Evolutionary origins of insulin resistance: a behavioral switch hypothesis

Abstract

Background: Insulin resistance, which can lead to a number of diseases including type 2 diabetes and coronary heart disease, is believed to have evolved as an adaptation to periodic starvation. The "thrifty gene" and "thrifty phenotype" hypotheses constitute the dominant paradigm for over four decades. With an increasing understanding of the diverse effects of impairment of the insulin signaling pathway, the existing hypotheses are proving inadequate.

Presentation of the hypothesis: We propose a hypothesis that insulin resistance is a socio-ecological adaptation that mediates two phenotypic transitions, (i) a transition in reproductive strategy from "r" (large number of offspring with little investment in each) to "K" (smaller number of offspring with more investment in each) and (ii) a transition from "stronger to smarter" or "soldier to diplomat" i.e. from relatively more muscle dependent to brain dependent lifestyle. A common switch could have evolved for the two transitions since the appropriate environmental conditions for the two transitions are highly overlapping and interacting.

Testing the hypothesis: Gestational insulin resistance diverts more energy through the placenta, resulting in increased investment per offspring. On the other hand, insulin resistance is associated with reduced ovulation. The insulin signaling pathway is also related to longevity. Insulin resistance diverts more nutrients to the brain as compared to muscle. Also, hyperinsulinemia has direct positive effects on cognitive functions of the brain. The hypothesis gets support from known patterns in human clinical data and recent research on the molecular interactions in the insulin signaling pathway. Further we state many predictions of the hypothesis that can be tested experimentally or epidemiologically.

Implications of the hypothesis: The hypothesis can bring about a significant change in the line of treatment as well as public health policies for the control of metabolic syndrome.

Figure 1

Causal relationships between environmental factors and the two transitions. Thick arrows indicate causations for which there is adequate evidence currently. Thin arrows are the causations suggested by our hypothesis that need to be tested.