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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2021, Vol. 15 Issue (3) : 372-382    https://doi.org/10.1007/s11684-021-0862-5
REVIEW
Mechanism of insulin resistance in obesity: a role of ATP
Jianping Ye()
Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
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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.

Keywords type 2 diabetes      energy expenditure      mitochondria      hyperinsulinemia      hyperglucagonemia      AMPK     
Corresponding Author(s): Jianping Ye   
Just Accepted Date: 08 May 2021   Online First Date: 28 May 2021    Issue Date: 18 June 2021
 Cite this article:   
Jianping Ye. Mechanism of insulin resistance in obesity: a role of ATP[J]. Front. Med., 2021, 15(3): 372-382.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0862-5
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I3/372
Fig.1  ATP-based insulin resistance model.
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