The interaction between S6K/IRS2/PDX1/eIF4G and 4E-BP2/eIF4E pathways to control insulin processing during normal states or insulin resistance is unclear but we speculate prolonged overactivation of mTORC1 in conditions of chronic overnutrition results in a predominant S6K negative-feedback loop with decrease in IRS1/2 levels and reduction of IRS/PDX1/eIF4G/CPE pathway. The gene discussed is IRS2; the disease is Insulin resistance.