The main environmental factors are obesity, sedentary behaviour, stress, nutritional factors (such as excessive intake of fructose in liquid form and branched-chain amino acids) and sleep deprivation.4 IR is associated with certain well-known human monogenic disorders.5 The first single gene mutation responsible for severe IR was discovered in the insulin receptor gene (INSR) in 1988.6, 7 A comprehensive review of monogenic forms of IR is given by Semple et al.,8 and we will list here only a few monogenic genes causing severe IR. This evidence concerns the gene INSR and obesity due to melanocortin 4 receptor deficiency.