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Molecular mechanism in β -cells development: the role of PDX1, Ngn3 and Pax4 proteins

Insulin-producing pancreatic β -cells are predominant and the most essential cell type of endocrine pancreas. Together with other endocrine cell types (glucagon-producing α -cells, somatostatin-producing δ -cells and pancreatic polypeptide-producing PP cells), beta cells are organized into spherical clusters, each containing about 2000 cells, which are dispersed within exocrine tissue of pancreas. These structures are known as islets of Langerhans. Main protein product of β -cells is insulin, the only hormone in the body with the ability to reduce blood glucose level. Insulin deficiency leads towards Diabetes mellitus, a devastating disease that affects approximately 450 million people worldwide. In patients suffering from Type I diabetes all β -cells are destroyed due to strong autoimmune attack. Because, islet beta cells per se have a limited capacity to self renewal after postfetal development, especially in the cause of an active autoimmune response, beta cell mass is rapidly decreased and causes the diabetes. After that most diabetic patients today have to lifelong insulin therapy. While insulin therapy offers a means to obtain normoglycemia, only pancreas or islet transplantations represent a actual “ cure” for the insulin-dependent diabetic patients. Unfortunately, availability of donor pancreata or islets as a source for transplantation is acutely limited. Nevertheless, these patients with time develop severe (diabetic late complications), life-threatening complications due to the lack of fine tuned mechanism of glucose sensing and physiologically regulated insulin release that would maintain constant level of blood glucose. Therefore diabetes is considered to be an incurable disease, and new approaches in developing therapy are needed to change that fact. One of the most promising approaches is cell replacement therapy based on in vitro differentiation of embryonic stem cells towards insulin-producing cells that would display β -cell phenotype. The most common strategy used by numerous research groups is an attempt to recapitulate normal embryonic development of β -cells in the context of pancreatogenesis in human organism. For that reason it is essential to get insight into the complex transcriptional networks governed by numerous cell extrinsic and intrinsic signals during formation of an adult organ from plurypotent cells of an early embryo. Due to the strict limitations of working with human embryonic stem cells and difficulties in obtaining the experimental material, mouse is the most common model organism for both developmental (in vivo) and differentiational (in vitro) studies.

Diabetes ; PDX1 ; Ngn3 and Pax4

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