Wang Guanyu
Department of Biology, South University of Science and Technology of China, Shenzhen, Guangdong 518055, People's Republic of China
J R Soc Interface. 2014 Dec 6;11(101):20140892. doi: 10.1098/rsif.2014.0892.
The epidemics of obesity and diabetes demand a deeper understanding of insulin resistance, for which the adjustable threshold hypothesis is formed in this paper. To test the hypothesis, mathematical modelling was used to analyse clinical data and to simulate biological processes at both molecular and organismal levels. I found that insulin resistance roots in the thresholds of the cell's bistable response. By assuming heterogeneity of the thresholds, single cells' all-or-none response can collectively produce a graded response at the whole-body level-conforming to existing data. The thresholds have to be adjustable to adapt to extreme conditions. During pregnancy, for example, the thresholds increase consistently to strengthen the mother's insulin resistance to meet the increasing glucose demand of the expanding fetal brain. I also found that hysteresis, a key element of the adjustable threshold hypothesis, can explain reactive hypoglycaemia, which is characteristic of diabetes complications but remains poorly understood. Contrary to the common belief that insulin promotes glucose disposal, the results imply that insulin is the body's 'ration stamp' to restricting glucose utilization by peripheral tissues and that insulin resistance is primarily a well-evolved mechanism. The hypothesis provides an intuitive and dynamical description of the previously formless insulin resistance, which may make the detection of pre-diabetes possible and may shed light on the optimal timing of therapeutic intervention. It also provides valuable clues to defining subtypes of type 2 diabetes that might respond differently to specific prevention and intervention strategies.
肥胖症和糖尿病的流行需要我们对胰岛素抵抗有更深入的了解，为此本文提出了可调阈值假说。为了验证这一假说，我们使用数学建模来分析临床数据，并在分子和机体水平上模拟生物过程。我发现胰岛素抵抗源于细胞双稳态反应的阈值。通过假设阈值的异质性，单细胞的全或无反应可以在全身水平上共同产生分级反应——这与现有数据相符。阈值必须是可调的，以适应极端情况。例如，在怀孕期间，阈值会持续升高，以增强母亲的胰岛素抵抗，以满足不断发育的胎儿大脑对葡萄糖需求的增加。我还发现，滞后现象作为可调阈值假说的一个关键要素，可以解释反应性低血糖，这是糖尿病并发症的一个特征，但目前仍了解不足。与普遍认为胰岛素促进葡萄糖代谢的观点相反，研究结果表明胰岛素是身体限制外周组织利用葡萄糖的“定量配给券”，而胰岛素抵抗主要是一种进化良好的机制。该假说为之前尚无定论的胰岛素抵抗提供了直观且动态的描述，这可能使糖尿病前期的检测成为可能，并可能为治疗干预的最佳时机提供线索。它还为定义2型糖尿病的亚型提供了有价值的线索，这些亚型可能对特定的预防和干预策略有不同的反应。
