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

From: Insulin resistance, selfish brain, and selfish immune system: an evolutionarily positively selected program used in chronic inflammatory diseases

Theory of insulin resistance Year Reference
Thrifty genotype hypothesis: quick hyperinsulinemia after food intake to store energy in fat tissue and elsewhere (quick insulin trigger) 1962, 1999 [50, 51]
(Not so) Thrifty genotype hypothesis: starvation induces a special form of IR in order to conserve nitrogen (= amino acids from muscle and elsewhere)a 1979 [54]
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) 1992, 2001 [55, 56]
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 1999 [61]
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 2004 [60]
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) 2004 [64]
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) 2004 [63]
Thrifty genotype: integration of cellular pathogen-sensing and nutrient-sensing pathways (cytokines, TLRs, JNK, Ikkβ, PKC, ER stress) 2006 [62]
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 2010, 2012 [65, 66]
  1. ER, endoplasmic reticulum; Ikkβ, inhibitor of nuclear factor-κB kinase β; IR, insulin resistance; JNK, jun-N-terminal kinase; PKC, protein kinase C; PTB-1B, protein tyrosine phosphatase 1B; SOCS3, suppressor of cytokine signaling 3; TLR, toll-like receptor; TNF, tumor necrosis factor. aThis is a special form of IR without hyperinsulinemia on the basis of a strong response of counterregulatory hormones. It is questionable to call it IR because of missing hyperinsulinemia and missing inflammation. In addition, activity of the sympathetic nervous system is low while activity of the hypothalamic-pituitary-adrenal axis is high in the typical nadir.