The Effect of Aerobic Exercise on Insulin Resistance: Narrative review of the Molecular Mechanisms

Farnaz  Sahebi; Mohammad Ali  Azarbayjani; Sirvan  Atashak; Maghsoud  Peeri; Saleh  Rahmati

doi:10.18502/ijdo.v18i2.21650

Farnaz Sahebi Department of Exercise Physiology, CT.C., Islamic Azad University, Tehran, Iran.
Mohammad Ali Azarbayjani Department of Exercise Physiology, CT.C., Islamic Azad University, Tehran, Iran.
Sirvan Atashak Department of Physical Education and Sport Sciences, mah.c., Islamic Azad University, Mahabad, Iran.
Maghsoud Peeri Department of Physical Education and Sport Sciences, mah.c., Islamic Azad University, Mahabad, Iran.
Saleh Rahmati Department of Physical Education and Sport Sciences, P.C., Islamic Azad University, Pardis Iran.

DOI: https://doi.org/10.18502/ijdo.v18i2.21650

Keywords: Aerobic exercise, Insulin resistance, Molecular mechanisms

Abstract

Insulin resistance (IR) is a central pathophysiological hallmark of type 2 diabetes mellitus (T2D) and related
cardio-metabolic disorders. This narrative review explores the impact of regular physical activity, particularly
aerobic and resistance exercise, on the mitigation of IR through various molecular mechanisms. Genetic
predispositions, chronic low-grade inflammation, dysregulated circulating metabolites, hormonal imbalances,
oxidative stress, and abnormal enzymatic activities collectively contribute to the pathogenesis of IR. Physical
activity, especially aerobic exercise, has significant anti-IR effects by modulating inflammatory processes.
This includes suppression of pro-inflammatory cytokines (e.g., TNF-α, IL-6) and adipokines (e.g., resistin,
visfatin), as well as an increase in anti-inflammatory myokines (e.g., irisin, muscle-derived IL-6) and
adiponectin/emilin-1 profiles. These changes create an anti-inflammatory environment that enhances insulin
signaling in skeletal muscle, liver, and adipose tissue. Hormonal adjustments, such as improved insulin
secretion, beta-cell function, and tissue sensitivity, further support these metabolic adaptations. Additionally,
exercise reduces oxidative stress by strengthening antioxidant defenses and inhibiting key IR-promoting
enzymes like PTP1B and 11β-HSD1. This preservation of tyrosine phosphorylation of the insulin receptor and
downstream IRS-1/PI3K/Akt pathway activation leads to increased GLUT4 translocation and glucose uptake.
In summary, regular exercise is a cost-effective, non-pharmacological intervention that targets interconnected
molecular factors in the etiology of IR. These diverse effects highlight its therapeutic potential in personalized
prevention and management strategies for IR and associated metabolic diseases, warranting its integration into
clinical guidelines.