Regulation Mechanism On Action Potentials In Pancreatic β-cells And The Dynamic Analysis

With the aging tendency of population,prevalence rate of diabetes is increasing,and to understanding physiological reason and therapy of this diabetes is urgent for current medical research.It has been found that malfunctioningβ-cells should be one of the most important reason that can lead to diabetes.β-cells,located within the pancreatic islets of Langerhans,are excitable cells that produce regular bursts of action potentials when stimulated by glucose.These micro-organs monitor the glucose concentration in the blood,and in response to elevated glucose levels its membrane potential bursts,cytosolic free Ca²⁺concentrations increasing which induces secretion of the hormone insulin.Since insulin is necessary for the uptake of glucose by other cells in the body,the proper functioning ofβ-cells is crucial for glucose homeostasis.This thesis is on theoretical research ofβ-cells,which discussed the effects of glucose concentration,inositol 1,4,5-trisphosphate(IP₃)concentration,ryanodine receptors(RyR)channel activity and stochastic of ionic channels on membrane potential.The results show the physiological mechanism ofβ-cells and can give some help for curing the disease.Therefore,the work is important for biology and medicine.This thesis discusses mechanism of action potential ofβ-cells,and main works are as follows:First,a new model of ATP-driven(SERCA)pump,which as function of glucose and cytosolic free Ca²⁺concentrations,is present,and this is a new theoritcal work that discusses effects of glucose on potential activity.We indeed explore theoretically the possible role of both glucose and IP₃ concentration in the regulation of potential oscillations on the membrane ofβ-cells.Main conclusions are as follows:(1)β-cells display a bursting pattern of action potential when the glucose concentration is up to stimulatory concentration,and the stimulatory concentration is affected by the concentration of IP₃.(2)The stimulatory glucose concentration is higher than 10mM with the physiological IP₃ concentration between 0.25 and 0.6μM.(3)The effects of intrinsic noise due to the random opening and closing of ionic channels are also considered in present paper.Our theoretical results indicate that strong noise induced by IP₃R channels can change the spike oscillation of membrane potential into bursting activity and average cytosolic free Ca²⁺ concentration also enhanced.Second,it is the first time that a RyR channel model is introduced intoβ-cell model.Main results are as follows:(1)Bursting action potential will be induced by activating RyR channels even though glucose concentration being a little lower than the stimulatory level.(2)Especially, RyR channels cause a kind of"complex bursting",and this form of potential activity seems more effective in insulin secretion.(3)Bifurcation diagram help us understand mechanism in the model. Results show that glucose concentration affects the position of Z-shape curve and in this way to regulate the membrane potential in the state of rest or bursting oscillation.Activation level and open probability of RyR channel induce changes of slope of c nullcline,and this changes lead rest state of potential into bursting activity.According to different IP₃ concentration,the position of c nullcline is different,and that is why IP₃ concentration affects bursting periods.The effects of intrinsic noise due to RyR channels are discussed,and it is shown the effect of RyR channels on membrane potential is not so notable as that of IP₃R channels.