Ciliary Neurotrophic Factor (CNTF)inhibits Glucose-Stimulated Insulin secretion from rats pancreatic islets: Mechanisms and Implications

• Grant number: 11/20567-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2012
• End date: August 31, 2013
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Antonio Carlos Boschiero
• Grantee: Luiz Fernando de Rezende
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 11/09012-6 - Molecular mechanisms involved in the dysfunction and death of pancreatic beta cells in Diabetes Mellitus: strategies for the prevention of islet dysfunction and for islet mass recuperation in different cellular and animal models, AP.TEM
• Associated scholarship(s): 12/19817-4 - Effects of ciliary neurotrophic factor (CNTF) over differentiation of exocrine acinar cells into insulin-secreting pancreatic beta cells, BE.EP.PD

Abstract

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.