Chaos, mitochondria and type 2 diabetes; does type 2 diabetes arise from a metabolic dysrhythmia?

Abstract

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.