Computational modeling of glucose transport in pancreatic β-cells identifies metabolic thresholds and therapeutic targets in diabetes.
Pancreatic β-cell dysfunction is a diagnostic criterion of Type 2 diabetes and includes defects in glucose transport and insulin secretion. In healthy individuals, β-cells maintain plasma glucose concentrations within a narrow range in concert with insulin action among multiple tissues. Postprandial...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3531366?pdf=render |
| _version_ | 1811336758140338176 |
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| author | Camilla Luni Jamey D Marth Francis J Doyle |
| author_facet | Camilla Luni Jamey D Marth Francis J Doyle |
| author_sort | Camilla Luni |
| collection | DOAJ |
| description | Pancreatic β-cell dysfunction is a diagnostic criterion of Type 2 diabetes and includes defects in glucose transport and insulin secretion. In healthy individuals, β-cells maintain plasma glucose concentrations within a narrow range in concert with insulin action among multiple tissues. Postprandial elevations in blood glucose facilitate glucose uptake into β-cells by diffusion through glucose transporters residing at the plasma membrane. Glucose transport is essential for glycolysis and glucose-stimulated insulin secretion. In human Type 2 diabetes and in the mouse model of obesity-associated diabetes, a marked deficiency of β-cell glucose transporters and glucose uptake occurs with the loss of glucose-stimulated insulin secretion. Recent studies have shown that the preservation of glucose transport in β-cells maintains normal insulin secretion and blocks the development of obesity-associated diabetes. To further elucidate the underlying mechanisms, we have constructed a computational model of human β-cell glucose transport in health and in Type 2 diabetes, and present a systems analysis based on experimental results from human and animal studies. Our findings identify a metabolic threshold or "tipping point" whereby diminished glucose transport across the plasma membrane of β-cells limits intracellular glucose-6-phosphate production by glucokinase. This metabolic threshold is crossed in Type 2 diabetes and results in β-cell dysfunction including the loss of glucose stimulated insulin secretion. Our model further discriminates among molecular control points in this pathway wherein maximal therapeutic intervention is achieved. |
| first_indexed | 2024-04-13T17:44:17Z |
| format | Article |
| id | doaj.art-6a43ad1c9e3942bbb05b920e7b2619c8 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T17:44:17Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-6a43ad1c9e3942bbb05b920e7b2619c82022-12-22T02:37:03ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01712e5313010.1371/journal.pone.0053130Computational modeling of glucose transport in pancreatic β-cells identifies metabolic thresholds and therapeutic targets in diabetes.Camilla LuniJamey D MarthFrancis J DoylePancreatic β-cell dysfunction is a diagnostic criterion of Type 2 diabetes and includes defects in glucose transport and insulin secretion. In healthy individuals, β-cells maintain plasma glucose concentrations within a narrow range in concert with insulin action among multiple tissues. Postprandial elevations in blood glucose facilitate glucose uptake into β-cells by diffusion through glucose transporters residing at the plasma membrane. Glucose transport is essential for glycolysis and glucose-stimulated insulin secretion. In human Type 2 diabetes and in the mouse model of obesity-associated diabetes, a marked deficiency of β-cell glucose transporters and glucose uptake occurs with the loss of glucose-stimulated insulin secretion. Recent studies have shown that the preservation of glucose transport in β-cells maintains normal insulin secretion and blocks the development of obesity-associated diabetes. To further elucidate the underlying mechanisms, we have constructed a computational model of human β-cell glucose transport in health and in Type 2 diabetes, and present a systems analysis based on experimental results from human and animal studies. Our findings identify a metabolic threshold or "tipping point" whereby diminished glucose transport across the plasma membrane of β-cells limits intracellular glucose-6-phosphate production by glucokinase. This metabolic threshold is crossed in Type 2 diabetes and results in β-cell dysfunction including the loss of glucose stimulated insulin secretion. Our model further discriminates among molecular control points in this pathway wherein maximal therapeutic intervention is achieved.http://europepmc.org/articles/PMC3531366?pdf=render |
| spellingShingle | Camilla Luni Jamey D Marth Francis J Doyle Computational modeling of glucose transport in pancreatic β-cells identifies metabolic thresholds and therapeutic targets in diabetes. PLoS ONE |
| title | Computational modeling of glucose transport in pancreatic β-cells identifies metabolic thresholds and therapeutic targets in diabetes. |
| title_full | Computational modeling of glucose transport in pancreatic β-cells identifies metabolic thresholds and therapeutic targets in diabetes. |
| title_fullStr | Computational modeling of glucose transport in pancreatic β-cells identifies metabolic thresholds and therapeutic targets in diabetes. |
| title_full_unstemmed | Computational modeling of glucose transport in pancreatic β-cells identifies metabolic thresholds and therapeutic targets in diabetes. |
| title_short | Computational modeling of glucose transport in pancreatic β-cells identifies metabolic thresholds and therapeutic targets in diabetes. |
| title_sort | computational modeling of glucose transport in pancreatic β cells identifies metabolic thresholds and therapeutic targets in diabetes |
| url | http://europepmc.org/articles/PMC3531366?pdf=render |
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