isolation performed. To examine the morphological change in pancreatic tissues between groups, the frozen pancreatic tissue sections of offspring were histologically examined using hematoxylin-eosine staining. Pancreatic tissue specimens were also stained with glucagon antibodies to determine cell characteristics for dedifferentiation in the mother subjects using immunohistochemistry. Additionally, RT-qPCR analysis was performed so that the transformation profiles of the pancreatic cells were determined at the gene expression level. Examined gene expressions were Neurogenin 3, Pancreatic and duodenal homeobox 1, Insulin, Somatostatin, Glucagon, Forkhead box O1, Chromogranin A, and Vimentin. Alongside the RT-qPCR analysis, full-genome transcriptome analysis was performed to clarify the transformation profile. Using Western blot analysis of insulin protein expression in the pancreas tissues, dedifferentiation was partially presented at the protein level. When the results of all experiments were considered, it was demonstrated that maternal obesity may affect the dedifferentiation of pancreatic beta cells in offspring and had a predisposing effect for diabetes. In conclusion, it was believed that physiological stress caused by a maternal metabolic disorder may cause a predisposition to the same metabolic disease in offspring through cellular transformation mechanisms.

Subject Keywords

Dedifferentiation, Diabetes, Maternal Obesity, Pancreatic beta cell, Transdifferentiation

URI

https://hdl.handle.net/11511/98130

Collections

Graduate School of Natural and Applied Sciences, Thesis