Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line
We integrated biological experimental data with mathematical modelling to gain insights into the role played by L-alanine in amino acid-stimulated insulin secretion (AASIS) and in D-glucose-stimulated insulin secretion (GSIS), details important to the understanding of complex β-cell metabolic coupli...
| Main Authors: | , , |
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| Format: | Journal Article |
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Public Library of Science
2013
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| Online Access: | http://hdl.handle.net/20.500.11937/14659 |
| _version_ | 1848748682343612416 |
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| author | Salvucci, Manuela Neufeld, Zoltan Newsholme, Philip |
| author_facet | Salvucci, Manuela Neufeld, Zoltan Newsholme, Philip |
| author_sort | Salvucci, Manuela |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | We integrated biological experimental data with mathematical modelling to gain insights into the role played by L-alanine in amino acid-stimulated insulin secretion (AASIS) and in D-glucose-stimulated insulin secretion (GSIS), details important to the understanding of complex β-cell metabolic coupling relationships. We present an ordinary differential equations (ODEs) based simplified kinetic model of core metabolic processes leading to ATP production (glycolysis, TCA cycle, L-alanine-specific reactions, respiratory chain, ATPase and proton leak) and Ca2+ handling (essential channels and pumps in the plasma membrane) in pancreatic β-cells and relate these to insulin secretion. Experimental work was performed using a clonal rat insulin-secreting cell line (BRIN-BD11) to measure the consumption or production of a range of important biochemical parameters (D-glucose, L-alanine, ATP, insulin secretion) and Ca2+ levels. These measurements were then used to validate the theoretical model and fine-tune the parameters. Mathematical modelling was used to predict L-lactate and L-glutamate concentrations following D-glucose and/or L-alanine challenge and Ca2+ levels upon stimulation with a non metabolizable L-alanine analogue. Experimental data and mathematical model simulations combined suggest that L-alanine produces a potent insulinotropic effect via both a stimulatory impact on β-cell metabolism and as a direct result of the membrane depolarization due to Ca2+ influx triggered by L-alanine/Na+ co-transport. Our simulations indicate that both high intracellular ATP and Ca2+ concentrations are required in order to develop full insulin secretory responses. The model confirmed that K+ ATP channel independent mechanisms of stimulation of intracellular Ca2+ levels, via generation of mitochondrial coupling messengers, are essential for promotion of the full and sustained insulin secretion response in β-cells. |
| first_indexed | 2025-11-14T07:08:55Z |
| format | Journal Article |
| id | curtin-20.500.11937-14659 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T07:08:55Z |
| publishDate | 2013 |
| publisher | Public Library of Science |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-146592017-09-13T14:05:39Z Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line Salvucci, Manuela Neufeld, Zoltan Newsholme, Philip We integrated biological experimental data with mathematical modelling to gain insights into the role played by L-alanine in amino acid-stimulated insulin secretion (AASIS) and in D-glucose-stimulated insulin secretion (GSIS), details important to the understanding of complex β-cell metabolic coupling relationships. We present an ordinary differential equations (ODEs) based simplified kinetic model of core metabolic processes leading to ATP production (glycolysis, TCA cycle, L-alanine-specific reactions, respiratory chain, ATPase and proton leak) and Ca2+ handling (essential channels and pumps in the plasma membrane) in pancreatic β-cells and relate these to insulin secretion. Experimental work was performed using a clonal rat insulin-secreting cell line (BRIN-BD11) to measure the consumption or production of a range of important biochemical parameters (D-glucose, L-alanine, ATP, insulin secretion) and Ca2+ levels. These measurements were then used to validate the theoretical model and fine-tune the parameters. Mathematical modelling was used to predict L-lactate and L-glutamate concentrations following D-glucose and/or L-alanine challenge and Ca2+ levels upon stimulation with a non metabolizable L-alanine analogue. Experimental data and mathematical model simulations combined suggest that L-alanine produces a potent insulinotropic effect via both a stimulatory impact on β-cell metabolism and as a direct result of the membrane depolarization due to Ca2+ influx triggered by L-alanine/Na+ co-transport. Our simulations indicate that both high intracellular ATP and Ca2+ concentrations are required in order to develop full insulin secretory responses. The model confirmed that K+ ATP channel independent mechanisms of stimulation of intracellular Ca2+ levels, via generation of mitochondrial coupling messengers, are essential for promotion of the full and sustained insulin secretion response in β-cells. 2013 Journal Article http://hdl.handle.net/20.500.11937/14659 10.1371/journal.pone.0052611 Public Library of Science fulltext |
| spellingShingle | Salvucci, Manuela Neufeld, Zoltan Newsholme, Philip Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line |
| title | Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line |
| title_full | Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line |
| title_fullStr | Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line |
| title_full_unstemmed | Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line |
| title_short | Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line |
| title_sort | mathematical model of metabolism and electrophysiology of amino acid and glucose stimulated insulin secretion: in vitro validation using a β-cell line |
| url | http://hdl.handle.net/20.500.11937/14659 |