Mechanism of insulin resistance in obesity: a role of ATP

Abstract

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.

Comparative Transcriptome Analysis Provides Insight into Spatio-Temporal Expression Characteristics and Genetic Regulatory Network in Postnatal Developing Subcutaneous and Visceral Fat of Bama Pig

“…We found that the expression of ATPase gene related to insulin secretion pathway was significantly higher in VAT than in SAT. ATP is a major signal of pancreatic IR ( Ye, 2021 ). In obesity, ATP overproduction promotes systemic IR through a several mechanisms, such as inhibition of AMPK, Mtor induction, hyperinsulinemia, hyper glucagon and mitochondrial dysfunction.…”

AMPK as a Potential Therapeutic Target for Intervertebral Disc Degeneration

“…Under obese circumstance, mitochondrial overheating is induced by oversupply of substrate to mitochondria in insulin-sensitive cells. Mitochondrial overheating brings about overproduction of ATP and the inhibition of AMPK ( Ye, 2021 ). Meanwhile, obesity is often accompanied by the hyposecretion of adiponectin, an endogenous AMPK activator ( Li et al, 2021 ).…”

“…Meanwhile, obesity is often accompanied by the hyposecretion of adiponectin, an endogenous AMPK activator ( Li et al, 2021 ). Through the modulation of AMPK activity, obesity results in the systemic insulin resistance and hyperglycemia ( Ye, 2021 ). As reported, ageing process is always accompanied with the reduction of AMPK activation ( Salminen et al, 2016 ).…”

Mitochondria in Sex Hormone-Induced Disorder of Energy Metabolism in Males and Females

“…This function is induced by substrates, hormones, and energy demand as discussed above. In a recent review, excessive substrate availability in obesity has been proposed as a major factor contributing to mitochondrial overproduction of ATP in the mechanism of insulin resistance (134). The insulin resistance occurs following ATP surplus in multiple tissues, in which ATP production exceeds demand (134).…”

“…In a recent review, excessive substrate availability in obesity has been proposed as a major factor contributing to mitochondrial overproduction of ATP in the mechanism of insulin resistance (134). The insulin resistance occurs following ATP surplus in multiple tissues, in which ATP production exceeds demand (134). ATP surplus in the pancreatic b-cells leads to more secretion of insulin for hyperinsulinemia.…”