Positive selection of type 2 diabetes genotypes - the glycaemic threshold hypothesis

The high prevalence of deleterious polygenic type 2 diabetes (T2D) is a paradox requiring explanation beyond food excess, inactivity and the obesity resulting from positive energy balance. Historically, hunting-foraging and later agrarian communities often manifested a converse negative energy balance due to nutritional deficit and/or high physical energy demand - both potentially resulting in hypoglycaemia. Since hypoglycaemia impairs both reproductive fitness and cognitive function, it is proposed that that by expressing resistance to hypoglycaemia, T2D phenotypes were subject to positive selection. The insulin resistance present in often-associated atherosclerotic cardiovascular disease, metabolic syndrome and polycystic ovarian disease may also explain their frequent coexistence and current prevalence.