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Stimulus secretion coupling in pancreatic beta-cells

胰腺β细胞的刺激分泌耦合

基本信息

批准号：
10919380
负责人：
Arthur Sherman
金额：
$ 19.01万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10919380
关键词：
Action Potentials Adult Agonist Alpha Cell Area Attention Behavior Beta Cell Biological Biophysical Process Calcium Calcium Channel Calcium Oscillations Carbohydrates Cell membrane Cells Chemicals Child Circulation Communication Coupled Coupling Cyclic AMP D Cells Data Defect Diabetes Mellitus Differential Equation Endocrine Endoplasmic Reticulum Enzymes Exocytosis Family Fasting Feedback Fructose GLP-I receptor Glucagon Glucokinase Glucose Glyburide Glycolysis Hereditary Disease Hormone secretion Human Hyperinsulinism Hypoglycemia Impairment Individual Industrialization Ingestion Insulin Ion Channel Islets of Langerhans Knowledge Life Link Liver Mathematics Mediating Medical Metabolic Modeling Non-Insulin-Dependent Diabetes Mellitus Oral Organ Organelles Pancreas Pathogenesis Pharmaceutical Preparations Physiologic pulse Physiological Plasma Play Potassium Problem Solving Protein Kinase C Reactive hypoglycemia Recording of previous events Reporting Rodent Role Signal Pathway Societies Somatostatin Stimulus Structure of beta Cell of islet Sulfonylurea Compounds System Time Tissues Tolbutamide Work Writing calcium metabolism cell type clinically significant dynamic system enzyme activity gain of function mutation genome wide association study glucose metabolism insulin granule insulin secretion interest ion dynamics islet lectures loss of function mutation mathematical model meetings millisecond model development neonatal diabetes mellitus news response restraint success tool

项目摘要

Impaired insulin secretion is a key step in the pathogenesis of type 2 diabetes, along with inefficient use of insulin by target tissues. The two main components of secretion are calcium entry into pancreatic beta cells and triggering of insulin granule exocytosis by that calcium. We have modeled both components and their contributions to diabetes. We have focused mainly on the mechanisms of calcium oscillations over a range of periods, from seconds to minutes. The slower class of oscillations (5 - 10 minute period) is the main driver of pulsatile insulin concentration in the circulation, which has been shown to be optimal for the response of insulin-sensitive tissues, especially the liver. Details of the historical development of the model can be found in our reports from previous years and in a current review article (ref. #1). We call the resulting model the integrated oscillator model (IOM) to indicate that the oscillations result from the partnership of an electrical oscillator (EO) and a metabolic oscillator (MO). The electrical oscillator (EO) is based on negative feedback of calcium onto ion channels, directly onto calcium-activated potassium (K(Ca)) channels and indirectly onto ATP-dependent potassium (K(ATP)) channels because calcium reduces the ATP/ADP ratio. The metabolic oscillator (MO) is governed by positive feedback of fructose 1,6 bisphosphate (FBP) on the enzyme in glycolysis that produces it, phosphofructokinase (PFK). The MO communicates with the EO via the K(ATP) channels, which transduce the metabolic state of the cell (ATP/ADP ratio) into electrical depolarization. K(ATP) channels are of clinical significance as they are a target of insulin-stimulating drugs, such as the sulfonylureas tolbutamide and glyburide, the first class of oral medications developed for the treatment of Type 2 Diabetes. Severe gain-of-function mutations of K(ATP) are a major cause of neo-natal diabetes mellitus, whereas moderate gain-of-function mutations have been linked in genome-wide association studies (GWAS) to the milder but more common adult-onset form of diabetes, type 2 diabetes. Conversely, loss-of-function mutations of K(ATP) are a major cause of familial hyperinsulinism, a hereditary disease found in children in which beta cells are persistently electrically active and secrete insulin in the face of normal or low glucose, causing life-threatening hypoglycemia. Another major cause of hyperinsulinism is excessive activity of the enzyme glucokinase (GK), which also plays a key role in the DOM. Our history of work in this area over four decades resulted in an invitation to give a plenary lecture at the biannual meeting on Dynamical Systems hosted by the Society for Industrial and Applied Mathematics (June, 2023). The well-received talk led to a further invitation to write a short news article highlighting some of the key messages of the talk, including the role of mathematical modeling in solving problems of key biological and medical interest in insulin secretion and the role of these biological applications in generating new mathematical knowledge. Though it has had many successes, the IOM was challenged this year by new data and a proposal for a new model. The new model holds that the oscillations in calcium and insulin secretion result not from calcium entry through plasma membrane ion channels under the control of K(ATP) channels but from calcium release from the primary intracellular storage organelle, the endoplasmic reticulum (ER). Such calcium release based oscillations are found in other cell types, but we argued in Ref. #1 that this mechanism cannot account for the large body of experimental observations that have been made in beta cells and are well accounted for by the canonical calcium entry model. We showed further that the canonical model can in fact account for the new observations that were claimed to invalidate it. We argued that the new observations nonetheless have value because they draw attention to a previously underappreciated role of calcium release and related mechanisms to modulate the threshold level at which oscillations begin. This is of great physiological importance because the threshold divides the basal (fasting) regime where insulin secretion must be throttled down to avoid hypoglycemia from the post-prandial regime where insulin secretion must be promptly increased by an order of magnitude to effectively restrain the rise in glucose from ingested carbohydrates. The highly successful family of glucagon-like peptide 1 (GLP-1) receptor agonists for treating T2D work in part by mediating small downward shifts in the threshold.

胰岛素分泌受损是2型糖尿病发病机制中的关键步骤，并伴随着靶组织对胰岛素的低效利用。分泌的两个主要成分是钙进入胰岛β细胞，并由钙触发胰岛素颗粒胞吐。我们已经对这两种成分及其对糖尿病的贡献进行了建模。我们主要集中在从几秒到几分钟的一系列周期内钙振荡的机制。较慢级别的振荡(5-10分钟周期)是循环中脉动性胰岛素浓度的主要驱动因素，已被证明对胰岛素敏感组织，特别是肝脏的反应是最佳的。该模式的历史发展细节可以在我们前几年的报告中找到，也可以在当前的一篇综述文章中找到(参考文献)。#1)。我们将所得到的模型称为集成振荡器模型(IOM)，以表明振荡是由电子振荡器(EO)和代谢振荡器(MO)的伙伴关系产生的。电子振荡器(EO)是基于钙对离子通道的负反馈，直接对钙激活的钾(K(Ca))通道的负反馈，以及间接对ATP依赖的钾(K(ATP)通道的负反馈，因为钙降低了ATP/ADP比率。代谢振荡器(MO)是由1，6-二磷酸果糖(FBP)对糖酵解中产生它的酶--磷酸果糖激酶(PFK)的正反馈控制的。MO通过K(ATP)通道与EO进行通讯，K(ATP)通道将细胞的代谢状态(ATP/ADP比率)转化为电去极化。 K(ATP)通道具有临床意义，因为它们是胰岛素刺激药物的靶标，如磺脲类药物甲苯磺脲和格列本脲，这是为治疗2型糖尿病开发的第一类口服药物。严重的K(ATP)功能获得突变是新生儿糖尿病的主要原因，而在全基因组关联研究(GWAS)中，适度的功能获得突变与较温和但更常见的成人起病形式的2型糖尿病有关。相反，K(ATP)功能丧失突变是家族性高胰岛素血症的主要原因，这是一种在儿童中发现的遗传性疾病，在正常或低血糖面前，β细胞持续电活动并分泌胰岛素，导致危及生命的低血糖。高胰岛素血症的另一个主要原因是葡萄糖激酶(GK)活性过高，它在DOM中也起着关键作用。我们在这一领域40多年的工作历史导致我们被邀请在工业和应用数学学会主办的关于动力系统的两年一次的会议(2023年6月)上做一次全体演讲。这一广受欢迎的演讲导致进一步邀请撰写一篇简短的新闻文章，重点介绍演讲的一些关键信息，包括数学建模在解决胰岛素分泌中关键的生物学和医学利益问题中的作用，以及这些生物学应用在产生新的数学知识方面的作用。尽管取得了许多成功，但国际移民组织今年受到了新数据和一项新模式提案的挑战。新的模型认为，钙和胰岛素分泌的振荡不是由于K(ATP)通道控制下的质膜离子通道的钙进入，而是来自细胞内主要的存储细胞器--内质网(ER)的钙释放。这种基于钙释放的振荡在其他类型的细胞中也被发现，但我们在参考文献中提出了论点。#1这种机制不能解释已经在β细胞中进行的大量实验观察，并被典型的钙进入模型很好地解释。我们进一步证明，正则模型实际上可以解释声称使其无效的新观测结果。我们认为，新的观察结果仍然有价值，因为它们引起了人们对钙释放之前被低估的作用的关注，以及调节振荡开始的阈值水平的相关机制。这是非常重要的生理意义，因为阈值区分了基础(空腹)方案和餐后方案，在基础(空腹)方案中必须抑制胰岛素分泌以避免低血糖，而在餐后方案中胰岛素分泌必须迅速增加一个数量级，以有效地抑制摄入碳水化合物导致的血糖上升。用于治疗T2D的非常成功的GLP-1受体激动剂家族在一定程度上通过调节阈值的微小下移发挥作用。