Postoperative cognitive dysfunction (POCD) refers to a series of changes in personality, social, and cognitive abilities that occur extensively in elderly patients after surgery. The condition is characterized by issues with memory, abstract thinking, and disorientation, accompanied by social dysfunction (Evered and Silbert, 2018). General anesthesia is considered a key risk factor for POCD (Evered et al., 2018). Pathogenesis of POCD mainly involves central inflammatory response, cerebral perfusion, blood–brain barrier damage, and circadian rhythm disorders (Kruthiventi et al., 2020; Tasbihgou and Absalom, 2021). The systemic inflammatory response caused by surgery increases the plasma levels of IL-1, IL-6, TNF-α, and other inflammatory factors, which induces the inflammatory response of CNS through various mechanisms, impairs cognitive function, and causes POCD (Li et al., 2022). However, there is still no specific and effective treatment for POCD.

Insulin can improve cognitive function by reducing intracellular amyloid plaque, promoting tau hypophosphorylation, stabilizing microtubules and promoting tubulin polymerization (Zilliox et al., 2016). Insulin directly affects inflammatory cells in the brain, reduces the release of pro-inflammatory cytokine TNFα, and may have an important role in the mechanism of action of insulin-based therapies currently being considered for CNS disorders (Brabazon et al., 2018). Exogenous insulin relies primarily on intranasal administration into the brain, which has the advantages of non-invasiveness, ease of handling, rapid absorption and onset of action, and avoidance of hepatic first-pass elimination (Born et al., 2002). Preclinical and clinical evidence suggested that intranasal insulin improves memory function (Badenes et al., 2021) and can also improve functional performance in patients with Alzheimer’s disease (AD) and Parkinson’s disease (PD) (Claxton et al., 2015; Novak et al., 2019). However, there is limited clinical evidence of intranasal insulin preventing POCD in elderly patients after laparoscopic radical resection of colorectal cancer.

Therefore, this study aimed to evaluate the efficacy and safety of intranasal insulin on POCD in elderly patients after laparoscopic radical resection of colorectal cancer.

Among 85 patients screened between August 2023 and November 2023, 12 were not interested in this research, 5 had diabetes mellitus, 1 had neurological disease, 1 had communication difficulty, and 2 had MMSE scores below the standard range. A total of 64 patients were included in the final analysis, with 32 patients being allocated to the insulin group and 32 to the control group. One patient was excluded due to rejection to participate in cognitive follow-up, and 1 was excluded due to surgery being canceled in the insulin group. One patient was also excluded from the control group due to surgery being canceled, resulting in 61 patients (including 30 in the insulin group) being enrolled in this study (Figure 1). The baseline characteristics between the insulin and control groups were comparable, including age, gender ratio, body mass index (BMI), ASA grade, TNM stage, MMSE scores, education years, and operation time between the control group and insulin group (all p > 0.05, Table 1).

The insulin group had a significantly lower POCD rate compared with the control group at postoperative day 7 [4 (13.3%) vs. 12 (38.7%), p = 0.024] (Table 2). There was no significant difference in all neuropsychological test parameters between the insulin and control groups at T₀. The mental control (mean difference, 5.03, 95% CI 0.73–9.33, p = 0.023) and digit symbol (mean difference, 4.67, 95% CI 1.06–8.28, p = 0.012) in the insulin group was significantly higher than that of the control group at T₆, and the Trail A (mean difference, −16.27, 95% CI -30.13--2.40, p = 0.022) was significantly lower than that of the control group at T₆ (Supplementary Table S1).

The serum IL-6 and TNF-α increased from T₁ to T₂ and decreased from T₂ to T_5. Moreover, the S100β levels increased from T₁ to T₄ and decreased from T₄ to T_5. Besides, the serum levels of IL-6, TNF-α and S100β at T_2-5 in the insulin group were significantly lower than those of the control group (IL-6: mean difference at T₂, −4.14, p = 0.036; T₃, −3.84, p = 0.039; T₄, −3.37, p = 0.013; T₅, −2.57, p = 0.042; TNF-α: mean difference at T₂, −3.19, p = 0.002; T₃, −2.35, p = 0.028; T₄, −2.30, p = 0.019; T₅, −1.96, p = 0.0181; S100β: mean difference at T₂, −8.30, p = 0.019; T₃, −23.95, p = 0.020; T₄, −20.01, p = 0.023; T₅, −17.67, p = 0.010; Figure 2). No insulin allergic reactions, nasal irritation, or hypoglycemic reactions were observed in either of the groups. The perioperative complications, such as pneumonia, incision infection, postoperative bleeding, cricoarytenoid joint dislocation, post-nausea and vomiting (PONV), fever, chills, acute renal insufficiency, and surgery-related complications, did not differ between the two groups.

This study found that intranasal insulin significantly reduced the risk of POCD and decreased the serum IL-6, TNF-α and S100β in older patients compared to patients treated with intranasal normal saline after laparoscopic radical resection of colorectal cancer, which provides a basis and support for preoperative intranasal insulin in older patients to improve cognitive function and decrease the risk of POCD.

Insulin is a small protein secreted by pancreatic β-cells and composed of 51 amino acid residues, which is known to regulate neural development and neuronal activities and has a key role in learning and memory (Chen et al., 2017). Currently, intranasal insulin has been reported as a treatment and prevention of postoperative delirium (POD) with a similar pathogenesis to AD (Craft et al., 2020; Nitchingham et al., 2021). It has been pointed out that POD and POCD sometimes occur in the same individual with overlapping risk factors, which suggests a common underlying neuropathogenesis (Daiello et al., 2019). Chen et al. (2017) showed that daily intranasal insulin for 3 days prior to anesthesia completely prevented the spatial learning and memory deficits in 3xTg-AD mice, which may restore insulin signaling, including GSK-3β disturbed by anesthesia via activating PI3K/PDK1/AKT pathway, and attenuate hyperphosphorylation of tau at multiple AD-associated sites (Kawano et al., 2016; Zhang et al., 2016; Li et al., 2019). Moreover, intranasal insulin can bypass the blood–brain barrier and enter the brain via olfactory and trigeminal-associated extracellular pathways and perivascular pathways, thus avoiding the side effects of peripheral insulin administration and contributing to memory improvement (Dhuria et al., 2010). Benedict et al. (2007) showed that intranasal insulin improved recall ability and self-confidence in cognitive tasks after 8-week treatment with intranasal insulin in healthy individuals. Kellar et al. (2022) found that patients in the insulin group had increased interferon-γ and eotaxin, and reduced IL-6 in cerebrospinal fluid (CSF) over the 12-month trial compared to the placebo group, suggesting alleviated neuroinflammation in cognitive impairment. Craft et al. found that insulin treatment improved delayed memory and preserved caregiver-rated functional ability, associated with changes in the Aβ42 level and the tau protein-to-Aβ42 ratio in CSF (Craft et al., 2012).

Khan et al. found that IL-6, TNF-α, and S100β were associated with poor cognitive function (Khan et al., 2020). It was also found that IL-6, TNF-α, and S100β levels were up-regulated after open cardiac surgery (Tang et al., 2017), which indicated neurological damage (Goettel et al., 2017; Liu et al., 2018). Prior literatures have demonstrated the relationship between POCD related to S100β and insulin resistance (D’Cunha et al., 2019; He et al., 2019). Huang et al. (2021) found that repeated preoperative intranasal insulin could reduce serum levels of TNF-a, IL-1, and IL-6 and prevented the development of POD after laparoscopic radical gastrointestinal surgery in elderly patients; the incidence rates of adverse events were comparable between the two groups. Huang et al. (2023) also found that preoperative intranasal insulin could significantly reduce the risk of POD in older patients undergoing radical esophagectomy, similar to this study’s results.

The present study still has several limitations. First, this study did not collect patients’ blood glucose and serum kalium information during the perioperative period to ensure safety. Secondly, this was a single-center study, and the sample size was relatively small, which limited the extrapolation of the conclusion to the general population. Third, patients often developed POCD from a few days to several months, while this study only focused on changes at postoperative 7 days and did not follow up long-term outcomes, thus failing to provide enough evidence to support the long-term efficacy of intranasal insulin on POCD. Fourthly, the biomarkers were collected from serum, which may not be the best choice for detecting biomarkers compared to CSF. Fifthly, the effects of dose and frequency of insulin administration on POCD were not investigated. Finally, this study did not explore the relationship between types of anesthetics and POCD. Although this study is a pilot study, which was conducted at a single institution on a homogeneous group of patients, our postoperative findings suggest a potentially positive role for intranasal insulin to prevent postoperative cognitive impairment and confirm that further study is warranted.

Intranasal insulin may decrease the risk of POCD and inhibit the elevated serum IL-6, TNF-α, and S100β levels in elderly patients after laparoscopic radical resection of colorectal cancer, which proves that intranasal insulin may be a promising therapeutic option for POCD. A large-sample multicenter randomized trial is needed to investigate the dose and frequency of insulin administration in POCD.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by Beijing Luhe Hospital, Capital Medical University (2023-LHKY-060-02). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

HZ: Data curation, Writing – original draft, Writing – review & editing. LZ: Data curation, Writing – original draft, Writing – review & editing. ML: Formal analysis, Writing – original draft, Writing – review & editing. XL: Formal analysis, Writing – original draft, Writing – review & editing. RL: Data curation, Writing – original draft, Writing – review & editing. DW: Data curation, Writing – original draft, Writing – review & editing.