Regulation of cAMP dynamics by Ca2+ and G protein-coupled receptors in the pancreatic β-cell: a computational approach

2007 ◽  
Vol 293 (6) ◽  
pp. C1924-C1933 ◽  
Author(s):  
Leonid E. Fridlyand ◽  
Mark C. Harbeck ◽  
Michael W. Roe ◽  
Louis H. Philipson
Keyword(s):  
Membrane Potential ◽  
G Protein ◽  
Low Frequency ◽  
Receptor Activation ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Calcium Indicator ◽  
Insulinoma Cells ◽  
G Protein Coupled

In this report we describe a mathematical model for the regulation of cAMP dynamics in pancreatic β-cells. Incretin hormones such as glucagon-like peptide 1 (GLP-1) increase cAMP and augment insulin secretion in pancreatic β-cells. Imaging experiments performed in MIN6 insulinoma cells expressing a genetically encoded cAMP biosensor and loaded with fura-2, a calcium indicator, showed that cAMP oscillations are differentially regulated by periodic changes in membrane potential and GLP-1. We modeled the interplay of intracellular calcium (Ca2+) and its interaction with calmodulin, G protein-coupled receptor activation, adenylyl cyclases (AC), and phosphodiesterases (PDE). Simulations with the model demonstrate that cAMP oscillations are coupled to cytoplasmic Ca2+ oscillations in the β-cell. Slow Ca2+ oscillations (<1 min−1) produce low-frequency cAMP oscillations, and faster Ca2+ oscillations (>3–4 min−1) entrain high-frequency, low-amplitude cAMP oscillations. The model predicts that GLP-1 receptor agonists induce cAMP oscillations in phase with cytoplasmic Ca2+ oscillations. In contrast, observed antiphasic Ca2+ and cAMP oscillations can be simulated following combined glucose and tetraethylammonium-induced changes in membrane potential. The model provides additional evidence for a pivotal role for Ca2+-dependent AC and PDE activation in coupling of Ca2+ and cAMP signals. Our results reveal important differences in the effects of glucose/TEA and GLP-1 on cAMP dynamics in MIN6 β-cells.

scholarly journals G protein-coupled receptor 119 agonist DS-8500a effects on pancreatic β-cells in Japanese type 2 diabetes mellitus patients

2018 ◽  
Vol 10 (1) ◽  
pp. 84-93 ◽  
Author(s):  
Hirotaka Watada ◽  
Masanari Shiramoto ◽  
Shin Irie ◽  
Yasuo Terauchi ◽  
Yuichiro Yamada ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
G Protein ◽  
G Protein Coupled Receptor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
G Protein Coupled

scholarly journals A Minimum of Fuel Is Necessary for Tolbutamide to Mimic the Effects of Glucose on Electrical Activity in Pancreatic β-Cells*

Endocrinology ◽  
1998 ◽  
Vol 139 (3) ◽  
pp. 993-998 ◽  
Author(s):  
Jean-Claude Henquin
Keyword(s):  
Membrane Potential ◽  
Electrical Activity ◽  
Slow Waves ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
K Channels ◽  
Low Concentrations ◽  
Low Glucose ◽  
Intracellular Microelectrodes

Glucose stimulation of pancreatic β-cells triggers electrical activity (slow waves of membrane potential with superimposed spikes) that is best monitored with intracellular microelectrodes. Closure of ATP-sensitive K+ channels underlies the depolarization to the threshold potential and participates in the increase in electrical activity produced by suprathreshold (&gt;7 mm) concentrations of glucose, but it is still unclear whether this is the sole mechanism of control. This was investigated by testing whether blockade of ATP-sensitive K+ channels by low concentrations of tolbutamide is able to mimic the effects of glucose on mouse β-cell electrical activity even in the absence of the sugar. The response to tolbutamide was influenced by the duration of the perifusion with the low glucose medium. Tolbutamide (25 μm) caused a rapid and sustained depolarization with continuous activity after 6 min of perifusion of the islet with 3 mm glucose, and a progressive depolarization with slow waves of the membrane potential after 20 min. In the absence of glucose, the β-cell response to tolbutamide was a transient phase of depolarization with rare slow waves (6 min) or a silent, small, but sustained, depolarization (20 min). Readministration of 3 mm glucose was sufficient to restore slow waves, whereas an increase in the glucose concentration to 5 and 7 mm was followed by a lengthening of the slow waves and a shortening of the intervals. In contrast, induction of slow waves by tolbutamide proved very difficult in the absence of glucose, because the β-cell membrane tended to depolarize from a silent level to the plateau level, at which electrical activity is continuous. Azide, a mitochondrial poison, abrogated the electrical activity induced by tolbutamide in the absence of glucose, which demonstrates the influence of the metabolism of endogenous fuels on the response to the sulfonylurea. The partial repolarization that azide also produced was reversed by increasing the concentration of tolbutamide, but reappearance of the spikes required the addition of glucose. It is concluded that inhibition of ATP-sensitive K+ channels is not the only mechanism by which glucose controls electrical activity inβ -cells.

scholarly journals Oxytocin signal contributes to the adaptative growth of islets during gestation

2021 ◽  
Author(s):  
Ping Gu ◽  
Yuege Lin ◽  
Qi Wan ◽  
Dongming Su ◽  
Qun Shu
Keyword(s):  
Insulin Secretion ◽  
Pregnant Women ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Adaptation ◽  
Β Cell Function ◽  
Insulinoma Cells

Background: Increased insulin production and secretion by pancreatic β-cells are important for ensuring the high insulin demand during gestation. However, the underlying mechanism of β-cell adaptation during gestation or in gestational diabetes mellitus (GDM) remains unclear. Oxytocin is an important physiological hormone in gestation and delivery, and it also contributes to the maintenance of β-cell function. The aim of this study was to investigate the role of oxytocin in β-cell adaptation during pregnancy. Methods: The relationship between the blood oxytocin level and pancreatic β-cell function in patients with GDM and healthy pregnant women was investigated. Gestating and non-gestating mice were used to evaluate the in vivo effect of oxytocin signal on β-cells during pregnancy. In vitro experiments were performed on INS-1 insulinoma cells. Results: The blood oxytocin levels were lower in patients with GDM than in healthy pregnant women and were associated with impaired pancreatic β-cell function. Acute administration of oxytocin increased insulin secretion in both gestating and non-gestating mice. A three-week oxytocin treatment promoted the proliferation of pancreatic β-cells and increased the β-cell mass in gestating but not non-gestating mice. Antagonism of oxytocin receptors by atosiban impaired insulin secretion and induced GDM in gestating but not non-gestating mice. Oxytocin enhanced glucose-stimulated insulin secretion, activated the mitogen-activated protein kinase pathway, and promoted cell proliferation in INS-1 cells. Conclusions: These findings provide strong evidence that oxytocin is needed for β-cell adaptation during pregnancy to maintain β-cell function, and lack of oxytocin could be associated with the risk of GDM.

scholarly journals Evidence for Osteocalcin Binding and Activation of GPRC6A in β-Cells

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 1866-1880 ◽  
Author(s):  
Min Pi ◽  
Karan Kapoor ◽  
Ruisong Ye ◽  
Satoru Kenneth Nishimoto ◽  
Jeremy C. Smith ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
G Protein ◽  
Computational Models ◽  
Transmembrane Domain ◽  
Structural Basis ◽  
G Protein Coupled Receptor ◽  
Β Cells ◽  
Β Cell ◽  
Cell Functions ◽  
G Protein Coupled

Abstract The possibility that G protein-coupled receptor family C member A (GPRC6A) is the osteocalcin (Ocn)-sensing G protein-coupled receptor that directly regulates pancreatic β-cell functions is controversial. In the current study, we found that Ocn and an Ocn-derived C-terminal hexapeptide directly activate GPRC6A-dependent ERK signaling in vitro. Computational models probe the structural basis of Ocn binding to GPRC6A and predict that the C-terminal hexapeptide docks to the extracellular side of the transmembrane domain of GPRC6A. Consistent with the modeling, mutations in the computationally identified binding pocket of GPRC6A reduced Ocn and C-terminal hexapeptide activation of this receptor. In addition, selective deletion of Gprc6a in β-cells (Gprc6aβ-cell-cko) by crossing Gprc6aflox/flox mice with Ins2-Cre mice resulted in reduced pancreatic weight, islet number, insulin protein content, and insulin message expression. Both islet size and β-cell proliferation were reduced in Gprc6aβ-cell-cko compared with control mice. Gprc6aβ-cell-cko exhibited abnormal glucose tolerance, but normal insulin sensitivity. Islets isolated from Gprc6aβ-cell-cko mice showed reduced insulin simulation index in response to Ocn. These data establish the structural basis for Ocn direct activation of GPRC6A and confirm a role for GPRC6A in regulating β-cell proliferation and insulin secretion.

scholarly journals Role of the G-Protein Coupled Receptor 3-Salt Inducible Kinase 2 Pathway in Human β Cell Proliferation

2021 ◽  
Author(s):  
Caterina Iorio ◽  
Jillian L Rourke ◽  
Lisa Wells ◽  
Jun-Ichi Sakamaki ◽  
Emily Moon ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
G Protein ◽  
Cell Mass ◽  
Standard Of Care ◽  
G Protein Coupled Receptor ◽  
Β Cells ◽  
Β Cell ◽  
Cell Therapies ◽  
G Protein Coupled

Loss of pancreatic β cells is the hallmark of type 1 diabetes (T1D), for which provision of insulin is the standard of care. While regenerative and stem cell therapies hold the promise of generating single-source or host-matched tissue to obviate immune-mediated complications, these will still require surgical intervention and immunosuppression. Thus, methods that harness the innate capacity of β cells to proliferate to increase β cell mass in vivo are considered vital for future T1D treatment. However, early in life β cells enter what appears to be a permanent state of quiescence, directed by an evolutionarily selected genetic program that establishes a β cell mass setpoint to guard against development of fatal endocrine tumours. Here we report the development of a high-throughput RNAi screening approach to identify upstream pathways that regulate adult human β cell quiescence and demonstrate in a screen of the GPCRome that silencing G-protein coupled receptor 3 (GPR3) leads to human pancreatic β cell proliferation. Loss of GPR3 leads to activation of Salt Inducible Kinase 2 (SIK2), which is necessary and sufficient to drive cell cycle entry, increase β cell mass, and enhance insulin secretion in mice. Taken together, targeting the GPR3-SIK2 pathway represents a novel avenue to stimulate the regeneration of β cells.

scholarly journals Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic β-cells

2009 ◽  
Vol 44 (3) ◽  
pp. 171-178 ◽  
Author(s):  
James E P Brown ◽  
David J Onyango ◽  
Manjunath Ramanjaneya ◽  
Alex C Conner ◽  
Snehal T Patel ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Receptor ◽  
Mrna Expression ◽  
Fold Increase ◽  
Receptor Activation ◽  
Nuclear Factor ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Nicotinamide Phosphoribosyltransferase

The role of the adipocyte-derived factor visfatin in metabolism remains controversial, although some pancreatic β-cell-specific effects have been reported. This study investigated the effects of visfatin upon insulin secretion, insulin receptor activation and mRNA expression of key diabetes-related genes in clonal mouse pancreatic β-cells. β-TC6 cells were cultured in RPMI 1640 and were subsequently treated with recombinant visfatin. One-hour static insulin secretion was measured by ELISA. Phospho-specific ELISA and western blotting were used to detect insulin receptor activation. Real-time SYBR Green PCR array technology was used to measure the expression of 84 diabetes-related genes in both treatment and control cells. Incubation with visfatin caused significant changes in the mRNA expression of several key diabetes-related genes, including marked up-regulation of insulin (9-fold increase), hepatocyte nuclear factor (HNF)1β (32-fold increase), HNF4α (16-fold increase) and nuclear factor κB (40-fold increase). Significant down-regulation was seen in angiotensin-converting enzyme (−3.73-fold) and UCP2 (−1.3-fold). Visfatin also caused a significant 46% increase in insulin secretion compared to control (P<0.003) at low glucose, and this increase was blocked by co-incubation with the specific nicotinamide phosphoribosyltransferase inhibitor FK866. Both visfatin and nicotinamide mononucleotide induced activation of both insulin receptor and extracellular signal-regulated kinase (ERK)1/2, with visfatin-induced insulin receptor/ERK1/2 activation being inhibited by FK866. We conclude that visfatin can significantly regulate insulin secretion, insulin receptor phosphorylation and intracellular signalling and the expression of a number of β-cell function-associated genes in mouse β-cells.

scholarly journals Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion

2021 ◽  
Author(s):  
Chien-Ting Wu ◽  
Keren I. Hilgendorf ◽  
Romina J. Bevacqua ◽  
Yan Hang ◽  
Janos Demeter ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
G Protein ◽  
Pancreatic Islet ◽  
Primary Cilia ◽  
G Protein Coupled Receptors ◽  
Endocrine Function ◽  
Prostaglandin E ◽  
Β Cells ◽  
Β Cell ◽  
G Protein Coupled

Multiple G protein-coupled receptors (GPCRs) are expressed in pancreatic islet cells, but the majority have unknown functions. We observed specific GPCRs localized to primary cilia, a prominent signaling organelle, in pancreatic α and β cells. Loss of cilia disrupts β-cell endocrine function, but the molecular drivers are unknown. Using functional expression, we identified multiple GPCRs localized to cilia in mouse and human islet α and β cells, including FFAR4, PTGER4, ADRB2, KISS1R, and P2RY14. Free fatty acid receptor 4 (FFAR4) and prostaglandin E receptor 4 (PTGER4) agonists stimulate ciliary cAMP signaling and promote glucagon and insulin secretion by α- and β-cell lines and by mouse and human islets. Transport of GPCRs to primary cilia requires TULP3, whose knockdown in primary human and mouse islets relocalized ciliary FFAR4 and PTGER4 and impaired regulated glucagon or insulin secretion, without affecting ciliary structure. Our findings provide index evidence that regulated hormone secretion by islet α and β cells is controlled by ciliary GPCRs providing new targets for diabetes.

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