Pathogenesis and prediction of diabetes mellitus: lessons from integrative physiology.
Pathogenesis and prediction of diabetes mellitus: lessons from integrative physiology.
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发表时间：
2002-10
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通讯作者：
R. Bergman
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作者：
R. Bergman
生物学中的分子革命提供了关于正常和病理条件下亚细胞事件的指数增长的数据体。即使是整合这些信息洪流中的一小部分，也是一项艰巨的挑战。许多综合监管原则仍然未知。本文认为，重要的原则可能会发现，通过简单的同构计算机或生物调节的数学模型的重复实验测试。以调节血糖的系统为例。在20多年前提出的最小模型中，隐含着一些具体但未经检验的假设。这些假设在随后的几十年里得到了验证，丰富了我们对代谢调节和糖尿病病因的理解。目前从模型中出现的公认概念包括：（a）缓慢的胰岛素转运通过毛细血管内皮在刺激葡萄糖摄取中的重要性;（B）单通道概念，即胰岛素转运通过脂肪组织的内皮抑制游离脂肪酸，这反过来又减少肝脏的内源性葡萄糖产生;（c）代谢综合征中单一途径机制的重要性，即腹腔室脂肪增加与胰岛素抵抗和2型糖尿病风险有关;以及（d）胰岛素作用和胰岛素分泌之间的双曲线关系，其提供了对糖尿病风险的准确预测。人们希望，代谢系统的经验将提供一个比喻，其他监管系统较少受到关键的定量分析。这种分析很可能导致对其他重要的综合生物系统的类似概念性理解，并为早期干预其他慢性和破坏性疾病的致病过程提供方法。
The molecular revolution in biology is providing an exponentially increasing body of data regarding subcellular events in normal and pathological conditions. The task of integrating even a small part of this deluge of information is a formidable challenge. Many integrative regulatory principles are still unknown. The present article argues that important principles may be discovered by the repetitive experimental testing of simple isomorphic computer or mathematical models of biological regulation. The system regulating the blood glucose is used as an example. Implicit in a minimal model, postulated more than 20 years ago, were specific but untested assumptions. These assumptions, which were tested over the ensuing decades, have enriched our understanding of metabolic regulation and the causes of diabetes. Currently accepted concepts emerging from modeling include: (a) the importance of sluggish insulin transport across the capillary endothelium in stimulation of glucose uptake; (b) the single gateway concept, that insulin transport across endothelium of adipose tissue suppresses free fatty acids, which act in turn to reduce endogenous glucose production by the liver; (c) the importance of the single gateway mechanism in the metabolic syndrome, whereby increased fat in the abdominal compartment relates to insulin resistance and risk for type 2 diabetes; and (d) the hyperbolic relationship between insulin action and insulin secretion, which provides an accurate prediction of diabetes risk. It is hoped that the experience with the metabolic system will provide a metaphor for other regulatory systems less subjected to critical quantitative analysis. Such analysis may well lead to analogous conceptual understanding of other important integrated biological systems, and provide approaches for early intervention in the pathogenic process of other chronic and devastating diseases.