Centre for Movement, Occupational and Rehabilitation Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, United Kingdom; Nuffield Department of Primary Care Health Sciences, University of Oxford, United Kingdom.
Med Hypotheses. 2019 Jun;127:71-75. doi: 10.1016/j.mehy.2019.03.032. Epub 2019 Mar 28.
The increasing incidence of type 2 diabetes transcends all cultures, largely due to populations transitioning from traditional diets and manual occupations, to sedentary, calorific lifestyles. Excess calorie intake leads to intramuscular fat accumulation and insulin resistance. Physical inactivity causes underutilization of mitochondria causing dysfunction and inflammation. Both insulin resistance and mitochondrial dysfunction mechanisms are known to be closely related and to antagonise one another, although the precise nature of the relationship has eluded characterization. It is poorly understood why this mutual dysfunction progresses on to clinical diabetes in only some patients, why progression is often stepwise and why diabetes control only weakly predicts future cardiovascular disease in individuals. Clinical prediction in patients is therefore currently unsatisfactory and current linear assumptions require challenging. Cells contain networks of oscillating ionic fluxes. Cellular activity is characterised by complex patterns of fluctuation with sudden transitions between patterns. The non-linear nature of these oscillations is well characterised in neuronal activity, cardiac impulses and more recently mitochondria, but not previously in relation to diabetes. Cells under metabolic stress demonstrate complex fluctuations of mitochondrial distribution, coupling strength and synchronisation resulting in periodic or chaotic oscillations of function, causing accumulation of intracellular fat and excess reactive oxygen species (ROS), which exacerbates insulin resistance. Glucose, insulin and HbA1c in patients are also known to oscillate in complex patterns but the mechanisms and significance are largely unknown. Drawing on existing evidence and models from other diseases, a nonlinear, dynamical hypothesis of diabetes onset and progression is proposed. Insulin receptor pathways and mitochondria are treated as two populations of coupled, phase oscillators. Health or disease states depend on system stability or instability and reflect the balance of substrate supply and energy demand. The implication of this novel mechanism is that diabetes and the complications are not the consequence of a distinct pathological agent or pathway, but more an evolving dysrhythmia of normal cellular energetics systems, resulting from accumulated adverse lifestyle conditions. This hypothesis is proposed with the intention of stimulating research into non-linear dynamical constructs as an alternative to current linear models, to improve risk prediction and trajectory analysis in type 2 diabetes.
2 型糖尿病的发病率不断上升，超越了所有文化，这主要是由于人们的饮食和职业从传统向久坐不动、高热量的生活方式转变。过量的卡路里摄入会导致肌肉内脂肪堆积和胰岛素抵抗。缺乏身体活动会导致线粒体利用不足，从而导致功能障碍和炎症。胰岛素抵抗和线粒体功能障碍机制被认为密切相关且相互拮抗，尽管这种关系的确切性质仍未被描述。人们还不清楚为什么这种相互功能障碍在只有部分患者中进展为临床糖尿病，为什么进展通常是逐步的，以及为什么个体的糖尿病控制仅能微弱预测未来的心血管疾病。因此，目前患者的临床预测并不令人满意，当前的线性假设需要受到挑战。细胞内含有离子流的振荡网络。细胞活动的特点是具有复杂的波动模式，模式之间存在突然的转变。这些振荡的非线性性质在神经元活动、心脏冲动以及最近的线粒体中得到了很好的描述，但以前与糖尿病无关。代谢应激下的细胞表现出线粒体分布、偶联强度和同步性的复杂波动，导致功能的周期性或混沌振荡，导致细胞内脂肪和过量活性氧物质（ROS）的积累，从而加剧胰岛素抵抗。已知患者的血糖、胰岛素和糖化血红蛋白（HbA1c）也呈复杂的波动模式，但这些机制和意义在很大程度上尚不清楚。根据现有证据和其他疾病的模型，提出了一种关于糖尿病发病和进展的非线性、动力学假设。胰岛素受体途径和线粒体被视为两个耦合的相振荡器群体。健康或疾病状态取决于系统的稳定性或不稳定性，并反映了底物供应和能量需求的平衡。这种新机制的含义是，糖尿病及其并发症不是特定病理因素或途径的结果，而是由于积累的不良生活条件，正常细胞能量系统的节律紊乱不断演变的结果。提出这个假设是为了鼓励研究非线性动力学结构作为当前线性模型的替代方法，以改善 2 型糖尿病的风险预测和轨迹分析。
