Table 3.

Stages of disease progression

	Stage I: healthy insulin sensitive	Stage II: physiological stress with appropriate compensation	Stage III: failure of compensation
Oxidative capacity and activity	Normal exercise capacity and activity	Inappropriately low relative to load, due to:	Further ⇊
		• Inactivity
		• Reduced fitness
		• Genetic susceptibility
		• Aging
Oxidative load	Normal	Increased, due to:	Sustained ⇈
		• Cellular overnutrition
		• Obesity
Cellular response patterns	Normal	• Initial ↑ mitochondrial biogenesis, inadequate to meet metabolic demand	• ⇊ Nuclear-encoded OXPHOS gene expression
		• ↑ Incomplete oxidation	• Vicious cycle of suboptimal oxidative capacity
		• ↑ ROS generation
		• ↑ Tissue lipid accumulation
Physiological consequences	Normal insulin sensitivity and secretion	Insulin resistance	• Progressive insulin resistance
			• Insulin secretory dysfunction
			• Type 2 DM

↓, Decrease; ↑, increase.