Pancreatic beta-cells insulin secretion is adjusted accordingly to circulating nutrients, especially glucose. It is also modulated, directly or indirectly, by neurons, neurotransmitters and pharmacological agents. Considering pancreatic beta-cells mass and secretory function for the glycemic control, and that those factors are altered in Type 2 Diabetes, it would be of great value to investigate mechanisms capable of simultaneously inhibiting beta-cell insulin secretion and death.Glucose-stimulated insulin secretion includes several mechanisms, self-complementary, that allow pancreatic beta-cells to detect fluctuations in plasma glucose concentrations that finally leads to insulin-containing granules. The main steps involve glucose uptake, influx and oxidation; pyruvate formation, mitochondrial transport and conversion to Oxaloacetate and Acetyl-CoA; Citrate formation; NAD(P)H and ATP generation; closure of ATP-sensitive Potassium channels, opening of voltage-dependent Calcium channels and Ca2+ influx; activation of Ca2+-sensitive proteins, such as CAMKII, CaM and SYT7; modulation of proteins involved in actin cytoskeleton rearrangement; and, lastly, to insulin granules traffic, docking and extrusion.Ciliary Neurotrophic Factor is an anti-inflammatory cytokine from IL6 family that signal through GP130-LIFR-CNTFR± receptor complex, usually promoting differentiation and/or survival of diverse cell-types, including pancreatic islets and ²-cells, in which CNTF also inhibits glucose-stimulated insulin secretion by mechanisms not yet fully understood. Given that, the aim of this Project will be to unveil the molecular mechanisms that allows CNTF to simultaneously inhibit glucose-stimulated insulin secretion and promote pancreatic ²-cell survival.
News published in Agência FAPESP Newsletter about the scholarship: