Obesity increases the risk of type 2 diabetes through the induction of insulin resistance.The mechanism of insulin resistance has been extensively investigated for more than 60 years,but the essential pathogenic signal remains missing.Existing hypotheses include inflammation,mitochondrial dysfunction,hyperinsulinemia,hyperglucagonemia,glucotoxicity,and lipotoxicity.Drug discoveries based on these hypotheses are unsuccessful in the development of new medicines.In this review,multidisciplinary literature is integrated to evaluate ATP as a primary signal for insulin resistance.The ATP production is elevated in insulin-sensitive cells under obese conditions independent of energy demand,which we have named “mitochondrial overheating.” Overheating occurs because of substrate oversupply to mitochondria,leading to extra ATP production.The ATP overproduction contributes to the systemic insulin resistance through several mechanisms,such as inhibition of AMPK,induction of mTOR,hyperinsulinemia,hyperglucagonemia,and mitochondrial dysfunction.Insulin resistance represents a feedback regulation of energy oversupply in cells to control mitochondrial overloading by substrates.Insulin resistance cuts down the substrate uptake to attenuate mitochondrial overloading.The downregulation of the mitochondrial overloading by medicines,bypass surgeries,calorie restriction,and physical exercise leads to insulin sensitization in patients.Therefore,ATP may represent the primary signal of insulin resistance in the cellular protective response to the substrate oversupply.The prevention of ATP overproduction represents a key strategy for insulin sensitization.