Biphasic glucose-stimulated insulin secretion over decades:a journey from measurements and modeling to mechanistic insights  

作　　者：Xiaohong Peng Kai Wang Liangyi Chen 

机构地区：[1]New Cornerstone Science Laboratory,State Key Laboratory of Membrane Biology,Beijing Key Laboratory of Cardiometabolic Molecular Medicine,Institute of Molecular Medicine,National Biomedical Imaging Center,The Beijing Laboratory of Biomedical Imaging,Peking-Tsinghua Center for Life Sciences,School of Future Technology,Peking University,Beijing 100871,China [2]Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Peking University,Beijing 100191,China [3]PKU-IDG/McGovern Institute for Brain Research,Beijing 100871,China

出　　处：《Life Metabolism》2025年第1期5-15,共11页生命代谢(英文)

基　　金：the National Center for Protein Sciences at Peking University in Beijing,China;supported by the National Natural Science Foundation of China(81925022,T2288102,and 32227802);the National Key Research and Development Program of China(2022YFC3400600);the Beijing Natural Science Foundation(Z20J00059 and 7244366);the Fundamental Research Funds for the Central Universities(PKU2024XGK011);supported by the New Cornerstone Science Foundation;the High-performance Computing Platform of Peking University.

摘　　要：Glucose-stimulated insulin release from pancreaticβ-cells is critical for maintaining blood glucose homeostasis.An abrupt increase in blood glucose concentration evokes a rapid and transient rise in insulin secretion followed by a prolonged,slower phase.A diminished first phase is one of the earliest indicators ofβ-cell dysfunction in individuals predisposed to develop type 2 diabetes.Consequently,researchers have explored the underlying mechanisms for decades,starting with plasma insulin measurements under physiological conditions and advancing to single-vesicle exocytosis measurements in individualβ-cells combined with molecular manipulations.Based on a chain of evidence gathered from genetic manipulation to in vivo mouse phenotyping,a widely accepted theory posits that distinct functional insulin vesicle pools inβ-cells regulate biphasic glucose-stimulated insulin secretion(GSIS)via activation of different metabolic signal pathways.Recently,we developed a high-resolution imaging technique to visualize single vesicle exocytosis fromβ-cells within an intact islet.Our findings reveal thatβ-cells within the islet exhibit heterogeneity in their secretory capabilities,which also differs from the heterogeneous Ca^(2+)signals observed in isletβ-cells in response to glucose stimulation.Most importantly,we demonstrate that biphasic GSIS emerges from the interactions amongα-,β-,andδ-cells within the islet and is driven by a small subset of hypersecretoryβ-cells.Finally,we propose that a shift from reductionism to holism may be required to fully understand the etiology of complex diseases such as diabetes.

关 键 词：glucose-stimulated insulin secretion vesicle pools readily releasableβ-cells β-cell heterogeneity 

分 类 号：R335.6[医药卫生—人体生理学]