Table 4 Characteristics of theories on insulin resistance as observed from an evolutionary medicine standpoint.

Thrifty genotype hypothesis: quick hyperinsulinemia after food intake to store energy in fat tissue and elsewhere (quick insulin trigger)

(Not so) Thrifty genotype hypothesis: starvation induces a special form of IR in order to conserve nitrogen (= amino acids from muscle and elsewhere)a

Thrifty phenotype hypothesis: intrauterine constraints induces IR and insulin deficiency, which allows the organism to survive long enough to reproduce in a nutritionally deprived environment but which leads to obesity in a world of plenty; maternal constraints support IR (small mother, first baby, many babies in parallel, maternal undernutrition, and similar)

Based on the thrifty genotype hypothesis: an insulin resistance genotype and a cytokine genotype exist (much IR, high cytokine response); IR is helpful for infections

Refined thrifty phenotype theory: predictive adaptive response model: the relative difference in nutrition between the prenatal and postnatal environment, rather than an absolute level of nutrition, determines the risk of IR

Central resistance model: there exists a homeostatic regulation of weight gain versus weight loss but defects in the weight loss system leads to obesity (for example, insulin and leptin signaling, SOCS3, PTB-1B)

Thrifty genotype plus breakdown of robustness: the basis is the thrifty genotype model; a robust glucose control system evolved during evolution, the breakdown of which induces positive disease-stabilizing feedback loops (TNF)

Thrifty genotype: integration of cellular pathogen-sensing and nutrient-sensing pathways (cytokines, TLRs, JNK, Ikkβ, PKC, ER stress)

Good calories-bad calories hypothesis: wrong nutrients, particularly carbohydrates, lead to obesity and IR; a paleolithic diet has quite different qualities that prevents obesity and western diseases