Effects of Intranasal Insulin on Postoperative Delirium in Older Patients with and without Type 2 Diabetes Mellitus: A Secondary Analysis of a Randomized Clinical Trial

Effects of Intranasal Insulin on Postoperative Delirium in Older Patients with and without Type 2 Diabetes Mellitus: A Secondary Analysis of a Randomized Clinical Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of Intranasal Insulin on Postoperative Delirium in Older Patients with and without Type 2 Diabetes Mellitus: A Secondary Analysis of a Randomized Clinical Trial Danyang Geng, Xianghan Ruan, Huikai Yang, Lulu Zhou, Mengyao Qu, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7097922/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background: This study further analyzed the data from a previous prospective, randomized, placebo-controlled clinical study to investigate the effects of intranasal insulin therapy on postoperative delirium (POD) in older patients with and without type 2 diabetes mellitus (T2DM). Materials and methods: In the current study, 128 patients were categorized into four groups based on intranasal treatment and the presence of T2DM: Group DM-S included 22 patients with T2DM receiving intranasal saline; Group DM-I included 28 patients with T2DM receiving intranasal insulin; Group Non-DM-S comprised 42 patients without T2DM receiving intranasal saline; and Group Non-DM-I included 36 patients without T2DM receiving intranasal insulin. The primary outcome was POD incidence between Group DM-S and Group DM-I, and between Group Non-DM-S and Group Non-DM-I. The secondary outcomes included the effects of intranasal insulin treatment on perioperative changes of Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment-Basic (MoCA-B) in participants with and without T2DM. Results: The incidences of POD in Group DM-S, Group DM-I, Group Non-DM-S, Group Non-DM-I were 36.4%, 10.7%, 19% and 11.1%, respectively. Intranasal insulin treatment significantly decreased the POD incidence in patients with T2DM (P=0.030). Additionally, the perioperative changes of MMSE scores were -0.36±1.50, 0.75±1.32, -0.83±1.41 and 0.36±1.38 in Group DM-S, Group DM-I, Group Non-DM-S, Group Non-DM-I, respectively. And the perioperative changes of MoCA-B scores were -0.14±2.05, 1.04±1.80, -0.14±1.89 and 0.78±1.42 in Group DM-S, Group DM-I, Group Non-DM-S, Group Non-DM-I, respectively. Intranasal insulin treatment significantly improved the perioperative changes of MMSE scores and MoCA-B scores both in Group DM ( P MMSE =0.008, P MoCA-B =0.037) and Group Non-DM ( P MMSE =0.022, P MoCA-B =0.019). Conclusion: Intranasal insulin decreased POD incidences in older patients with T2DM and potentially offered better therapeutic effects on postoperative cognitive function compared to older patients without T2DM. Intranasal insulin postoperative delirium (POD) type 2 diabetes mellitus (T2DM) secondary analysis older patients Figures Figure 1 Introduction Postoperative delirium (POD) is an acute cognitive disorder characterized by fluctuating disturbances in attention, consciousness, and perception[ 1 ]. POD is a common complication, particularly among older adults undergoing major surgery[ 1 ]. The incidence varies widely, with reports suggesting that 10–50% of older surgical patients may experience POD[ 2 ]. POD is associated with higher mortality rates, prolonged hospital stay, increased healthcare costs[ 2 ]. Therefore, the prevention and management of POD is a key focus in the field of anesthesiology. The exact mechanisms underlying POD are not fully understood and the main risk factors for POD include advanced age, preexisting cognitive impairment, severe illness or comorbidities, type and duration of surgery, postoperative pain and opioid use, sleep deprivation and electrolyte imbalance[ 3 ]. However, while no drug is specifically approved for POD prevention, careful management of medications, including minimizing the use of deliriogenic drugs such as benzodiazepines and anticholinergics, is crucial[ 3 ]. Some studies explore the use of antipsychotics and melatonin, but results were mixed and should be used with caution[ 3 ]. Therefore, identifying high-risk patients through comprehensive preoperative assessments, including cognitive evaluations, can guide tailored interventions. Patients with type 2 diabetes mellitus (T2DM) are at an increased risk for more frequent and severe postoperative complications compared to non-diabetic individuals[ 4 ]. As a common complication in older surgical patients, T2DM is also a significant risk factor for POD[ 5 ]. Moreover, as of 2021, the global prevalence of DM had reached 536.6 million individuals, with approximately half of these patients likely to require surgical intervention at some point during their lifetime[ 6 ]. Therefore, individuals with T2DM are considered a high-risk group for POD, and research on prevention and management strategies for POD in patients with T2DM holds significant clinical importance. Insulin in the brain plays several important roles beyond its well-known functions in glucose metabolism, including neurotransmitter regulation, synaptic plasticity and cognition, neuroprotection, cell growth and survival[ 7 ]. Intranasal administration of insulin can rapidly, safely, and effectively increase insulin levels in the brain and has shown cognitive improvement in studies involving Alzheimer's disease (AD) patients[ 8 ]. Additionally, our previous animal studies had indicated that supplementing brain insulin levels can alleviate cognitive dysfunction and ferroptosis mediated by neuroinflammation[ 9 , 10 ], which are important mechanisms of POD. Therefore, research on the effects of intranasal insulin on postoperative cognitive function changes and POD in older patients was conducted, and the results demonstrated that intranasal insulin treatment could reduce the incidence of POD in older surgical patients[ 11 – 13 ]. However, the therapeutic effect of intranasal insulin on POD in older patients with T2DM remains unclear. In this study, we hypothesized that the incidence of POD in diabetic patients is higher than in non-diabetic patients, and that intranasal insulin treatment had a more pronounced effect on preventing POD in patients with T2DM. Therefore, we conducted a subgroup analysis of the participants from a previous randomized clinical trial (RCT), categorizing them based on the presence or absence of T2DM, to observe the impact of intranasal insulin on the incidence of POD and perioperative cognitive changes in older surgical patients. Materials and methods The study protocol and informed consent were approved by the ethical committee of Chinese PLA General Hospital (S202112001) and were registered on the Chinese Clinical Trial Registry (No.2100046299) on May 2021. The previous study protocol was published[ 11 ] and was also provided as the supplementary material. In brief, 128 older patients undergoing elective orthopedic surgery or pancreatic surgery with general anesthesia were randomised to intranasal administration of 40 IU insulin (Group I) or equal volume of normal saline (Group S), respectively, once daily from 5 minutes before anesthesia induction until 3 days postoperatively. The occurrence of POD was evaluated using the 3-minute Diagnostic Interview for CAM (3D-CAM) on days 1 to 3 post-surgery. To avoid missing the occurrence of POD between cognitive assessments, the medical records of patients with suspected POD were reviewed by a neurologist blinded to therapy group assignment and a final determination was made in accordance with Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria[ 11 ]. Additionally, the changes in perioperative cognitive function scores were assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment-Basic (MoCA-B) scales one day before surgery and on the third day after surgery. Fasting venous blood samples were collected from the patients at three time points: one day before surgery, one hour after skin incision during surgery, and one day after surgery. These samples were used to measure blood glucose and insulin levels. The homeostasis model assessment (HOMA) index was calculated using a formula to reflect insulin resistance: HOMA-IR = Fasting Insulin (µU/ml) × Fasting Glucose (mmol/l) / 22.5[ 11 ]. For the current study, 50 patients with T2DM (22 and 28 participants in Group DM-S and Group DM-I, respectively) and 78 patients without T2DM (42 and 36 participants in Group Non-DM-S and Group Non-DM-I, respectively) were included (Fig. 1). The primary outcome in present study was the effect of intranasal insulin on POD incidence during the three days after surgery in older patients with and without T2DM. Secondary outcomes included the effect of intranasal insulin on changes in perioperative cognitive function and HOMA-IR changes during the perioperative period in older patients with and without T2DM. The change in MMSE scores = Postoperative MMSE score - Preoperative MMSE score. The change in MoCA-B scores = Postoperative MoCA-B score - Preoperative MoCA-B score. Statistical analyses were conducted by using SPSS version 26.0. Quantitative data are expressed as mean ± standard deviation (SD) or median (interquartile range) with normal or non-normal distributions, and categorical variables are expressed as number (percentage). Statistical differences within DM or Non-DM groups were determined using Student’s t-test or the Mann Whitney U test for quantitative data with normal or non-normal distributions, respectively. The chi-square test or Fisher’s exact test were used for categorical data analysis within DM or Non-DM groups. Two-way analysis of variance (ANOVA) was used to compare fasting blood glucose, fasting insulin, and HOMA-IR between groups at different time points. Due to the limitations imposed on the statistical analysis by the sample size, univariate and multivariate logistic regression were employed to further determine the effects of intranasal insulin therapy on patients with and without T2DM, specifically observing its impact on POD. Additionally, univariate and multivariate linear regression analyses were used to assess the effects of intranasal insulin therapy on changes in perioperative cognitive function. Due to the limited numbers of POD patients and the fact that only intranasal therapy was significant in the univariate analysis (Supplementary Table 1), the conventional characteristics of age and gender were included in the multivariate analysis. Subgroup analysis for T2DM was conducted in all the regression analyses. P values < 0.05 were regarded as statistically significant. Results Participant characteristics For the present secondary analysis, the 128 patients were grouped into four subgroups: diabetic patients with saline treatment (DM-S), diabetic patients with insulin treatment (DM-I), non diabetic patients with saline treatment (Non-DM-S), non diabetic patients with insulin treatment (Non-DM-I). Among the 128 patients analyzed, the preoperative characteristics were similar between Group DM-S and Group DM-I and between Group Non-DM-S and Group Non-DM-I (Table 1 ). Table 1 Perioperative characteristics of participants Characteristic DM (50) DM-S (22) DM-I (28) P value Non-DM (78) Non-DM-S (42) Non-DM-I (36) P value Age (years) 68.68(2.82) 69.09(3.09) 68.39(2.62) 0.423 68.83(3.74) 68.76(3.92) 68.92(3.57) 0.857 Female (number) 30(60%) 14(63.3%) 16(57.1%) 0.642 49(62.8%) 25(59.5%) 24(66.7%) 0.515 BMI (kg/m 2 ) 25.28(3.40) 24.53(3.31) 25.86(3.42) 0.172 25.94(3.79) 25.50(3.82) 26.45(3.75) 0.272 Education level (> 6 years) 28(56%) 16(72.7%) 12(42.9%) 0.035 43(55.1%) 22(52.4%) 21(58.3%) 0.598 Smoking (number) 8(16%) 3(13.6%) 5(17.9%) 0.686 6(7.7%) 3(7.1%) 3(8.3%) 0.844 Alcohol use (number) 6(12%) 3(13.6%) 3(10.7%) 0.752 9(11.5%) 4(9.5%) 5(13.9%) 0.547 Hypertension (number) 26(52%) 8(36.4%) 18(64.3%) 0.050 45(57.7%) 28(66.7%) 17(47.2%) 0.083 Cardiac disease (number) 4(8%) 1(4.5%) 3(10.7%) 0.425 8(10.3%) 4(9.5%) 4(11.1%) 0.818 Surgery time (min) 186.90 (63.95) 197.23 (69.32) 178.79 (59.40) 0.316 183.99 (62.93) 190.02 (68.41) 176.94 (56.00) 0.364 Postoperative delirium (number) 11(22.0%) 8(36.4%) 3(10.7%) 0.030 12(15.4%) 8(19.0%) 4(11.1%) 0.333 Preoperative MMSE scores 27.38(1.73) 27.41(1.87) 27.36(1.64) 0.917 27.65(1.69) 27.67(1.69) 27.61(1.71) 0.838 Postoperative MMSE scores 27.64(1.87) 27.05(2.36) 28.11(1.23) 0.045 27.62(1.65) 27.31(1.87) 27.97(1.30) 0.077 Changes of MMSE scores 0.26(1.50) −0.36(1.50) 0.75(1.32) 0.008 −0.04(1.44) −0.83(1.41) 0.36(1.38) 0.022 Preoperative MoCA-B scores 23.78(2.33) 23.50(2.43) 24.00(2.28) 0.457 24.37(2.47) 24.33(2.40) 24.42(2.59) 0.883 Postoperative MoCA-B scores 24.30(2.69) 23.36(2.95) 25.04(2.25) 0.028 24.65(2.49) 24.19(2.65) 25.19(2.19) 0.075 Changes of MoCA-B scores 0.52(1.98) −0.14(2.05) 1.04(1.80) 0.037 0.28(1.74) −0.14(1.89) 0.78(1.42) 0.019 Preoperative fasting glucose (mmol/L) 5.15(1.30) 4.83(1.20) 5.41(1.35) 0.119 4.69(0.78) 4.66(0.83) 4.73(0.74) 0.694 Intraoperative fasting glucose (mmol/L) 6.39(2.34) 6.32(2.72) 6.45(2.04) 0.850 5.46(1.48) 5.72(1.43) a 5.17(1.52) 0.102 Postoperative fasting glucose (mmol/L) 7.97(3.00) 7.99(2.90) a 7.96(3.13) a 0.967 6.91(2.18) 7.05(2.54) ab 6.75(1.68) ab 0.550 Preoperative fasting insulin (µU/ml) 12.56(3.30) 12.10(3.06) 12.92(3.49) 0.388 12.33(3.23) 12.50(3.14) 12.17(3.38) 0.661 Intraoperative fasting insulin (µU/ml) 17.82(4.02) 17.03(3.54) a 18.44(4.31) a 0.222 18.15(3.74) 17.64(3.95) a 18.74(3.44) a 0.196 Postoperative fasting insulin (µU/ml) 15.02(3.75) 15.16(3.90) 14.91(3.61) b 0.819 15.65(4.08) 14.92(3.41) ab 16.50(4.66) a 0.088 Preoperative HOMA-IR 2.88(1.08) 2.62(1.06) 3.09(1.07) 0.128 2.56(0.72) 2.59(0.76) 2.53(0.69) 0.713 Intraoperative HOMA-IR 5.04(2.12) 4.66(1.86) a 5.33(2.30) a 0.274 4.36(1.30) 4.40(1.10) a 4.32(1.52) a 0.803 Postoperative HOMA-IR 5.36(2.39) 5.43(2.39) a 5.30(2.42) a 0.854 4.76(1.72) 4.64(1.79) a 4.90(1.66) a 0.509 Categorical variables are expressed as number (percentage); continuous variables are expressed as mean (standard deviation). Changes of perioperative MMSE = Postoperative MMSE - Preoperative MMSE; Changes of perioperative MoCA-B = Postoperative MoCA-B - Preoperative MoCA-B; BMI, body mass index. MMSE, Mini-Mental Status Examination. MoCA-B, Montreal cognitive assessment-Basic. POD, postoperative delirium. HOMA-IR, Homeostasis model assessment − insulin resistance. * P < 0.05; ** P < 0.01; a P < 0.05 vs Preoperative; b P < 0.05 vs Intraoperative. Effect of intranasal insulin treatment on POD in older patients with and without T2DM As shown in Table 1 , the overall incidences of POD in patients with and without T2DM were 22.0% and 15.4%, respectively. And the incidences of POD in Group DM-S, Group DM-I, Group Non-DM-S, Group Non-DM-I were 36.4%, 10.7%, 19% and 11.1%, respectively. There was a higher POD incidence in Group DM-S, and the relative risk (RR) of POD in Group DM-S to Group Non-DM-S is 1.91. However, intranasal insulin treatment significantly decreased the POD incidence in patients with T2DM ( P = 0.030). The POD incidences in Group Non-DM-I were also decreased compared to Group Non-DM-S ( P = 0.333). Univariate and multivariate logistic regression were employed to analyze the impact of intranasal insulin treatment on POD in older patients, as well as the role of T2DM in this context. In the univariate analysis for POD (Table 2 ), the ORs of intranasal insulin treatment were 0.368 (95% CI: 0.132–0.939, P = 0.043), 0.210 (95% CI: 0.041–0.855, P = 0.039), and 0.531 (95% CI: 0.131–1.860, P = 0.338) in total participants, Group DM and Group Non-DM, respectively. In the multivariate logistic regression analyses including age and gender (Table 2 ), the ORs of intranasal insulin treatment were 0.366 (95% CI: 0.131–0.937, P = 0.043), 0.195 (95% CI: 0.036–0.826, P = 0.035), and 0.566 (95% CI: 0.135–2.081, P = 0.404) in total participants, Group DM and Group Non-DM, respectively. The ORs in Group DM were smaller than ORs in total participants and Group Non-DM. And intranasal insulin treatment was an independent protective factor against POD in total participants and patients with T2DM. Table 2 Association between intranasal insulin treatment and POD with logistic regression models Total participants DM Non-DM Model OR 95% CI P value OR 95% CI P value OR 95% CI P value Univariate 0.368 0.132–0.939 0.043 0.210 0.041–0.855 0.039 0.531 0.131–1.860 0.338 Multivariate 0.366 0.131–0.937 0.043 0.195 0.036–0.826 0.035 0.566 0.135–2.081 0.404 OR is the odd ratio of intranasal insulin treatment; Variables in multivariate logistic regression model include age and gender. DM, the group of patients with type 2 diabetes mellitus. Non-DM, the group of patients without type 2 diabetes mellitus. Effect of intranasal insulin treatment on perioperative changes of MMSE scores in older patients with and without T2DM As shown in Table 1 , preoperative MMSE scores were similar between Group DM-S and Group DM-I ( P = 0.917), and between Group Non-DM-S and Group Non-DM-I ( P = 0.838). However, the postoperative MMSE scores in Group DM-I were significantly increased than in Group DM-S ( P = 0.045) while there was no significant difference in postoperative MMSE scores between Group Non-DM-S and Group Non-DM-I ( P = 0.077). What’s more, the perioperative changes of MMSE scores were − 0.36 ± 1.50, 0.75 ± 1.32, -0.83 ± 1.41 and 0.36 ± 1.38 in Group DM-S, Group DM-I, Group Non-DM-S, Group Non-DM-I, respectively. Intranasal insulin treatment significantly improved the perioperative changes of MMSE scores both in Group DM ( P = 0.008) and Group Non-DM ( P = 0.022). As shown in Table 3 , intranasal insulin treatment was positively correlated with perioperative MMSE score changes, according to both univariate (β = 0.906, 95% CI: 0.418–1.394, P < 0.001) and multivariate linear regression analysis (β = 0.890, 95% CI: 0.411–1.370, P < 0.001). In the subgroup analysis, intranasal insulin treatment was both positively correlated with perioperative MMSE score changes in Group DM and Group Non-DM, according to univariate (β DM = 1.114, 95% CI DM : 0.311–1.917, P DM = 0.008; β Non - DM = 0.742, 95% CI Non−DM : 0.110–1.374, P Non−DM = 0.022) and multivariate linear regression analysis (β DM = 1.042, 95% CI DM : 0.230–1.854, P DM = 0.013; β Non - DM = 0.748, 95% CI Non−DM : 0.124–1.373, P Non−DM = 0.019). The β for perioperative changes of MMSE scores in Group DM was higher than in Group Non-DM. Table 3 Association between intranasal insulin treatment and perioperative changes of MMSE scores with linear regression models Total participants DM Non-DM Model β 95% CI P value β 95% CI P value β 95% CI P value Univariate 0.906 0.418–1.394 < 0.001 1.114 0.311–1.917 0.008 0.742 0.110–1.374 0.022 Multivariate 0.890 0.411–1.370 < 0.001 1.042 0.230–1.854 0.013 0.748 0.124–1.373 0.019 β is the standardized regression coefficient of intranasal insulin treatment; Variables in multivariate linear regression model include age and gender. DM, the group of patients with type 2 diabetes mellitus. Non-DM, the group of patients without type 2 diabetes mellitus. MMSE, Mini-Mental Status Examination. Effect of intranasal insulin treatment on perioperative changes of MoCA-B scores in older patients with and without T2DM With the similar trends of MMSE scores, there was no significant difference in preoperative MoCA-B scores between Group DM-S and Group DM-I ( P = 0.457), and between Group Non-DM-S and Group Non-DM-I ( P = 0.883). However, the postoperative MoCA-B scores in Group DM-I were significantly increased than in Group DM-S ( P = 0.028) while there was no significant difference in postoperative MoCA-B scores between Group Non-DM-S and Group Non-DM-I ( P = 0.075). What’s more, the perioperative changes of MoCA-B scores were − 0.14 ± 2.05, 1.04 ± 1.80, -0.14 ± 1.89 and 0.78 ± 1.42 in Group DM-S, Group DM-I, Group Non-DM-S, Group Non-DM-I, respectively. Intranasal insulin treatment significantly improved the perioperative changes of MoCA-B scores both in Group DM ( P = 0.037) and Group Non-DM ( P = 0.019). As shown in Table 4 , intranasal insulin treatment was positively correlated with perioperative MoCA-B score changes, according to both univariate (β = 1.031, 95% CI: 0.413–1.650, P = 0.001) and multivariate linear regression analysis (β = 1.037, 95% CI: 0.414–1.659, P = 0.001). In the subgroup analysis, intranasal insulin treatment was both positively correlated with perioperative MoCA-B score changes in Group DM and Group Non-DM, according to univariate (β DM = 1.172, 95% CI DM : 0.077–2.268, P DM = 0.036; β Non - DM = 0.921, 95% CI Non−DM : 0.156–1.686, P Non−DM = 0.019) and multivariate linear regression analysis (β DM = 1.093, 95% CI DM : 0.013–2.173, P DM = 0.047; β Non - DM = 0.887, 95% CI Non−DM : 0.116–1.658, P Non−DM = 0.025). The β for perioperative changes of MoCA-B scores in Group DM was higher than in Group Non-DM. Table 4 Association between intranasal insulin treatment and perioperative changes of MoCA-B scores with linear regression models Total participants DM Non-DM Model β 95% CI P value β 95% CI P value β 95% CI P value Univariate 1.031 0.413–1.650 0.001 1.172 0.077–2.268 0.036 0.921 0.156–1.686 0.019 Multivariate 1.037 0.414–1.659 0.001 1.093 0.013–2.173 0.047 0.887 0.116–1.658 0.025 β is the standardized regression coefficient of intranasal insulin treatment; Variables in multivariate linear regression model include age and gender. DM, the group of patients with type 2 diabetes mellitus. Non-DM, the group of patients without type 2 diabetes mellitus. MoCA-B, Montreal cognitive assessment-Basic. Effect of intranasal insulin treatment on levels of fasting glucose, fasting insulin and HOMA-IR in older patients with and without T2DM To further explore the effect of intranasal insulin treatment on peripheral glucose metabolism in older patients with and without T2DM, the perioperative levels of fasting glucose, fasting insulin and HOMA-IR were analyzed. As shown in Table 1 , there was no statistical difference in perioperative levels of fasting glucose, fasting insulin, or HOMA-IR values between Group DM-S and Group DM-I, and between Group Non-DM-S and Group Non-DM-I. What’s more, in all groups, the intraoperative and postoperative HOMA-IR values were significantly increased compared to baseline. However, in the DMI group, HOMA-IR values decreased after surgery compared to the intraoperative levels, while in all other groups, HOMA-IR values increased after surgery compared to the intraoperative levels. This result was due to a significant decrease in fasting insulin levels in Group DM-I after surgery compared to introperative levels. Discussion The global diabetic patients in 2019 were estimated to be 463 million, rising to 578 million by 2030 and 700 million by 2045. And 50.1% of people living with diabetes didn’t know that they have diabetes[ 6 ]. As reported, T2DM accounts for more than 90% of all diabetes cases and approximately 50% of all patients with T2DM will undergo surgery at some points in their lifetime[ 4 ]. Moreover, diabetic patients are considered a high-risk group for cognitive impairment due to a combination of factors including metabolic disturbances, vascular complications, increased comorbidity, polypharmacy, and a heightened inflammatory response[ 14 ]. Research has shown that these factors contribute to a higher incidence of POD in diabetic patients, especially following complex surgeries or in the presence of multiple comorbid conditions[ 5 ]. In present study, older diabetic patients without intranasal insulin treatment had the highest incidence of POD among the groups, indicating that T2DM is indeed a high risk for POD. Therefore, the clinical prevention and management of POD in older patients with T2DM have significant clinical importance. Insulin resistance (IR), as the primary pathological mechanism of T2DM, is mainly characterized by a decreased sensitivity of the body to insulin[ 7 ]. Our previous research indicated that the severity of IR was closely associated with POD in older patients with T2DM[ 2 ]. As insulin plays a crucial physiological role in the brain, leading to the concept of brain IR, characterized by reduced sensitivity to insulin in the brain, relative insulin deficiency, and decreased glucose metabolism[ 15 ]. Brain IR has been identified as a key pathological mechanism underlying cognitive decline in AD and T2DM[ 15 ]. Therefore, addressing the relative insufficiency of brain insulin levels associated with this resistance by supplementing central insulin levels can improve cognitive function. Our previous animal studies found that intracerebroventricular injection of insulin can improve cognitive impairment caused by neuroinflammation by regulating glucose metabolism and inhibiting ferroptosis[ 9 , 10 ]. Previous studies have also reported that intranasal insulin therapy can improve postoperative cognitive dysfunction in mice induced by surgery and anesthesia[ 16 , 17 ]. Therefore, we attempted to use central insulin supplementation in a clinical study to improve POD. Multiple studies have shown that administering a specific dose of intranasal insulin can rapidly increase central insulin levels via transport through the olfactory and trigeminal nerve pathways without affecting peripheral insulin and blood glucose levels[ 18 ]. This method has demonstrated cognitive improvement in patients with AD and mild cognitive impairment (MCI)[ 19 ]. Additionally, since POD shares similar pathological mechanisms and clinical manifestations with AD[ 20 ], intranasal insulin therapy may have a potential therapeutic effect on POD. Therefore, we conducted a RCT to observe the effects of intranasal insulin therapy on postoperative cognitive function and POD in older patients. The results found that intranasal insulin therapy could enhance postoperative cognitive function scores and reduce the incidence of POD in older patients[ 11 ]. Currently, other studies utilizing intranasal insulin therapy for POD have reached similar conclusions[ 12 , 13 ], but the number of studies is limited, and there have been no studies specifically targeting diabetic patients. Therefore, we conducted a secondary analysis of previous RCT data to examine the impact of intranasal insulin therapy on the incidence of POD in patients with and without T2DM. In our previous RCT study, we did not exclude diabetic patients because we aimed to observe the safety and glycemic effects of intranasal insulin application in diabetic patients. Although our initial study was conducted according to the experimental protocol without specifically including diabetic patients, nearly 40% of the final participants were diabetic. This allowed us to conduct a secondary analysis using diabetes as a subgroup. In this study, older patients with T2DM exhibited a higher incidence of POD compared to non-diabetic older patients, and intranasal insulin therapy showed a more significant improvement in POD among older patients with T2DM. This suggests that intranasal insulin therapy could be a potential preventative and therapeutic approach for POD in older patients with T2DM. However, due to the limited sample size, these results could not be validated with more precise statistical methods. Hence we are planning a dedicated clinical trial to validate this finding. In the previous RCT study, the primary outcome was the change in perioperative cognitive scores[ 11 ]. However, due to potential learning effects, our participants did not exhibit a significant decline in postoperative cognitive scores compared to other studies[ 21 , 22 ]. Therefore, in this secondary analysis, we focused on POD as the primary outcome to better demonstrate the therapeutic effects of intranasal insulin therapy in older patients with and without T2DM. Consistent with previous results, intranasal insulin therapy did not significantly affect perioperative insulin and blood glucose levels in older patients, regardless of diabetic status. This indicates that while intranasal insulin therapy may not improve insulin resistance in diabetic and non-diabetic patients, it possesses good safety. Although the study results suggest that intranasal insulin therapy significantly improves POD and postoperative cognitive function in older patients with T2DM, there are several limitations to this research. First, as a secondary analysis, this study faced sample size limitations due to the initial trial design not accounting for subgroup analyses, which restricted the ability to conduct complex multigroup comparisons. Despite this, these findings are clinically significant and lay the groundwork for further research on intranasal insulin therapy for POD in older patients with T2DM. Second, the lack of some critical case data, such as missing glycated hemoglobin information for diabetic patients, along with the small overall sample size and number of POD occurrences, hindered the ability to conduct comprehensive multivariate logistic regression analysis for the incidence of POD in diabetic patients. Consequently, only two common variables, gender and age, were included in the multivariate logistic regression analysis. Future clinical studies could utilize relevant retrospective database information and conduct targeted prospective studies to further explore the key risk factors for POD in older patients with T2DM. Conclusions Intranasal insulin therapy had shown to improve POD in older patients with T2DM and potentially offered better therapeutic effects on postoperative cognitive function compared to non-T2DM older patients. Based on the results of this study, a foundation is established for future clinical research to further explore the impact of intranasal insulin therapy on POD in older T2DM patients. Abbreviations POD Postoperative Delirium RCT Randomized Controlled Trial DM Diabetes Mellitus T2DM Type 2 Diabetes Mellitus AD Alzheimer's Disease MCI Mild Cognitive Impairment 3D-CAM 3-minute Diagnostic Interview for Confusion Assessment Method MMSE Mini-Mental State Examination MoCA-B Montreal Cognitive Assessment-Basic DSM-IV Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition HOMA-IR Homeostatic Model Assessment for Insulin Resistance IR Insulin Resistance[1] Declarations Ethics approval and consent to participate The study protocol and informed consent forms were approved by the Ethics Committee of Chinese PLA General Hospital (Approval No. S2021-120-01). Written informed consent was obtained from all participants prior to enrollment. For participants with impaired decision-making capacity, consent was obtained from legally authorized representatives. This study was conducted in compliance with the Declaration of Helsinki (https://www.wma.net/policies-post/wma-declaration-of-helsinki/) and all methods were performed in accordance with relevant guidelines and regulations. Consent for publication Not Applicable. Availability of data and materials The datasets collected and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing of interests The authors declare that they have no competing interests. Funding None. Author contributions Conception and design: Miao Sun, Weidong Mi, Yulong Ma. Provision of study materials or patients: Xianghan Ruan. Collection and assembly of data: Huikai Yang, Lulu Zhou. Data analysis and interpretation: Mengyao Qu, Yanan He. Manuscript writing: Danyang Geng, Yan Tian. Final approval of manuscript: All authors Acknowledgements None. References Li T, Li J, Yuan L, et al. Effect of Regional vs General Anesthesia on Incidence of Postoperative Delirium in Older Patients Undergoing Hip Fracture Surgery: The RAGA Randomized Trial. JAMA. 2022;327(1):50–8. Sun M, Liu M, Zhang F, et al. Triglyceride-glucose index predicts postoperative delirium in elderly patients with type 2 diabetes mellitus: a retrospective cohort study. Lipids Health Dis. 2024;23(1):107. Jin Z, Hu J, Ma D. Postoperative delirium: perioperative assessment, risk reduction, and management. Br J Anaesth. 2020;125(4):492–504. Drayton DJ, Birch RJ, D'Souza-Ferrer C, Ayres M, Howell SJ, Ajjan RA. Diabetes mellitus and perioperative outcomes: a scoping review of the literature. Br J Anaesth. 2022;128(5):817–28. Feinkohl I, Winterer G, Pischon T. Diabetes is associated with risk of postoperative cognitive dysfunction: A meta-analysis. Diabetes Metab Res Rev. 2017;33(5). Sun H, Saeedi P, Karuranga S, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119. Chen W, Cai W, Hoover B, Kahn CR. Insulin action in the brain: cell types, circuits, and diseases. Trends Neurosci. 2022;45(5):384–400. Kellar D, Craft S. Brain insulin resistance in Alzheimer's disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol. 2020;19(9):758–66. Sun M, Li Y, Liu M, et al. Insulin alleviates lipopolysaccharide-induced cognitive impairment via inhibiting neuroinflammation and ferroptosis. Eur J Pharmacol. 2023;955:175929. Sun M, Liu M, Li Q, et al. Insulin attenuates LPS-induced cognitive impairment and ferroptosis through regulation of glucose metabolism in hippocampus. CNS Neurosci Ther. 2024;30(7):e14887. Sun M, Ruan X, Zhou Z, et al. Effect of intranasal insulin on perioperative cognitive function in older adults: a randomized, placebo-controlled, double-blind clinical trial. Age Ageing. 2024;53(9):afae188. Huang Q, Li Q, Qin F, et al. Repeated Preoperative Intranasal Administration of Insulin Decreases the Incidence of Postoperative Delirium in Elderly Patients Undergoing Laparoscopic Radical Gastrointestinal Surgery: A Randomized, Placebo-Controlled, Double-Blinded Clinical Study. Am J Geriatr Psychiatry. 2021;29(12):1202–11. Huang Q, Wu X, Lei N, et al. Effects of Intranasal Insulin Pretreatment on Preoperative Sleep Quality and Postoperative Delirium in Patients Undergoing Valve Replacement for Rheumatic Heart Disease. Nat Sci Sleep. 2024;16:613–23. Michailidis M, Moraitou D, Tata DA, et al. Alzheimer's Disease as Type 3 Diabetes: Common Pathophysiological Mechanisms between Alzheimer's Disease and Type 2 Diabetes. Int J Mol Sci. 2022;23(5):2687. Arnold SE, Arvanitakis Z, Macauley-Rambach SL, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14(3):168–81. Roque PS, Hooshmandi M, Neagu-Lund L, et al. Intranasal insulin rescues repeated anesthesia-induced deficits in synaptic plasticity and memory and prevents apoptosis in neonatal mice via mTORC1. Sci Rep. 2021;11(1):15490. Zhang Y, Dai CL, Chen Y, et al. Intranasal Insulin Prevents Anesthesia-Induced Spatial Learning and Memory Deficit in Mice. Sci Rep. 2016;6:21186. Hallschmid M. Intranasal Insulin for Alzheimer's Disease. CNS Drugs. 2021;35(1):21–37. Avgerinos KI, Kalaitzidis G, Malli A, et al. Intranasal insulin in Alzheimer's dementia or mild cognitive impairment: a systematic review. J Neurol. 2018;265(7):1497–510. Lu J, Liang F, Bai P, et al. Blood tau-PT217 contributes to the anesthesia/surgery-induced delirium-like behavior in aged mice. Alzheimers Dement. 2023;19(9):4110–26. Brattinga B, Plas M, Spikman JM, et al. The link between the early surgery-induced inflammatory response and postoperative cognitive dysfunction in older patients. J Am Geriatr Soc. 2024;72(5):1360–72. Wang P, Yin X, Chen G, et al. Perioperative probiotic treatment decreased the incidence of postoperative cognitive impairment in elderly patients following non-cardiac surgery: A randomised double-blind and placebo-controlled trial. Clin Nutr. 2021;40(1):64–71. Additional Declarations No competing interests reported. Supplementary Files Supplementarytable1.docx CONSORT2010Checklist.doc strocss2021.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 24 Aug, 2025 Reviewers invited by journal 08 Aug, 2025 Editor assigned by journal 05 Aug, 2025 Editor invited by journal 16 Jul, 2025 Submission checks completed at journal 14 Jul, 2025 First submitted to journal 14 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7097922","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":498250060,"identity":"e89b2120-82ce-48e1-bcf9-ee74d097a5b7","order_by":0,"name":"Danyang Geng","email":"","orcid":"","institution":"The First Medical Center of Chinese PLA General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Danyang","middleName":"","lastName":"Geng","suffix":""},{"id":498250061,"identity":"a7524737-44cb-4aa5-9ddb-3f92ec9ef708","order_by":1,"name":"Xianghan Ruan","email":"","orcid":"","institution":"The First Medical Center of Chinese 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10:42:38","extension":"doc","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":199192,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORT2010Checklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-7097922/v1/09a660582e07022f6d5bbe06.doc"},{"id":89066602,"identity":"f1a1c38d-57eb-4db1-9984-a82b1a415942","added_by":"auto","created_at":"2025-08-14 10:42:45","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":33235,"visible":true,"origin":"","legend":"","description":"","filename":"strocss2021.docx","url":"https://assets-eu.researchsquare.com/files/rs-7097922/v1/2c38816446471a50a993e25d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of Intranasal Insulin on Postoperative Delirium in Older Patients with and without Type 2 Diabetes Mellitus: A Secondary Analysis of a Randomized Clinical Trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePostoperative delirium (POD) is an acute cognitive disorder characterized by fluctuating disturbances in attention, consciousness, and perception[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. POD is a common complication, particularly among older adults undergoing major surgery[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The incidence varies widely, with reports suggesting that 10\u0026ndash;50% of older surgical patients may experience POD[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. POD is associated with higher mortality rates, prolonged hospital stay, increased healthcare costs[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Therefore, the prevention and management of POD is a key focus in the field of anesthesiology.\u003c/p\u003e\u003cp\u003eThe exact mechanisms underlying POD are not fully understood and the main risk factors for POD include advanced age, preexisting cognitive impairment, severe illness or comorbidities, type and duration of surgery, postoperative pain and opioid use, sleep deprivation and electrolyte imbalance[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, while no drug is specifically approved for POD prevention, careful management of medications, including minimizing the use of deliriogenic drugs such as benzodiazepines and anticholinergics, is crucial[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Some studies explore the use of antipsychotics and melatonin, but results were mixed and should be used with caution[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Therefore, identifying high-risk patients through comprehensive preoperative assessments, including cognitive evaluations, can guide tailored interventions.\u003c/p\u003e\u003cp\u003ePatients with type 2 diabetes mellitus (T2DM) are at an increased risk for more frequent and severe postoperative complications compared to non-diabetic individuals[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. As a common complication in older surgical patients, T2DM is also a significant risk factor for POD[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Moreover, as of 2021, the global prevalence of DM had reached 536.6\u0026nbsp;million individuals, with approximately half of these patients likely to require surgical intervention at some point during their lifetime[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Therefore, individuals with T2DM are considered a high-risk group for POD, and research on prevention and management strategies for POD in patients with T2DM holds significant clinical importance.\u003c/p\u003e\u003cp\u003eInsulin in the brain plays several important roles beyond its well-known functions in glucose metabolism, including neurotransmitter regulation, synaptic plasticity and cognition, neuroprotection, cell growth and survival[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Intranasal administration of insulin can rapidly, safely, and effectively increase insulin levels in the brain and has shown cognitive improvement in studies involving Alzheimer's disease (AD) patients[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Additionally, our previous animal studies had indicated that supplementing brain insulin levels can alleviate cognitive dysfunction and ferroptosis mediated by neuroinflammation[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], which are important mechanisms of POD. Therefore, research on the effects of intranasal insulin on postoperative cognitive function changes and POD in older patients was conducted, and the results demonstrated that intranasal insulin treatment could reduce the incidence of POD in older surgical patients[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, the therapeutic effect of intranasal insulin on POD in older patients with T2DM remains unclear.\u003c/p\u003e\u003cp\u003eIn this study, we hypothesized that the incidence of POD in diabetic patients is higher than in non-diabetic patients, and that intranasal insulin treatment had a more pronounced effect on preventing POD in patients with T2DM. Therefore, we conducted a subgroup analysis of the participants from a previous randomized clinical trial (RCT), categorizing them based on the presence or absence of T2DM, to observe the impact of intranasal insulin on the incidence of POD and perioperative cognitive changes in older surgical patients.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e The study protocol and informed consent were approved by the ethical committee of Chinese PLA General Hospital (S202112001) and were registered on the Chinese Clinical Trial Registry (No.2100046299) on May 2021. The previous study protocol was published[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] and was also provided as the supplementary material. In brief, 128 older patients undergoing elective orthopedic surgery or pancreatic surgery with general anesthesia were randomised to intranasal administration of 40 IU insulin (Group I) or equal volume of normal saline (Group S), respectively, once daily from 5 minutes before anesthesia induction until 3 days postoperatively.\u003c/p\u003e\u003cp\u003eThe occurrence of POD was evaluated using the 3-minute Diagnostic Interview for CAM (3D-CAM) on days 1 to 3 post-surgery. To avoid missing the occurrence of POD between cognitive assessments, the medical records of patients with suspected POD were reviewed by a neurologist blinded to therapy group assignment and a final determination was made in accordance with Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Additionally, the changes in perioperative cognitive function scores were assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment-Basic (MoCA-B) scales one day before surgery and on the third day after surgery.\u003c/p\u003e\u003cp\u003eFasting venous blood samples were collected from the patients at three time points: one day before surgery, one hour after skin incision during surgery, and one day after surgery. These samples were used to measure blood glucose and insulin levels. The homeostasis model assessment (HOMA) index was calculated using a formula to reflect insulin resistance: HOMA-IR\u0026thinsp;=\u0026thinsp;Fasting Insulin (\u0026micro;U/ml) \u0026times; Fasting Glucose (mmol/l) / 22.5[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFor the current study, 50 patients with T2DM (22 and 28 participants in Group DM-S and Group DM-I, respectively) and 78 patients without T2DM (42 and 36 participants in Group Non-DM-S and Group Non-DM-I, respectively) were included (Fig.\u0026nbsp;1). The primary outcome in present study was the effect of intranasal insulin on POD incidence during the three days after surgery in older patients with and without T2DM. Secondary outcomes included the effect of intranasal insulin on changes in perioperative cognitive function and HOMA-IR changes during the perioperative period in older patients with and without T2DM. The change in MMSE scores\u0026thinsp;=\u0026thinsp;Postoperative MMSE score - Preoperative MMSE score. The change in MoCA-B scores\u0026thinsp;=\u0026thinsp;Postoperative MoCA-B score - Preoperative MoCA-B score.\u003c/p\u003e\u003cp\u003eStatistical analyses were conducted by using SPSS version 26.0. Quantitative data are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or median (interquartile range) with normal or non-normal distributions, and categorical variables are expressed as number (percentage). Statistical differences within DM or Non-DM groups were determined using Student\u0026rsquo;s t-test or the Mann Whitney U test for quantitative data with normal or non-normal distributions, respectively. The chi-square test or Fisher\u0026rsquo;s exact test were used for categorical data analysis within DM or Non-DM groups. Two-way analysis of variance (ANOVA) was used to compare fasting blood glucose, fasting insulin, and HOMA-IR between groups at different time points. Due to the limitations imposed on the statistical analysis by the sample size, univariate and multivariate logistic regression were employed to further determine the effects of intranasal insulin therapy on patients with and without T2DM, specifically observing its impact on POD. Additionally, univariate and multivariate linear regression analyses were used to assess the effects of intranasal insulin therapy on changes in perioperative cognitive function. Due to the limited numbers of POD patients and the fact that only intranasal therapy was significant in the univariate analysis (Supplementary Table\u0026nbsp;1), the conventional characteristics of age and gender were included in the multivariate analysis. Subgroup analysis for T2DM was conducted in all the regression analyses. \u003cem\u003eP\u003c/em\u003e values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were regarded as statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eParticipant characteristics\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFor the present secondary analysis, the 128 patients were grouped into four subgroups: diabetic patients with saline treatment (DM-S), diabetic patients with insulin treatment (DM-I), non diabetic patients with saline treatment (Non-DM-S), non diabetic patients with insulin treatment (Non-DM-I). Among the 128 patients analyzed, the preoperative characteristics were similar between Group DM-S and Group DM-I and between Group Non-DM-S and Group Non-DM-I (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePerioperative characteristics of participants\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDM\u003c/p\u003e\u003cp\u003e(50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDM-S\u003c/p\u003e\u003cp\u003e(22)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDM-I\u003c/p\u003e\u003cp\u003e(28)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNon-DM\u003c/p\u003e\u003cp\u003e(78)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNon-DM-S (42)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNon-DM-I (36)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e68.68(2.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e69.09(3.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e68.39(2.62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.423\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e68.83(3.74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e68.76(3.92)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e68.92(3.57)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.857\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale (number)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30(60%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14(63.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16(57.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.642\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e49(62.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e25(59.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e24(66.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.515\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25.28(3.40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24.53(3.31)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25.86(3.42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.172\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e25.94(3.79)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e25.50(3.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e26.45(3.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.272\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEducation level (\u0026gt;\u0026thinsp;6 years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28(56%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16(72.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12(42.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.035\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e43(55.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e22(52.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e21(58.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.598\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSmoking (number)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8(16%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3(13.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5(17.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.686\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e6(7.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e3(7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e3(8.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.844\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlcohol use (number)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6(12%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3(13.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3(10.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.752\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e9(11.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4(9.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e5(13.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.547\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension (number)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26(52%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8(36.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e18(64.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.050\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e45(57.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e28(66.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e17(47.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.083\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiac disease (number)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4(8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1(4.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3(10.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.425\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e8(10.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4(9.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e4(11.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.818\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSurgery time (min)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e186.90\u003c/p\u003e\u003cp\u003e(63.95)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e197.23\u003c/p\u003e\u003cp\u003e(69.32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e178.79\u003c/p\u003e\u003cp\u003e(59.40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.316\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e183.99\u003c/p\u003e\u003cp\u003e(62.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e190.02\u003c/p\u003e\u003cp\u003e(68.41)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e176.94\u003c/p\u003e\u003cp\u003e(56.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.364\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostoperative delirium (number)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11(22.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8(36.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3(10.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.030\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e12(15.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e8(19.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e4(11.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.333\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePreoperative MMSE scores\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27.38(1.73)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27.41(1.87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e27.36(1.64)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.917\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e27.65(1.69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e27.67(1.69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e27.61(1.71)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.838\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostoperative MMSE scores\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27.64(1.87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27.05(2.36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28.11(1.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.045\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e27.62(1.65)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e27.31(1.87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e27.97(1.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.077\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChanges of MMSE scores\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.26(1.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026minus;0.36(1.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.75(1.32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026minus;0.04(1.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026minus;0.83(1.41)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.36(1.38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.022\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePreoperative MoCA-B scores\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23.78(2.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23.50(2.43)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e24.00(2.28)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.457\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e24.37(2.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e24.33(2.40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e24.42(2.59)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.883\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostoperative MoCA-B scores\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24.30(2.69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23.36(2.95)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25.04(2.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.028\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e24.65(2.49)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e24.19(2.65)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e25.19(2.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.075\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChanges of MoCA-B scores\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.52(1.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026minus;0.14(2.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.04(1.80)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.037\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.28(1.74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026minus;0.14(1.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.78(1.42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.019\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePreoperative fasting glucose (mmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.15(1.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.83(1.20)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.41(1.35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4.69(0.78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4.66(0.83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e4.73(0.74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.694\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntraoperative fasting glucose (mmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.39(2.34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.32(2.72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.45(2.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.850\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e5.46(1.48)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e5.72(1.43)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e5.17(1.52)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.102\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostoperative fasting glucose (mmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.97(3.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.99(2.90)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.96(3.13)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.967\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e6.91(2.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e7.05(2.54)\u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e6.75(1.68)\u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.550\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePreoperative fasting insulin (\u0026micro;U/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12.56(3.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.10(3.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12.92(3.49)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.388\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e12.33(3.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e12.50(3.14)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e12.17(3.38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.661\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntraoperative fasting insulin (\u0026micro;U/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17.82(4.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17.03(3.54)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e18.44(4.31)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.222\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e18.15(3.74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e17.64(3.95)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e18.74(3.44)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.196\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostoperative fasting insulin (\u0026micro;U/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15.02(3.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15.16(3.90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14.91(3.61)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.819\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e15.65(4.08)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e14.92(3.41)\u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e16.50(4.66)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.088\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePreoperative HOMA-IR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.88(1.08)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.62(1.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.09(1.07)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.128\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.56(0.72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.59(0.76)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e2.53(0.69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.713\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntraoperative HOMA-IR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.04(2.12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.66(1.86)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.33(2.30)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.274\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4.36(1.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4.40(1.10)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e4.32(1.52)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.803\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostoperative HOMA-IR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.36(2.39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.43(2.39)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.30(2.42)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.854\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4.76(1.72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4.64(1.79)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e4.90(1.66)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.509\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003eCategorical variables are expressed as number (percentage); continuous variables are expressed as mean (standard deviation). Changes of perioperative MMSE\u0026thinsp;=\u0026thinsp;Postoperative MMSE - Preoperative MMSE; Changes of perioperative MoCA-B\u0026thinsp;=\u0026thinsp;Postoperative MoCA-B - Preoperative MoCA-B; BMI, body mass index. MMSE, Mini-Mental Status Examination. MoCA-B, Montreal cognitive assessment-Basic. POD, postoperative delirium. HOMA-IR, Homeostasis model assessment\u0026thinsp;\u0026minus;\u0026thinsp;insulin resistance. \u003cb\u003e*\u003c/b\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05; \u003cb\u003e**\u003c/b\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; \u003csup\u003ea\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 vs Preoperative; \u003csup\u003eb\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 vs Intraoperative.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eEffect of intranasal insulin treatment on POD in older patients with and without T2DM\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the overall incidences of POD in patients with and without T2DM were 22.0% and 15.4%, respectively. And the incidences of POD in Group DM-S, Group DM-I, Group Non-DM-S, Group Non-DM-I were 36.4%, 10.7%, 19% and 11.1%, respectively. There was a higher POD incidence in Group DM-S, and the relative risk (RR) of POD in Group DM-S to Group Non-DM-S is 1.91. However, intranasal insulin treatment significantly decreased the POD incidence in patients with T2DM (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030). The POD incidences in Group Non-DM-I were also decreased compared to Group Non-DM-S (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.333).\u003c/p\u003e\u003cp\u003eUnivariate and multivariate logistic regression were employed to analyze the impact of intranasal insulin treatment on POD in older patients, as well as the role of T2DM in this context. In the univariate analysis for POD (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), the ORs of intranasal insulin treatment were 0.368 (95% CI: 0.132\u0026ndash;0.939, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043), 0.210 (95% CI: 0.041\u0026ndash;0.855, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.039), and 0.531 (95% CI: 0.131\u0026ndash;1.860, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.338) in total participants, Group DM and Group Non-DM, respectively. In the multivariate logistic regression analyses including age and gender (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), the ORs of intranasal insulin treatment were 0.366 (95% CI: 0.131\u0026ndash;0.937, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043), 0.195 (95% CI: 0.036\u0026ndash;0.826, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.035), and 0.566 (95% CI: 0.135\u0026ndash;2.081, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.404) in total participants, Group DM and Group Non-DM, respectively. The ORs in Group DM were smaller than ORs in total participants and Group Non-DM. And intranasal insulin treatment was an independent protective factor against POD in total participants and patients with T2DM.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAssociation between intranasal insulin treatment and POD with logistic regression models\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eTotal participants\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u003cp\u003eDM\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e\u003cp\u003eNon-DM\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eUnivariate\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.368\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.132\u0026ndash;0.939\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.043\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.210\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.041\u0026ndash;0.855\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.039\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.531\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.131\u0026ndash;1.860\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.338\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMultivariate\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.366\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.131\u0026ndash;0.937\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.043\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.195\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.036\u0026ndash;0.826\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.035\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.566\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.135\u0026ndash;2.081\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.404\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003eOR is the odd ratio of intranasal insulin treatment; Variables in multivariate logistic regression model include age and gender. DM, the group of patients with type 2 diabetes mellitus. Non-DM, the group of patients without type 2 diabetes mellitus.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eEffect of intranasal insulin treatment on perioperative changes of MMSE scores in older patients with and without T2DM\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, preoperative MMSE scores were similar between Group DM-S and Group DM-I (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.917), and between Group Non-DM-S and Group Non-DM-I (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.838). However, the postoperative MMSE scores in Group DM-I were significantly increased than in Group DM-S (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.045) while there was no significant difference in postoperative MMSE scores between Group Non-DM-S and Group Non-DM-I (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.077). What\u0026rsquo;s more, the perioperative changes of MMSE scores were \u0026minus;\u0026thinsp;0.36\u0026thinsp;\u0026plusmn;\u0026thinsp;1.50, 0.75\u0026thinsp;\u0026plusmn;\u0026thinsp;1.32, -0.83\u0026thinsp;\u0026plusmn;\u0026thinsp;1.41 and 0.36\u0026thinsp;\u0026plusmn;\u0026thinsp;1.38 in Group DM-S, Group DM-I, Group Non-DM-S, Group Non-DM-I, respectively. Intranasal insulin treatment significantly improved the perioperative changes of MMSE scores both in Group DM (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008) and Group Non-DM (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022).\u003c/p\u003e\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, intranasal insulin treatment was positively correlated with perioperative MMSE score changes, according to both univariate (β\u0026thinsp;=\u0026thinsp;0.906, 95% CI: 0.418\u0026ndash;1.394, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and multivariate linear regression analysis (β\u0026thinsp;=\u0026thinsp;0.890, 95% CI: 0.411\u0026ndash;1.370, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In the subgroup analysis, intranasal insulin treatment was both positively correlated with perioperative MMSE score changes in Group DM and Group Non-DM, according to univariate (β\u003csub\u003eDM\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.114, 95% CI\u003csub\u003eDM\u003c/sub\u003e: 0.311\u0026ndash;1.917, \u003cem\u003eP\u003c/em\u003e\u003csub\u003eDM\u003c/sub\u003e = 0.008; β\u003csub\u003eNon\u003c/sub\u003e-\u003csub\u003eDM\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.742, 95% CI\u003csub\u003eNon\u0026minus;DM\u003c/sub\u003e: 0.110\u0026ndash;1.374, \u003cem\u003eP\u003c/em\u003e\u003csub\u003eNon\u0026minus;DM\u003c/sub\u003e = 0.022) and multivariate linear regression analysis (β\u003csub\u003eDM\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.042, 95% CI\u003csub\u003eDM\u003c/sub\u003e: 0.230\u0026ndash;1.854, \u003cem\u003eP\u003c/em\u003e\u003csub\u003eDM\u003c/sub\u003e = 0.013; β\u003csub\u003eNon\u003c/sub\u003e-\u003csub\u003eDM\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.748, 95% CI\u003csub\u003eNon\u0026minus;DM\u003c/sub\u003e: 0.124\u0026ndash;1.373, \u003cem\u003eP\u003c/em\u003e\u003csub\u003eNon\u0026minus;DM\u003c/sub\u003e = 0.019). The β for perioperative changes of MMSE scores in Group DM was higher than in Group Non-DM.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAssociation between intranasal insulin treatment and perioperative changes of MMSE scores with linear regression models\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eTotal participants\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u003cp\u003eDM\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e\u003cp\u003eNon-DM\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eβ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eβ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eβ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eUnivariate\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.906\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.418\u0026ndash;1.394\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.114\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.311\u0026ndash;1.917\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.742\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.110\u0026ndash;1.374\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.022\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMultivariate\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.890\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.411\u0026ndash;1.370\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.042\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.230\u0026ndash;1.854\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.748\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.124\u0026ndash;1.373\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.019\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003eβ is the standardized regression coefficient of intranasal insulin treatment; Variables in multivariate linear regression model include age and gender. DM, the group of patients with type 2 diabetes mellitus. Non-DM, the group of patients without type 2 diabetes mellitus. MMSE, Mini-Mental Status Examination.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eEffect of intranasal insulin treatment on perioperative changes of MoCA-B scores in older patients with and without T2DM\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWith the similar trends of MMSE scores, there was no significant difference in preoperative MoCA-B scores between Group DM-S and Group DM-I (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.457), and between Group Non-DM-S and Group Non-DM-I (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.883). However, the postoperative MoCA-B scores in Group DM-I were significantly increased than in Group DM-S (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.028) while there was no significant difference in postoperative MoCA-B scores between Group Non-DM-S and Group Non-DM-I (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.075). What\u0026rsquo;s more, the perioperative changes of MoCA-B scores were \u0026minus;\u0026thinsp;0.14\u0026thinsp;\u0026plusmn;\u0026thinsp;2.05, 1.04\u0026thinsp;\u0026plusmn;\u0026thinsp;1.80, -0.14\u0026thinsp;\u0026plusmn;\u0026thinsp;1.89 and 0.78\u0026thinsp;\u0026plusmn;\u0026thinsp;1.42 in Group DM-S, Group DM-I, Group Non-DM-S, Group Non-DM-I, respectively. Intranasal insulin treatment significantly improved the perioperative changes of MoCA-B scores both in Group DM (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037) and Group Non-DM (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019).\u003c/p\u003e\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, intranasal insulin treatment was positively correlated with perioperative MoCA-B score changes, according to both univariate (β\u0026thinsp;=\u0026thinsp;1.031, 95% CI: 0.413\u0026ndash;1.650, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) and multivariate linear regression analysis (β\u0026thinsp;=\u0026thinsp;1.037, 95% CI: 0.414\u0026ndash;1.659, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). In the subgroup analysis, intranasal insulin treatment was both positively correlated with perioperative MoCA-B score changes in Group DM and Group Non-DM, according to univariate (β\u003csub\u003eDM\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.172, 95% CI\u003csub\u003eDM\u003c/sub\u003e: 0.077\u0026ndash;2.268, \u003cem\u003eP\u003c/em\u003e\u003csub\u003eDM\u003c/sub\u003e = 0.036; β\u003csub\u003eNon\u003c/sub\u003e-\u003csub\u003eDM\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.921, 95% CI\u003csub\u003eNon\u0026minus;DM\u003c/sub\u003e: 0.156\u0026ndash;1.686, \u003cem\u003eP\u003c/em\u003e\u003csub\u003eNon\u0026minus;DM\u003c/sub\u003e = 0.019) and multivariate linear regression analysis (β\u003csub\u003eDM\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.093, 95% CI\u003csub\u003eDM\u003c/sub\u003e: 0.013\u0026ndash;2.173, \u003cem\u003eP\u003c/em\u003e\u003csub\u003eDM\u003c/sub\u003e = 0.047; β\u003csub\u003eNon\u003c/sub\u003e-\u003csub\u003eDM\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.887, 95% CI\u003csub\u003eNon\u0026minus;DM\u003c/sub\u003e: 0.116\u0026ndash;1.658, \u003cem\u003eP\u003c/em\u003e\u003csub\u003eNon\u0026minus;DM\u003c/sub\u003e = 0.025). The β for perioperative changes of MoCA-B scores in Group DM was higher than in Group Non-DM.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAssociation between intranasal insulin treatment and perioperative changes of MoCA-B scores with linear regression models\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eTotal participants\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u003cp\u003eDM\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e\u003cp\u003eNon-DM\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eβ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eβ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eβ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eUnivariate\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.031\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.413\u0026ndash;1.650\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.172\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.077\u0026ndash;2.268\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.036\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.921\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.156\u0026ndash;1.686\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.019\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMultivariate\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.037\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.414\u0026ndash;1.659\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.093\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.013\u0026ndash;2.173\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.047\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.887\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.116\u0026ndash;1.658\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.025\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003eβ is the standardized regression coefficient of intranasal insulin treatment; Variables in multivariate linear regression model include age and gender. DM, the group of patients with type 2 diabetes mellitus. Non-DM, the group of patients without type 2 diabetes mellitus. MoCA-B, Montreal cognitive assessment-Basic.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eEffect of intranasal insulin treatment on levels of fasting glucose, fasting insulin and HOMA-IR in older patients with and without T2DM\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo further explore the effect of intranasal insulin treatment on peripheral glucose metabolism in older patients with and without T2DM, the perioperative levels of fasting glucose, fasting insulin and HOMA-IR were analyzed. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, there was no statistical difference in perioperative levels of fasting glucose, fasting insulin, or HOMA-IR values between Group DM-S and Group DM-I, and between Group Non-DM-S and Group Non-DM-I. What\u0026rsquo;s more, in all groups, the intraoperative and postoperative HOMA-IR values were significantly increased compared to baseline. However, in the DMI group, HOMA-IR values decreased after surgery compared to the intraoperative levels, while in all other groups, HOMA-IR values increased after surgery compared to the intraoperative levels. This result was due to a significant decrease in fasting insulin levels in Group DM-I after surgery compared to introperative levels.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe global diabetic patients in 2019 were estimated to be 463\u0026nbsp;million, rising to 578\u0026nbsp;million by 2030 and 700\u0026nbsp;million by 2045. And 50.1% of people living with diabetes didn\u0026rsquo;t know that they have diabetes[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. As reported, T2DM accounts for more than 90% of all diabetes cases and approximately 50% of all patients with T2DM will undergo surgery at some points in their lifetime[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Moreover, diabetic patients are considered a high-risk group for cognitive impairment due to a combination of factors including metabolic disturbances, vascular complications, increased comorbidity, polypharmacy, and a heightened inflammatory response[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Research has shown that these factors contribute to a higher incidence of POD in diabetic patients, especially following complex surgeries or in the presence of multiple comorbid conditions[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In present study, older diabetic patients without intranasal insulin treatment had the highest incidence of POD among the groups, indicating that T2DM is indeed a high risk for POD. Therefore, the clinical prevention and management of POD in older patients with T2DM have significant clinical importance.\u003c/p\u003e\u003cp\u003eInsulin resistance (IR), as the primary pathological mechanism of T2DM, is mainly characterized by a decreased sensitivity of the body to insulin[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Our previous research indicated that the severity of IR was closely associated with POD in older patients with T2DM[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. As insulin plays a crucial physiological role in the brain, leading to the concept of brain IR, characterized by reduced sensitivity to insulin in the brain, relative insulin deficiency, and decreased glucose metabolism[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Brain IR has been identified as a key pathological mechanism underlying cognitive decline in AD and T2DM[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Therefore, addressing the relative insufficiency of brain insulin levels associated with this resistance by supplementing central insulin levels can improve cognitive function. Our previous animal studies found that intracerebroventricular injection of insulin can improve cognitive impairment caused by neuroinflammation by regulating glucose metabolism and inhibiting ferroptosis[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Previous studies have also reported that intranasal insulin therapy can improve postoperative cognitive dysfunction in mice induced by surgery and anesthesia[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Therefore, we attempted to use central insulin supplementation in a clinical study to improve POD.\u003c/p\u003e\u003cp\u003eMultiple studies have shown that administering a specific dose of intranasal insulin can rapidly increase central insulin levels via transport through the olfactory and trigeminal nerve pathways without affecting peripheral insulin and blood glucose levels[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This method has demonstrated cognitive improvement in patients with AD and mild cognitive impairment (MCI)[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Additionally, since POD shares similar pathological mechanisms and clinical manifestations with AD[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], intranasal insulin therapy may have a potential therapeutic effect on POD. Therefore, we conducted a RCT to observe the effects of intranasal insulin therapy on postoperative cognitive function and POD in older patients. The results found that intranasal insulin therapy could enhance postoperative cognitive function scores and reduce the incidence of POD in older patients[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Currently, other studies utilizing intranasal insulin therapy for POD have reached similar conclusions[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], but the number of studies is limited, and there have been no studies specifically targeting diabetic patients. Therefore, we conducted a secondary analysis of previous RCT data to examine the impact of intranasal insulin therapy on the incidence of POD in patients with and without T2DM.\u003c/p\u003e\u003cp\u003eIn our previous RCT study, we did not exclude diabetic patients because we aimed to observe the safety and glycemic effects of intranasal insulin application in diabetic patients. Although our initial study was conducted according to the experimental protocol without specifically including diabetic patients, nearly 40% of the final participants were diabetic. This allowed us to conduct a secondary analysis using diabetes as a subgroup. In this study, older patients with T2DM exhibited a higher incidence of POD compared to non-diabetic older patients, and intranasal insulin therapy showed a more significant improvement in POD among older patients with T2DM. This suggests that intranasal insulin therapy could be a potential preventative and therapeutic approach for POD in older patients with T2DM. However, due to the limited sample size, these results could not be validated with more precise statistical methods. Hence we are planning a dedicated clinical trial to validate this finding.\u003c/p\u003e\u003cp\u003eIn the previous RCT study, the primary outcome was the change in perioperative cognitive scores[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, due to potential learning effects, our participants did not exhibit a significant decline in postoperative cognitive scores compared to other studies[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Therefore, in this secondary analysis, we focused on POD as the primary outcome to better demonstrate the therapeutic effects of intranasal insulin therapy in older patients with and without T2DM. Consistent with previous results, intranasal insulin therapy did not significantly affect perioperative insulin and blood glucose levels in older patients, regardless of diabetic status. This indicates that while intranasal insulin therapy may not improve insulin resistance in diabetic and non-diabetic patients, it possesses good safety.\u003c/p\u003e\u003cp\u003eAlthough the study results suggest that intranasal insulin therapy significantly improves POD and postoperative cognitive function in older patients with T2DM, there are several limitations to this research. First, as a secondary analysis, this study faced sample size limitations due to the initial trial design not accounting for subgroup analyses, which restricted the ability to conduct complex multigroup comparisons. Despite this, these findings are clinically significant and lay the groundwork for further research on intranasal insulin therapy for POD in older patients with T2DM. Second, the lack of some critical case data, such as missing glycated hemoglobin information for diabetic patients, along with the small overall sample size and number of POD occurrences, hindered the ability to conduct comprehensive multivariate logistic regression analysis for the incidence of POD in diabetic patients. Consequently, only two common variables, gender and age, were included in the multivariate logistic regression analysis. Future clinical studies could utilize relevant retrospective database information and conduct targeted prospective studies to further explore the key risk factors for POD in older patients with T2DM.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIntranasal insulin therapy had shown to improve POD in older patients with T2DM and potentially offered better therapeutic effects on postoperative cognitive function compared to non-T2DM older patients. Based on the results of this study, a foundation is established for future clinical research to further explore the impact of intranasal insulin therapy on POD in older T2DM patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003ePOD\u003c/strong\u003e Postoperative Delirium\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRCT\u003c/strong\u003e Randomized Controlled Trial\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDM\u003c/strong\u003e Diabetes Mellitus\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eT2DM\u0026nbsp;\u003c/strong\u003eType 2 Diabetes Mellitus\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAD\u003c/strong\u003e Alzheimer\u0026apos;s Disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMCI\u003c/strong\u003e Mild Cognitive Impairment\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3D-CAM\u003c/strong\u003e 3-minute Diagnostic Interview for Confusion Assessment Method\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMMSE\u003c/strong\u003e Mini-Mental State Examination\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMoCA-B\u003c/strong\u003e Montreal Cognitive Assessment-Basic\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDSM-IV\u003c/strong\u003e Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHOMA-IR\u003c/strong\u003e Homeostatic Model Assessment for Insulin Resistance\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIR\u003c/strong\u003e Insulin Resistance[1]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol and informed consent forms were approved by the Ethics Committee of Chinese PLA General Hospital (Approval No. S2021-120-01). Written informed consent was obtained from all participants prior to enrollment. For participants with impaired decision-making capacity, consent was obtained from legally authorized representatives. This study was conducted in compliance with the Declaration of Helsinki (https://www.wma.net/policies-post/wma-declaration-of-helsinki/) and all methods were performed in accordance with relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets collected and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: Miao Sun, Weidong Mi, Yulong Ma.\u003c/p\u003e\n\u003cp\u003eProvision of study materials or patients: Xianghan Ruan.\u003c/p\u003e\n\u003cp\u003eCollection and assembly of data: Huikai Yang, Lulu Zhou.\u003c/p\u003e\n\u003cp\u003eData analysis and interpretation: Mengyao Qu, Yanan He.\u003c/p\u003e\n\u003cp\u003eManuscript writing: Danyang Geng, Yan Tian.\u003c/p\u003e\n\u003cp\u003eFinal approval of manuscript: All authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLi T, Li J, Yuan L, et al. Effect of Regional vs General Anesthesia on Incidence of Postoperative Delirium in Older Patients Undergoing Hip Fracture Surgery: The RAGA Randomized Trial. JAMA. 2022;327(1):50\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSun M, Liu M, Zhang F, et al. Triglyceride-glucose index predicts postoperative delirium in elderly patients with type 2 diabetes mellitus: a retrospective cohort study. Lipids Health Dis. 2024;23(1):107.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJin Z, Hu J, Ma D. Postoperative delirium: perioperative assessment, risk reduction, and management. Br J Anaesth. 2020;125(4):492\u0026ndash;504.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDrayton DJ, Birch RJ, D'Souza-Ferrer C, Ayres M, Howell SJ, Ajjan RA. Diabetes mellitus and perioperative outcomes: a scoping review of the literature. Br J Anaesth. 2022;128(5):817\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFeinkohl I, Winterer G, Pischon T. Diabetes is associated with risk of postoperative cognitive dysfunction: A meta-analysis. Diabetes Metab Res Rev. 2017;33(5).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSun H, Saeedi P, Karuranga S, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen W, Cai W, Hoover B, Kahn CR. Insulin action in the brain: cell types, circuits, and diseases. Trends Neurosci. 2022;45(5):384\u0026ndash;400.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKellar D, Craft S. Brain insulin resistance in Alzheimer's disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol. 2020;19(9):758\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSun M, Li Y, Liu M, et al. Insulin alleviates lipopolysaccharide-induced cognitive impairment via inhibiting neuroinflammation and ferroptosis. Eur J Pharmacol. 2023;955:175929.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSun M, Liu M, Li Q, et al. Insulin attenuates LPS-induced cognitive impairment and ferroptosis through regulation of glucose metabolism in hippocampus. CNS Neurosci Ther. 2024;30(7):e14887.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSun M, Ruan X, Zhou Z, et al. Effect of intranasal insulin on perioperative cognitive function in older adults: a randomized, placebo-controlled, double-blind clinical trial. Age Ageing. 2024;53(9):afae188.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuang Q, Li Q, Qin F, et al. Repeated Preoperative Intranasal Administration of Insulin Decreases the Incidence of Postoperative Delirium in Elderly Patients Undergoing Laparoscopic Radical Gastrointestinal Surgery: A Randomized, Placebo-Controlled, Double-Blinded Clinical Study. Am J Geriatr Psychiatry. 2021;29(12):1202\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuang Q, Wu X, Lei N, et al. Effects of Intranasal Insulin Pretreatment on Preoperative Sleep Quality and Postoperative Delirium in Patients Undergoing Valve Replacement for Rheumatic Heart Disease. Nat Sci Sleep. 2024;16:613\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMichailidis M, Moraitou D, Tata DA, et al. Alzheimer's Disease as Type 3 Diabetes: Common Pathophysiological Mechanisms between Alzheimer's Disease and Type 2 Diabetes. Int J Mol Sci. 2022;23(5):2687.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArnold SE, Arvanitakis Z, Macauley-Rambach SL, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14(3):168\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRoque PS, Hooshmandi M, Neagu-Lund L, et al. Intranasal insulin rescues repeated anesthesia-induced deficits in synaptic plasticity and memory and prevents apoptosis in neonatal mice via mTORC1. Sci Rep. 2021;11(1):15490.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang Y, Dai CL, Chen Y, et al. Intranasal Insulin Prevents Anesthesia-Induced Spatial Learning and Memory Deficit in Mice. Sci Rep. 2016;6:21186.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHallschmid M. Intranasal Insulin for Alzheimer's Disease. CNS Drugs. 2021;35(1):21\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAvgerinos KI, Kalaitzidis G, Malli A, et al. Intranasal insulin in Alzheimer's dementia or mild cognitive impairment: a systematic review. J Neurol. 2018;265(7):1497\u0026ndash;510.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLu J, Liang F, Bai P, et al. Blood tau-PT217 contributes to the anesthesia/surgery-induced delirium-like behavior in aged mice. Alzheimers Dement. 2023;19(9):4110\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBrattinga B, Plas M, Spikman JM, et al. The link between the early surgery-induced inflammatory response and postoperative cognitive dysfunction in older patients. J Am Geriatr Soc. 2024;72(5):1360\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang P, Yin X, Chen G, et al. Perioperative probiotic treatment decreased the incidence of postoperative cognitive impairment in elderly patients following non-cardiac surgery: A randomised double-blind and placebo-controlled trial. Clin Nutr. 2021;40(1):64\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-anesthesiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bane","sideBox":"Learn more about [BMC Anesthesiology](http://bmcanesthesiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bane","title":"BMC Anesthesiology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Intranasal insulin, postoperative delirium (POD), type 2 diabetes mellitus (T2DM), secondary analysis, older patients","lastPublishedDoi":"10.21203/rs.3.rs-7097922/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7097922/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThis study further analyzed the data from a previous prospective, randomized, placebo-controlled clinical study to investigate the effects of intranasal insulin therapy on postoperative delirium (POD) in older patients with and without type 2 diabetes mellitus (T2DM).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and methods:\u003c/strong\u003e In the current study, 128 patients were categorized into four groups based on intranasal treatment and the presence of T2DM: Group DM-S included 22 patients with T2DM receiving intranasal saline; Group DM-I included 28 patients with T2DM receiving intranasal insulin; Group Non-DM-S comprised 42 patients without T2DM receiving intranasal saline; and Group Non-DM-I included 36 patients without T2DM receiving intranasal insulin. The primary outcome was POD incidence between Group DM-S and Group DM-I, and between Group Non-DM-S and Group Non-DM-I. The secondary outcomes included the effects of intranasal insulin treatment on perioperative changes of Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment-Basic (MoCA-B) in participants with and without T2DM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe incidences of POD in Group DM-S, Group DM-I, Group Non-DM-S, Group Non-DM-I were 36.4%, 10.7%, 19% and 11.1%, respectively. Intranasal insulin treatment significantly decreased the POD incidence in patients with T2DM (P=0.030). Additionally, the perioperative changes of MMSE scores were -0.36±1.50, 0.75±1.32, -0.83±1.41 and 0.36±1.38 in Group DM-S, Group DM-I, Group Non-DM-S, Group Non-DM-I, respectively. And the perioperative changes of MoCA-B scores were -0.14±2.05, 1.04±1.80, -0.14±1.89 and 0.78±1.42 in Group DM-S, Group DM-I, Group Non-DM-S, Group Non-DM-I, respectively. Intranasal insulin treatment significantly improved the perioperative changes of MMSE scores and MoCA-B scores both in Group DM (\u003cem\u003eP\u003c/em\u003e\u003csub\u003eMMSE\u003c/sub\u003e=0.008, \u003cem\u003eP\u003c/em\u003e\u003csub\u003eMoCA-B\u003c/sub\u003e=0.037) and Group Non-DM (\u003cem\u003eP\u003c/em\u003e\u003csub\u003eMMSE\u003c/sub\u003e=0.022, \u003cem\u003eP\u003c/em\u003e\u003csub\u003eMoCA-B\u003c/sub\u003e=0.019).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eIntranasal insulin decreased POD incidences in older patients with T2DM and potentially offered better therapeutic effects on postoperative cognitive function compared to older patients without T2DM.\u003c/p\u003e","manuscriptTitle":"Effects of Intranasal Insulin on Postoperative Delirium in Older Patients with and without Type 2 Diabetes Mellitus: A Secondary Analysis of a Randomized Clinical Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-14 10:02:06","doi":"10.21203/rs.3.rs-7097922/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"124388809810823290082480246256674698361","date":"2025-08-24T21:17:57+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-08T06:50:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-05T07:21:41+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-16T05:36:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-14T15:39:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Anesthesiology","date":"2025-07-14T15:33:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-anesthesiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bane","sideBox":"Learn more about [BMC Anesthesiology](http://bmcanesthesiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bane","title":"BMC Anesthesiology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d8d61baa-c250-4fc3-9653-fe818e27127c","owner":[],"postedDate":"August 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-08-14T10:02:06+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-14 10:02:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7097922","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7097922","identity":"rs-7097922","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}