Potential molecular mechanism of exercise reversing insulin resistance and improving neurodegenerative diseases

Abstract

Neurodegenerative diseases are debilitating nervous system disorders attributed to various conditions such as body aging, gene mutations, genetic factors, and immune system disorders. Prominent neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Insulin resistance refers to the inability of the peripheral and central tissues of the body to respond to insulin and effectively regulate blood sugar levels. Insulin resistance has been observed in various neurodegenerative diseases and has been suggested to induce the occurrence, development, and exacerbation of neurodegenerative diseases. Furthermore, an increasing number of studies have suggested that reversing insulin resistance may be a critical intervention for the treatment of neurodegenerative diseases. Among the numerous measures available to improve insulin sensitivity, exercise is a widely accepted strategy due to its convenience, affordability, and significant impact on increasing insulin sensitivity. This review examines the association between neurodegenerative diseases and insulin resistance and highlights the molecular mechanisms by which exercise can reverse insulin resistance under these conditions. The focus was on regulating insulin resistance through exercise and providing practical ideas and suggestions for future research focused on exercise-induced insulin sensitivity in the context of neurodegenerative diseases.

Keywords: Parkinson’s disease; alzheimer’s disease; amyotrophic lateral sclerosis; exercise; huntington’s disease; insulin resistance; multiple sclerosis.

FIGURE 1

Detection methods, molecular mechanisms, and potential inducing factors of insulin resistance. (A), Insulin detection methods and diseases potentially caused by hyperglycemia. (B1), Insulin resistance in the liver induces IRS/PI3K/Akt to inhibit lipid, protein, and glycogen synthesis. (B2), Insulin resistance in the skeletal muscle impairs the ability of GLUT4 to transport extra-cellular glucose into the muscle cells. (C), Potential inducers of insulin resistance in the liver and skeletal muscle.

FIGURE 2

Molecular mechanisms of insulin resistance in neurodegenerative diseases. (A), Insulin resistance aggravates AD development by inhibiting the PI3K/Akt/GSK3β pathway and inducing tau protein hyperphosphorylation. Additionally, insulin resistance impedes the Wnt signaling pathway and exacerbates Aβ deposition. These mechanisms further escalate the occurrence of insulin resistance. (B), Insulin resistance activates starvation in glial cells and microglia induces apoptosis and lowers the proportion of neurons to worsen PD progression. (C), HD caused by GCA sequence duplication leads to insulin resistance, while the regulation of Socrs1, Hh-II, and Vldlr in HD further amplifies disease progression. (D), The increase in free fatty acid (FFA) levels in patients with ALS induces insulin resistance that in turn leads to decreases in IR and IRS-1/β expression. (E), Insulin resistance further increases cognitive decline in patients with MS. AD, Alzheimer’s disease; PD, Parkinson’s disease; HD, Huntington’s disease; ALS, amyotrophic lateral sclerosis; Aβ, amyloid beta.

FIGURE 3

Potential molecular mechanisms of exercise for improving insulin resistance. A, Exercise alleviates insulin resistance by improving mitochondrial quality (A), reducing ROS (B), decreasing endoplasmic reticulum stress (C), activating AMPK to induce autophagy (D), and inhibiting microglial activation and JNK and NF-κB phosphorylation as well as lowering neuroinflammatory factors (E).