Computational Modeling of Glucose Transport in Pancreatic β-Cells Identifies Metabolic Thresholds and Therapeutic Targets in Diabetes
Computational Modeling of Glucose Transport in Pancreatic β-Cells Identifies Metabolic Thresholds and Therapeutic Targets in Diabetes
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DOI：
10.1371/journal.pone.0053130
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发表时间：
2012-12-27
期刊：
影响因子：
3.7
通讯作者：
Doyle, Francis J., III
中科院分区：
文献类型：
--
作者：
Luni, Camilla;Marth, Jamey D.;Doyle, Francis J., III
胰腺β细胞功能障碍是2型糖尿病的诊断标准，包括葡萄糖转运和胰岛素分泌缺陷。在健康个体中，β细胞将血浆葡萄糖浓度维持在一个狭窄的范围内，与多个组织中的胰岛素作用相一致。餐后血糖升高通过位于质膜上的葡萄糖转运蛋白扩散，促进葡萄糖摄取到β细胞中。葡萄糖转运对于糖酵解和葡萄糖刺激的胰岛素分泌至关重要。在人类 2 型糖尿病和肥胖相关糖尿病小鼠模型中，随着葡萄糖刺激的胰岛素分泌的丧失，β 细胞葡萄糖转运蛋白和葡萄糖摄取明显缺乏。最近的研究表明，β细胞中葡萄糖转运的保存可以维持正常的胰岛素分泌并阻止肥胖相关糖尿病的发展。为了进一步阐明其潜在机制，我们构建了健康和 2 型糖尿病中人类 β 细胞葡萄糖转运的计算模型，并根据人类和动物研究的实验结果进行了系统分析。我们的研究结果确定了一个代谢阈值或“临界点”，通过该阈值，穿过β细胞质膜的葡萄糖转运减少会限制葡萄糖激酶在细胞内产生葡萄糖-6-磷酸。在 2 型糖尿病中，这种代谢阈值会被突破，并导致 β 细胞功能障碍，包括葡萄糖刺激的胰岛素分泌丧失。我们的模型进一步区分该途径中的分子控制点，其中实现了最大的治疗干预。
Pancreatic beta-cell dysfunction is a diagnostic criterion of Type 2 diabetes and includes defects in glucose transport and insulin secretion. In healthy individuals, beta-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 beta-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 beta-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 beta-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 beta-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 beta-cells limits intracellular glucose-6-phosphate production by glucokinase. This metabolic threshold is crossed in Type 2 diabetes and results in beta-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.