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Mathematical modelling of local calcium and regulated exocytosis during inhibition and stimulation of glucagon secretion from pancreatic alpha‐cells
Author(s) -
Montefusco Francesco,
Pedersen Morten Gram
Publication year - 2015
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp270777
Subject(s) - exocytosis , secretion , glucagon , stimulation , alpha (finance) , alpha cell , calcium , chemistry , microbiology and biotechnology , endocrinology , medicine , biology , hormone , beta cell , insulin , islet , construct validity , nursing , patient satisfaction
Key points The control of glucagon secretion from pancreatic alpha‐cells is still unclear and, when defective, is involved in the development of diabetes. We propose a mathematical model of Ca 2+ dynamics and exocytosis to understand better the intracellular mechanisms downstream of electrical activity that control glucagon secretion. The model exploits compartmental modelling of Ca 2+ levels near open and closed high voltage‐activated Ca 2+ channels involved in exocytosis, in the sub‐membrane Ca 2+ compartment, in the bulk cytosol and in the endoplasmic reticulum. The model reproduces the effects of glucose, glucagon‐like peptide 1 (GLP‐1) and adrenaline, providing insight into the relative contributions of the various subcellular Ca 2+ compartments in the control of glucagon secretion. Our results highlight that the number of open Ca 2+ channels is a dominant factor in glucagon release, and clarify why cytosolic Ca 2+ is a poor read‐out of alpha‐cell secretion.Abstract Glucagon secretion from pancreatic alpha‐cells is dysregulated in diabetes. Despite decades of investigations of the control of glucagon release by glucose and hormones, the underlying mechanisms are still debated. Recently, mathematical models have been applied to investigate the modification of electrical activity in alpha‐cells as a result of glucose application. However, recent studies have shown that paracrine effects such as inhibition of glucagon secretion by glucagon‐like peptide 1 (GLP‐1) or stimulation of release by adrenaline involve cAMP‐mediated effects downstream of electrical activity. In particular, depending of the intracellular cAMP concentration, specific types of Ca 2+ channels are inhibited or activated, which interacts with mobilization of secretory granules. To investigate these aspects of alpha‐cell function theoretically, we carefully developed a mathematical model of Ca 2+ levels near open or closed Ca 2+ channels of various types, which was linked to a description of Ca 2+ below the plasma membrane, in the bulk cytosol and in the endoplasmic reticulum. We investigated how the various subcellular Ca 2+ compartments contribute to control of glucagon‐exocytosis in response to glucose, GLP‐1 or adrenaline. Our studies refine previous modelling studies of alpha‐cell function, and provide deeper insight into the control of glucagon secretion.