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Pancreatic Beta Cell in Health and Disease

DOI: 10.1007/978-4-431-75452-7_6

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Ion Channels and Insulin Secretion

David A. Jacobson

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Louis H. Philipson

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Cited by 3 publications

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“…Several studies suggest that voltage-gated K + channels might be also regulated by PIP 2 [ 43 , 44 ]. However, K v 2.1 channels, that are the main voltage-gated K + channels in β-cells [ 2 , 4 ] are not sensitive to PIP 2 depletion [ 43 ]. For this reason we excluded the influence of PIP 2 on voltage-gated K + channels.…”

Section: Models and Methodsmentioning

confidence: 99%

“…Glucose-stimulated insulin secretion (GSIS) includes an increase in ATP/ADP ratio leading to a closure of ATP sensitive potassium (K ATP ) channels, plasma membrane (PM) depolarization, opening of voltage-gated calcium channels(VGCC) with corresponding calcium influx and an increased cytosolic Ca 2+ . The rise in intracellular free calcium concentration ([Ca 2+ ] c ) is an important signal in the initiation of β-cell insulin secretion [ 2 – 4 ]. The β-cell has numerous G protein coupled receptors (GPCRs) that can activate or inhibit β-cell insulin secretion [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Pancreatic Beta Cell G-Protein Coupled Receptors and Second Messenger Interactions: A Systems Biology Computational Analysis

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2016

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Insulin secretory in pancreatic beta-cells responses to nutrient stimuli and hormonal modulators include multiple messengers and signaling pathways with complex interdependencies. Here we present a computational model that incorporates recent data on glucose metabolism, plasma membrane potential, G-protein-coupled-receptors (GPCR), cytoplasmic and endoplasmic reticulum calcium dynamics, cAMP and phospholipase C pathways that regulate interactions between second messengers in pancreatic beta-cells. The values of key model parameters were inferred from published experimental data. The model gives a reasonable fit to important aspects of experimentally measured metabolic and second messenger concentrations and provides a framework for analyzing the role of metabolic, hormones and neurotransmitters changes on insulin secretion. Our analysis of the dynamic data provides support for the hypothesis that activation of Ca2+-dependent adenylyl cyclases play a critical role in modulating the effects of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and catecholamines. The regulatory properties of adenylyl cyclase isoforms determine fluctuations in cytoplasmic cAMP concentration and reveal a synergistic action of glucose, GLP-1 and GIP on insulin secretion. On the other hand, the regulatory properties of phospholipase C isoforms determine the interaction of glucose, acetylcholine and free fatty acids (FFA) (that act through the FFA receptors) on insulin secretion. We found that a combination of GPCR agonists activating different messenger pathways can stimulate insulin secretion more effectively than a combination of GPCR agonists for a single pathway. This analysis also suggests that the activators of GLP-1, GIP and FFA receptors may have a relatively low risk of hypoglycemia in fasting conditions whereas an activator of muscarinic receptors can increase this risk. This computational analysis demonstrates that study of second messenger pathway interactions will improve understanding of critical regulatory sites, how different GPCRs interact and pharmacological targets for modulating insulin secretion in type 2 diabetes.

“…Several studies suggest that voltage-gated K + channels might be also regulated by PIP 2 [ 43 , 44 ]. However, K v 2.1 channels, that are the main voltage-gated K + channels in β-cells [ 2 , 4 ] are not sensitive to PIP 2 depletion [ 43 ]. For this reason we excluded the influence of PIP 2 on voltage-gated K + channels.…”

Section: Models and Methodsmentioning

confidence: 99%

“…Glucose-stimulated insulin secretion (GSIS) includes an increase in ATP/ADP ratio leading to a closure of ATP sensitive potassium (K ATP ) channels, plasma membrane (PM) depolarization, opening of voltage-gated calcium channels(VGCC) with corresponding calcium influx and an increased cytosolic Ca 2+ . The rise in intracellular free calcium concentration ([Ca 2+ ] c ) is an important signal in the initiation of β-cell insulin secretion [ 2 – 4 ]. The β-cell has numerous G protein coupled receptors (GPCRs) that can activate or inhibit β-cell insulin secretion [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Pancreatic Beta Cell G-Protein Coupled Receptors and Second Messenger Interactions: A Systems Biology Computational Analysis

¹

,

²

2016

Self Cite

View full text Add to dashboard Cite

Insulin secretory in pancreatic beta-cells responses to nutrient stimuli and hormonal modulators include multiple messengers and signaling pathways with complex interdependencies. Here we present a computational model that incorporates recent data on glucose metabolism, plasma membrane potential, G-protein-coupled-receptors (GPCR), cytoplasmic and endoplasmic reticulum calcium dynamics, cAMP and phospholipase C pathways that regulate interactions between second messengers in pancreatic beta-cells. The values of key model parameters were inferred from published experimental data. The model gives a reasonable fit to important aspects of experimentally measured metabolic and second messenger concentrations and provides a framework for analyzing the role of metabolic, hormones and neurotransmitters changes on insulin secretion. Our analysis of the dynamic data provides support for the hypothesis that activation of Ca2+-dependent adenylyl cyclases play a critical role in modulating the effects of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and catecholamines. The regulatory properties of adenylyl cyclase isoforms determine fluctuations in cytoplasmic cAMP concentration and reveal a synergistic action of glucose, GLP-1 and GIP on insulin secretion. On the other hand, the regulatory properties of phospholipase C isoforms determine the interaction of glucose, acetylcholine and free fatty acids (FFA) (that act through the FFA receptors) on insulin secretion. We found that a combination of GPCR agonists activating different messenger pathways can stimulate insulin secretion more effectively than a combination of GPCR agonists for a single pathway. This analysis also suggests that the activators of GLP-1, GIP and FFA receptors may have a relatively low risk of hypoglycemia in fasting conditions whereas an activator of muscarinic receptors can increase this risk. This computational analysis demonstrates that study of second messenger pathway interactions will improve understanding of critical regulatory sites, how different GPCRs interact and pharmacological targets for modulating insulin secretion in type 2 diabetes.

What Drives Calcium Oscillations in β-Cells? New Tasks for Cyclic Analysis

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²

2011

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Bursting and calcium oscillations in pancreatic β-cells: specific pacemakers for specific mechanisms

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2010

American Journal of Physiology-Endocrinology and Metabolism

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Fridlyand LE, Tamarina N, Philipson LH. Bursting and calcium oscillations in pancreatic ␤-cells: specific pacemakers for specific mechanisms. Am J Physiol Endocrinol Metab 299: E517-E532, 2010. First published July 13, 2010; doi:10.1152/ajpendo.00177.2010.-Oscillatory phenomenon in electrical activity and cytoplasmic calcium concentration in response to glucose are intimately connected to multiple key aspects of pancreatic ␤-cell physiology. However, there is no single model for oscillatory mechanisms in these cells. We set out to identify possible pacemaker candidates for burst activity and cytoplasmic Ca 2ϩ oscillations in these cells by analyzing published hypotheses, their corresponding mathematical models, and relevant experimental data. We found that although no single pacemaker can account for the variety of oscillatory phenomena in ␤-cells, at least several separate mechanisms can underlie specific kinds of oscillations. According to our analysis, slowly activating Ca 2ϩ -sensitive K ϩ channels can be responsible for very fast Ca 2ϩ oscillations; changes in the ATP/ADP ratio and in the endoplasmic reticulum calcium concentration can be pacemakers for both fast bursts and cytoplasmic calcium oscillations, and cyclical cytoplasmic Na ϩ changes may underlie patterning of slow calcium oscillations. However, these mechanisms still lack direct confirmation, and their potential interactions raises new issues. Further studies supported by improved mathematical models are necessary to understand oscillatory phenomena in ␤-cell physiology. endoplasmic reticulum; channels; diabetes; mathematical model; metabolism IN PANCREATIC ␤-CELLS, glucose-stimulated insulin secretion is mediated by an elevated cytosolic free calcium concentration ([Ca 2ϩ ] c ). This results from calcium influx through voltagedependent Ca 2ϩ channels (VDCCs) located in the plasma membrane (PM), which open in response to secretagogues, primarily glucose. Stimulation-secretion coupling in ␤-cells is different from most other cell types, because instead of being mediated by receptor binding, glucose must be transported into the cytoplasm and metabolized.Glucose initiates changes in the PM potential via an increase in the cytoplasmic [ATP]/[ADP] ratio derived from glycolysis and oxidative phosphorylation. This results in closure of ATPsensitive K ϩ (K ATP ) channels. Closure of these channels leads to PM depolarization up to a threshold potential, causing the cell to move from quiescence to initiate electrical activity and VDCC opening. Ca 2ϩ influx through VDCCs leads to increased [Ca 2ϩ ] c , which is a key signal in the initiation of insulin secretion from the pancreatic ␤-cells. Consensus mechanisms of glucose-induced PM, cytosolic, and mitochondrial processes are summarized in Fig. 1 (for recent review, see Refs. 71,74,76,and 140).The ␤-cell membrane is hyperpolarized to a resting potential of about Ϫ60 mV at low glucose levels (ϳ3-6 mM). Dean and Matthews (32,33) showed that when glucose rises the PM depolarizes and then generates an ...

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