Laron syndrome with decreased IIS is associated with a reduced prevalence of acne, T2D and cancer. In contrast, up-regulated IIS by Western diet appears to promote the development of chronic diseases of civilization. Paleolithic diet, which excludes hyperglycemic carbohydrates and insulinotropic dairy, has been successfully introduced for the prevention and treatment of acne, T2D and cardiovascular diseases [16
]. Future efforts should be undertaken to lower the high insulinemic index of milk (I.I. 140) and other whey-based milk products to reach values of beef (I.I. 51) or cheese (I.I. 45) [16
]. Furthermore, combinations of hyperglycemic carbohydrates and insulinotropic dairy with potentiating effects on IIS should be restricted.
Individuals with genetic single nucleotide polymorphisms (SNPs) resulting in hyperactive IIS may be at special risk for the development of age-related diseases, predominantly when their high intrinsic IIS is superposed by exaggerated IIS of Western diet. Intriguingly, genetic variations with reduced IIS due to SNPs of interacting components of the IIS cascades (GH1, IGF1, IGF1R, IRS1, FoxO1A, FoxO3A
) and have been associated with increased longevity [30
]. Thus, future research should consider the impact of interacting intrinsic genetic as well as extrinsic dietary factors involved in the regulation of IIS.
The access to higher amounts of insulinotropic and IGF-1-raising foods (sugar, grains and dairy) occurred about 10,000 years ago during the Neolithic Revolution
and was further augmented by the Industrial Revolution
. However, the human genome may not have adapted to this "recent switch" to higher IIS driven by Western diet. According to mitochondrial DNA data, modern humans with nearly similar genomic structure lived roughly 200,000 years ago and consumed a less insulinotropic Paleolithic diet. In this regards, it has been proposed to re-adapt our nutrition to the beneficial characteristics of our pre-agricultural diets [32
]. The time point introducing a well-balanced Paleolithic diet may be a special issue of concern as proper IIS is important for the function of the reproductive and central nervous system. In adulthood however, dietary restrictions decreasing IIS may reduce the risk of age-associated pathology like proteotoxicity as recently demonstrated in a mouse model of Alzheimer disease [33