Overview of the thrifty genotype hypothesis

Abstract

The thrifty genotype hypothesis was proposed by Neel in 1962 to explain the increasing incidence of diabetes in the western world. Since then it has been invoked frequently to explain the epidemics of obesity and non-insulin dependent diabetes (NIDDM) in populations all over the world as they have made the rapid transition to a westernised lifestyle in the twentieth century. An examination of the archaeological record indicates that human populations were exposed to nutritional stresses throughout history (both as hunter-gatherers and agriculturalists) which could have selected strongly for a "thrifty" metabolism. The metabolic basis of the "thrifty" genotype has been attributed to selective insulin resistance, in which the gluco-regulatory pathways of insulin action are affected primarily, thereby promoting compensatory hyperinsulinaemia and overstimulation of those pathways less affected by insulin resistance such as those involved in fat deposition. Both physical inactivity and an energy-dense diet high in saturated fat and fibre-depleted carbohydrate have been shown to increase insulin resistance. Thus, key components of the western lifestyle act to exacerbate insulin resistance and facilitate weight gain, which itself also worsens insulin resistance. Finally, Hales and Barker have argued provocatively for a "thrifty" phenotype as the major predisposing factor in NIDDM: that poor nutrition in the perinatal period is associated with increased risk of NIDDM in adulthood, mediated either through sustained effects on b -cell function or insulin sensitivity. The difficulties in differentiating between "nature" and "nurture" in the aetiology of this complex condition cannot be overstated.