Hypothesis: Enhanced glucose availability and insulin resistance enhances an activated immune system and accounts for the obesity paradox

Many studies have demonstrated an 'obesity paradox' where people with obesity have reduced mortality in the context of acute critical illnesses compared to people of normal weight. In contrast, obesity is associated with reduced life expectancy in the population in general and is associated with an increased risk for type 2 diabetes, cardiovascular disease and other health problems. However, the absence of the metabolic syndrome is associated a lower mortality than when the metabolic syndrome is present regardless of body mass index status and the obesity paradox appears to only occur in association with the metabolic syndrome, but cardiorespiratory fitness modifies these outcomes. Enhanced glucose availability is important when the immune system is activated not only because it has an acute onset, a high consumption of glucose and is substantially an obligate glucose utilizer but also because it has priority over most other tissues and cells for the available glucose. Thus, for vulnerable populations, such as children with severe infections, this increases the risk of hypoglycaemia and death. The obesity paradox may be substantially a consequence of two features associated with obesity. One is endogenous glucose production (EGP). Obesity is associated with an increased capacity for EGP and thus is associated with enhanced glucose availability. Second is insulin resistance that reduces the amount of glucose metabolized by cells that are not obligate glucose utilizers and increases the release of fatty acids and glycerol from adipose stores that are alternative fuels for tissues and cells.