Trehalose, a natural disaccharide, has gained attention in the medical community for its wide-ranging therapeutic potential. As a neuroprotective agent, it offers benefits for cellular energy, hydration, antioxidant defense, and protein stabilization. 

The impact of trehalose on glucose metabolism is especially important for surgical stress response modulation. By balancing the glucose curve, spikes are flattened, and insulin resistance is lowered, potentially lowering infection risk and reducing secondary complications. 

Naturopathic practitioners have utilized trehalose in the management of neurodegenerative diseases, leveraging its capacity to promote autophagy, prevent protein misfolding and aggregation, and reduce neuroinflammation -- key factors in conditions such as postoperative cognitive dysfunction (POCD) and delirium.

Mechanisms of Action and Benefits:

• Glucose Metabolism and Insulin Sensitivity
  Trehalose's impact on glucose metabolism is noteworthy. It has been shown to reduce glycemic and insulinotropic responses when compared with sucrose, resulting in a flatter blood glucose absorption curve. These effects are beneficial in preventing spikes in blood glucose and improving insulin sensitivity, which can help mitigate insulin resistance and its complications, such as secondary cardiomyopathies.(1,2,3,4,5)
• Protein Stabilization and Autophagy
  Trehalose exhibits chaperone-like activity, assisting in the proper folding of proteins and preventing their aggregation under stress conditions. By inducing autophagy, it facilitates the clearance of accumulated proteins, which can otherwise contribute to neurodegenerative processes. This function is particularly significant in addressing amyloid-β aggregation, a characteristic pathology of Alzheimer's disease, and other forms of protein misfolding linked to cognitive decline.(7,8)
• Anti-Inflammatory and Antioxidant Effects
  The compound is known for its ability to suppress inflammatory responses by inhibiting the NF-κB pathway, thereby protecting cells from inflammation. It also exhibits antioxidant properties, scavenging free radicals and mitigating oxidative damage, which is associated with various age-related and neurodegenerative conditions. Trehalose can decrease reactive oxygen species and hydrogen peroxide levels in a dose-dependent manner in animal models of type 2 diabetes. Furthermore, it upregulates antioxidant gene expression, such as superoxide dismutase, glutathione, and catalase, by promoting the nuclear translocation of Nrf2.(6,8)
• Neuroprotection through Gut-Brain Axis
  Emerging evidence suggests that trehalose's neuroprotective effects may be mediated through mechanisms involving the gut microbiota. The modulation of gut-brain communication pathways further supports its role in treating neurodegenerative disorders.(6)
• Prevention of Glycation and Lipid Peroxidation
  Unlike other sugars, trehalose does not participate in glycation reactions, owing to the absence of a reducing end hydroxyl group, thus reducing the risk of harmful protein modifications. Additionally, it stabilizes membrane structure and prevents lipid peroxidation induced by reactive oxygen species, further contributing to its protective properties in various tissues. It has been confirmed to diminish amyloid formation, including the neuropathology underlying Alzheimer's disease, and prevent insulin-induced amyloid formation. Trehalose also exerts a stabilizing effect on membrane structure and function. (6,7,8)

References:

1. Zhang Y, DeBosch BJ. Using trehalose to prevent and treat metabolic function: effectiveness and mechanisms. Curr Opin Clin Nutr Metab Care. 2019;22(4):303-310. doi:10.1097/MCO.0000000000000568
2. DeBosch BJ, Heitmeier MR, Mayer AL, et al. Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. 2016;9-21. 
3. Xu C, Chen X, Sheng W-B, Yang P. Trehalose restores functional autophagy suppressed by high glucose. Reproductive Toxicology. 2019.
4. Yoshizane C, Mizote A, Arai C, et al. Daily consumption of one teaspoon of trehalose can help maintain glucose homeostasis: a double-blind, randomized controlled trial conducted in healthy volunteers. Nutrition J. 2020.
5. Mizote A, Yamada M, Yoshizane C, et al. Daily intake of trehalose is effective in the prevention of lifestyle-related diseases in individuals with risk factors for metabolic syndrome. J Nutrition Sci Vitaminol. 2016;62:380-7.
6. Lee HJ, Yoon YS, Lee SJ. Mechanism of neuroprotection by trehalose: controversy surrounding autophagy induction. Cell Death Dis. 2018;9(7):712. doi:10.1038/s41419-018-0749-9
7. Welch WJ, Brown CR. Influence of molecular and chemical chaperones on protein folding. Cell Stress & Chaperones. 1996;1:109–115.
8. Khalifeh M, Barreto GE, Sahebkar A. Trehalose as a promising therapeutic candidate for the treatment of Parkinson's disease. Br J Pharmacol. 2019;176(9):1173-1189. doi:10.1111/bph.14623