scholarly journals Symbiosis of Electrical and Metabolic Oscillations in Pancreatic β-Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Isabella Marinelli ◽  
Patrick A. Fletcher ◽  
Arthur S. Sherman ◽  
Leslie S. Satin ◽  
Richard Bertram
Keyword(s):  
Mathematical Modeling ◽  
Mathematical Model ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Intracellular Ca ◽  
Metabolic Oscillations ◽  
Insulin Exocytosis ◽  
The Relationship ◽  
Contradictory Data ◽  
Oscillatory Processes

Insulin is secreted in a pulsatile pattern, with important physiological ramifications. In pancreatic β-cells, which are the cells that synthesize insulin, insulin exocytosis is elicited by pulses of elevated intracellular Ca2+ initiated by bursts of electrical activity. In parallel with these electrical and Ca2+ oscillations are oscillations in metabolism, and the periods of all of these oscillatory processes are similar. A key question that remains unresolved is whether the electrical oscillations are responsible for the metabolic oscillations via the effects of Ca2+, or whether the metabolic oscillations are responsible for the electrical oscillations due to the effects of ATP on ATP-sensitive ion channels? Mathematical modeling is a useful tool for addressing this and related questions as modeling can aid in the design of well-focused experiments that can test the predictions of particular models and subsequently be used to improve the models in an iterative fashion. In this article, we discuss a recent mathematical model, the Integrated Oscillator Model (IOM), that was the product of many years of development. We use the model to demonstrate that the relationship between calcium and metabolism in beta cells is symbiotic: in some contexts, the electrical oscillations drive the metabolic oscillations, while in other contexts it is the opposite. We provide new insights regarding these results and illustrate that what might at first appear to be contradictory data are actually compatible when viewed holistically with the IOM.

Non-functional role of syntaxin 2 in insulin exocytosis by pancreatic β cells

1997 ◽  
Vol 15 (4) ◽  
pp. 237-242 ◽  
Author(s):  
Shinya Nagamatsu ◽  
Hiroki Sawa ◽  
Yoko Nakamichi ◽  
Yoshinori Kondo ◽  
Satsuki Matsushima ◽  
...  
Keyword(s):  
Functional Role ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Insulin Exocytosis

scholarly journals Intragranular targeting of syncollin, but not a syncollinGFP chimera, inhibits regulated insulin exocytosis in pancreatic β-cells

2005 ◽  
Vol 185 (1) ◽  
pp. 57-67 ◽  
Author(s):  
L B Hays ◽  
B Wicksteed ◽  
Y Wang ◽  
J F McCuaig ◽  
L H Philipson ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Fluorescent Protein ◽  
Zymogen Granule ◽  
Β Cells ◽  
Rat Islets ◽  
Intracellular Ca ◽  
Specific Localization ◽  
Glucagon Like Peptide 1 ◽  
Green Fluorescent ◽  
Insulin Exocytosis

Several proteins play a role in the mechanism of insulin exocytosis. However, these ‘exocytotic proteins’ have yet to account for the regulated aspect of insulin exocytosis, and other factors are involved. In pancreatic exocrine cells, the intralumenal zymogen granule protein, syncollin, is required for efficient regulated exocytosis, but it is not known whether intragranular peptides similarly influence regulated insulin exocytosis. Here, this issue has been addressed using expression of syncollin and a syncollin-green fluorescent protein (syncollinGFP) chimera in rat islet β-cells as experimental tools. Syncollin is not normally expressed in β-cells but adenoviral-mediated expression of both syncollin and syncollinGFP indicated that these were specifically targeted to the lumen of β-granules. Syncollin expression in isolated rat islets had no effect on basal insulin secretion but significantly inhibited regulated insulin secretion stimulated by glucose (16.7 mM), glucagon-like peptide-1 (GLP-1) (10 nM) and glyburide (5μM). Consistent with specific localization of syncollin to β-granules, constitutive secretion was unchanged by syncollin expression in rat islets. Syncollin-mediated inhibition of insulin secretion was not due to inadequate insulin production. Moreover, secretagogue-induced increases in cytosolic intracellular Ca2+, which is a prerequisite for triggering insulin exocytosis, were unaffected in syncollin-expressing islets. Therefore, syncollin was most likely acting downstream of secondary signals at the level of insulin exocytosis. Thus, syncollin expression in β-cells has highlighted the importance of intralumenal β-granule peptide factors playing a role in the control of insulin exocytosis. In contrast to syncollin, syncollinGFP had no effect on insulin secretion, underlining its usefulness as a ‘fluorescent tag’ to track β-granule transport and exocytosis in real time.

scholarly journals A Mathematical Modeling Approach to the Cort-Fitness Hypothesis

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
F El Moustaid ◽  
S J Lane ◽  
I T Moore ◽  
L R Johnson
Keyword(s):  
Mathematical Modeling ◽  
Mathematical Model ◽  
Reproductive Strategies ◽  
Evolutionary Biology ◽  
Positive Relationship ◽  
Negative Relationship ◽  
Environmental Challenges ◽  
Field Endocrinology ◽  
Empirical Tests ◽  
The Relationship

Abstract The Cort-Fitness Hypothesis has generated much interest from investigators integrating field endocrinology with evolutionary biology, ecology, and conservation. The hypothesis was developed to test the assumption that if glucocorticoid levels increase with environmental challenges and fitness decreases with environmental challenges, then there should be a negative relationship between baseline glucocorticoid levels and fitness. Indeed, studies across diverse taxa have found that the relationship between baseline glucocorticoid levels and fitness are not consistent: some studies show a positive relationship, others negative, and some show no correlation. Hence, a deeper understanding of the mechanisms underlying the relationship between baseline glucocorticoid levels, environmental challenges, and fitness is needed. We propose a mathematical model representing the links between baseline glucocorticoid levels, environmental challenges, and fitness. Our model describes how variation in the predictability and intensity of environmental challenges, reproductive strategies, and fitness metrics can all contribute to the variability observed in empirical tests of the Cort-Fitness Hypothesis. We provide qualitative results showing that much of the inconsistency in previous studies can be explained and we discuss how the model can be used to inform future Cort-Fitness studies.

scholarly journals The Rab27a effector exophilin7 promotes fusion of secretory granules that have not been docked to the plasma membrane

2013 ◽  
Vol 24 (3) ◽  
pp. 319-330 ◽  
Author(s):  
Hao Wang ◽  
Ray Ishizaki ◽  
Jun Xu ◽  
Kazuo Kasai ◽  
Eri Kobayashi ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Knockout Mice ◽  
Secretory Granules ◽  
Small Gtpase ◽  
Membrane Phospholipids ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Insulin Granules ◽  
Insulin Exocytosis

Granuphilin, an effector of the small GTPase Rab27a, mediates the stable attachment (docking) of insulin granules to the plasma membrane and inhibits subsequent fusion of docked granules, possibly through interaction with a fusion-inhibitory Munc18-1/syntaxin complex. However, phenotypes of insulin exocytosis differ considerably between Rab27a- and granuphilin-deficient pancreatic β cells, suggesting that other Rab27a effectors function in those cells. We found that one of the putative Rab27a effector family proteins, exophilin7/JFC1/Slp1, is expressed in β cells; however, unlike granuphilin, exophilin7 overexpressed in the β-cell line MIN6 failed to show granule-docking or fusion-inhibitory activity. Furthermore, exophilin7 has no affinities to either Munc18-1 or Munc18-1–interacting syntaxin-1a, in contrast to granuphilin. Although β cells of exophilin7-knockout mice show no apparent abnormalities in intracellular distribution or in ordinary glucose-induced exocytosis of insulin granules, they do show impaired fusion in response to some stronger stimuli, specifically from granules that have not been docked to the plasma membrane. Exophilin7 appears to mediate the fusion of undocked granules through the affinity of its C2A domain toward the plasma membrane phospholipids. These findings indicate that the two Rab27a effectors, granuphilin and exophilin7, differentially regulate the exocytosis of either stably or minimally docked granules, respectively.

Lacking of estradiol reduces insulin exocytosis from pancreatic β-cells and increases hepatic insulin degradation

Steroids ◽  
2016 ◽  
Vol 114 ◽  
pp. 16-24 ◽  
Author(s):  
Roberta S. Santos ◽  
Thiago M. Batista ◽  
Rafael L. Camargo ◽  
Priscila N. Morato ◽  
Patrícia C. Borck ◽  
...  
Keyword(s):  
Insulin Degradation ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Insulin Exocytosis

scholarly journals The Rab3-interacting molecule RIM is expressed in pancreatic β-cells and is implicated in insulin exocytosis

FEBS Letters ◽  
2000 ◽  
Vol 474 (1) ◽  
pp. 66-70 ◽  
Author(s):  
Mariella Iezzi ◽  
Romano Regazzi ◽  
Claes B. Wollheim
Keyword(s):  
Β Cells ◽  
Pancreatic Β Cells ◽  
Insulin Exocytosis

Modeling of Ca2+ flux in pancreatic β-cells: role of the plasma membrane and intracellular stores

2003 ◽  
Vol 285 (1) ◽  
pp. E138-E154 ◽  
Author(s):  
Leonid E. Fridlyand ◽  
Natalia Tamarina ◽  
Louis H. Philipson
Keyword(s):  
Plasma Membrane ◽  
Calcium Oscillations ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Ionic Flux ◽  
Inositol 1,4,5 Trisphosphate ◽  
Intracellular Ca ◽  
Uptake And Release

We have developed a detailed mathematical model of ionic flux in β-cells that includes the most essential channels and pumps in the plasma membrane. This model is coupled to equations describing Ca2+, inositol 1,4,5-trisphosphate (IP3), ATP, and Na+ homeostasis, including the uptake and release of Ca2+ by the endoplasmic reticulum (ER). In our model, metabolically derived ATP activates inward Ca2+ flux by regulation of ATP-sensitive K+ channels and depolarization of the plasma membrane. Results from the simulations support the hypothesis that intracellular Na+ and Ca2+ in the ER can be the main variables driving both fast (2–7 osc/min) and slow intracellular Ca2+ concentration oscillations (0.3–0.9 osc/min) and that the effect of IP3 on Ca2+ leak from the ER contributes to the pattern of slow calcium oscillations. Simulations also show that filling the ER Ca2+ stores leads to faster electrical bursting and Ca2+ oscillations. Specific Ca2+ oscillations in isolated β-cell lines can also be simulated.

[Ca2+]i regulates trafficking of Cav1.3 (α1D Ca2+ channel) in insulin-secreting cells

2004 ◽  
Vol 286 (2) ◽  
pp. C213-C221 ◽  
Author(s):  
Luping Huang ◽  
Arin Bhattacharjee ◽  
James T. Taylor ◽  
Min Zhang ◽  
Brian M. Keyser ◽  
...  
Keyword(s):  
Surface Proteins ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Glucose Stimulation ◽  
Channel Trafficking ◽  
Insulin Secreting Cells ◽  
High Concentrations ◽  
The Relationship ◽  
Insulin Secretory Response

Chronic exposure of pancreatic β-cells to high concentrations of glucose impairs the insulin secretory response to further glucose stimulation. This phenomenon is referred to as glucose desensitization. It has been shown that glucose desensitization is associated with abnormal elevation of β-cell basal intracellular free Ca2+ concentration ([Ca2+]i). We have investigated the relationship between the basal intracellular free Ca2+ and the L-type (Cav1.3) Ca2+ channel translocation in insulin-secreting cells. Glucose stimulation or membrane depolarization induced a nifedipine-sensitive Ca2+ influx, which was attenuated when the basal [Ca2+]i was elevated. Using voltage-clamp techniques, we found that changing [Ca2+]i could regulate the amplitude of the Ca2+ current. This effect was attenuated by drugs that interfere with the cytoskeleton. Immunofluorescent labeling of Cav1.3 showed an increase in the cytoplasmic distribution of the channels under high [Ca2+]i conditions by deconvolution microscopy. The [Ca2+]i-dependent translocation of Cav1.3 channel was also demonstrated by Western blot analysis of biotinylation/NeutrAvidin-bead-eluted surface proteins in cells preincubated at various [Ca2+]i. These results suggest that Cav1.3 channel trafficking is involved in glucose desensitization of pancreatic β-cells.

scholarly journals Linoleic acid induces Ca2+-induced inactivation of voltage-dependent Ca2+ currents in rat pancreatic β-cells

2007 ◽  
Vol 196 (2) ◽  
pp. 377-384 ◽  
Author(s):  
Dan-Dan Feng ◽  
Yu-Feng Zhao ◽  
Zi-Qiang Luo ◽  
Damien J Keating ◽  
Chen Chen
Keyword(s):  
Insulin Secretion ◽  
Linoleic Acid ◽  
Specific Protein ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Cell Dysfunction ◽  
Cell Recording ◽  
Voltage Dependent ◽  
Intracellular Ca ◽  
G Protein Coupled

Free fatty acids (FFAs) regulate insulin secretion in a complex pattern and induce pancreatic β-cell dysfunction in type 2 diabetes. Voltage-dependent Ca2+ channels (VDCC) in β-cells play a major role in regulating insulin secretion. The aim of present study is to clarify the action of the FFA, linoleic acid, on VDCC in β-cells. The VDCC current in primary cultured rat β-cells were recorded under nystatin-perforated whole-cell recording configuration. The VDCC was identified as high-voltage-gated Ca2+ channels due to there being no difference in current amplitude under holding potential between −70 and −40 mV. Linoleic acid (10 μM) significantly inhibited VDCC currents in β-cells, an effect which was fully reversible upon washout. Methyl-linoleic acid, which does not activate G protein coupled receptor (GPR)40, neither did alter VDCC current in rat β-cells nor did influence linoleic acid-induced inhibition of VDCC currents. Linoleic acid-induced inhibition of VDCC current was not blocked by preincubation of β-cells with either the specific protein kinase A (PKA) inhibitor, H89, or the PKC inhibitor, chelerythrine. However, pretreatment of β-cells with thapsigargin, which depletes intracellular Ca2+ stores, completely abolished linoleic acid-induced decrease in VDCC current. Measurement of intracellular Ca2+ concentration ([Ca2+]i) illustrated that linoleic acid induced an increase in [Ca2+]i and that thapsigargin pretreatment inhibited this increase. Methyl-linoleic acid neither did induce increase in [Ca2+]i nor did it block linoleic acid-induced increase in [Ca2+]i. These results suggest that linoleic acid stimulates Ca2+ release from intracellular Ca2+ stores and inhibits VDCC currents in rat pancreatic β-cells via Ca2+-induced inactivation of VDCC.

scholarly journals Exocytosis from pancreatic β-cells: mathematical modelling of the exit of low-molecular-weight granule content

2010 ◽  
Vol 1 (1) ◽  
pp. 143-152 ◽  
Author(s):  
Juris Galvanovskis ◽  
Matthias Braun ◽  
Patrik Rorsman
Keyword(s):  
Molecular Weight ◽  
Membrane Receptors ◽  
Fusion Pore ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Release Process ◽  
Cell Plasma ◽  
Insulin Granules ◽  
Large Dense Core Vesicles ◽  
Insulin Exocytosis

Pancreatic β-cells use Ca 2+ -dependent exocytosis of large dense core vesicles to release insulin. Exocytosis in β-cells has been studied biochemically, biophysically and optically. We have previously developed a biophysical method to monitor release of endogenous intragranular constituents that are co-released with insulin. This technique involves the expression of ionotropic membrane receptors in the β-cell plasma membrane and enables measurements of exocytosis of individual vesicles with sub-millisecond resolution. Like carbon fibre amperometry, this method allows fine details of the release process, like the expansion of the fusion pore (the narrow connection between the granule lumen and the extracellular space), to be monitored. Here, we discuss experimental data obtained with this method within the framework of a simple mathematical model that describes the release of low-molecular constituents during exocytosis of the insulin granules. Our findings suggest that the fusion pore functions as a molecular sieve, allowing differential release of low- and high-molecular-weight granule constituents.

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