Intranasal Insulin Diminishes Postoperative Delirium and Elevated Osteocalcin and Brain Derived Neurotrophic Factor in Older Patients Undergoing Joint Replacement: A Randomized, Double-Blind, Placebo-Controlled Trial.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2025-02-01 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S491300

Mi Yang, Lei Zhou, Ge Long, Xing Liu, Wen Ouyang, Chang Xie, Xi He

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Abstract

Background: Brain energy metabolism disorders, including glucose utilization disorders and abnormal insulin sensitivity, are linked to the pathogenesis of postoperative delirium. Intranasal insulin has shown significant benefits in improving glucose metabolism, insulin sensitivity and cognitive function. However, its impact on postoperative delirium and insulin sensitivity biomarkers remains unknown.

Aim: This randomized, double-blind, placebo-controlled trial was to evaluate whether intranasal insulin reduces the incidence and severity of postoperative delirium (POD) in older patients undergoing joint replacement, and its effect on insulin sensitivity-related biomarkers.

Methods: 212 older patients (≥65 years) were randomly assigned to receive either 40 IU of intranasal insulin (n=106) or a placebo (n=106) for 8 days. The primary objective was to determine the incidence and severity of POD within 5 days after surgery, estimated using the Confusion Assessment Method (CAM) and the Delirium Rating Scale (DRS)-98. The secondary objective was insulin sensitivity, which was assessed using the homeostasis model Assessment of Insulin Resistance (HOMA-IR) and biomarkers, including total osteocalcin (tOC), uncarboxylated osteocalcin (ucOC), and brain-derived neurotrophic factor (BDNF).

Main results: Compared to placebo, intranasal insulin significantly reduced the incidence of delirium within 5 days after surgery (8 [8.33%] vs 23 [23.23%], P = 0.004, odds ratio [OR] = 3.33 [95% CI 1.41-7.88]) and the severity of delirium (P<0.001). Intranasal insulin elevated the levels of tOC, ucOC, and BDNF in the CSF on D₀ (all P<0.001) and tOC levels in the plasma on D₀, D₁ and D₃ (all P<0.001). It elevated ucOC levels in the plasma of the insulin group on D₀ but not on D₁ and D₃ (all P<0.001). Intranasal insulin administration reduced the HOMA-IR on D₃ (P=0.002).

Conclusion: Intranasal insulin notably reduced the incidence and severity of POD in older patients undergoing joint replacement, which may be related to the elevation in osteocalcin and BDNF levels.

Trial registry numbers: Chinese Clinical Trial Registry (ChiCTR2300068073).

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鼻内胰岛素减少老年关节置换术患者术后谵妄、骨钙素和脑源性神经营养因子升高：一项随机、双盲、安慰剂对照试验

背景：脑能量代谢障碍，包括葡萄糖利用障碍和胰岛素敏感性异常，与术后谵妄的发病机制有关。鼻内胰岛素在改善葡萄糖代谢、胰岛素敏感性和认知功能方面显示出显著的益处。然而，其对术后谵妄和胰岛素敏感性生物标志物的影响尚不清楚。目的：这项随机、双盲、安慰剂对照试验旨在评估鼻内胰岛素是否能降低老年关节置换术患者术后谵妄（POD）的发生率和严重程度，以及其对胰岛素敏感性相关生物标志物的影响。方法：212例老年患者（≥65岁）随机分配接受40 IU鼻内胰岛素（n=106）或安慰剂（n=106），为期8天。主要目的是确定手术后5天内POD的发生率和严重程度，使用混淆评估法（CAM）和谵妄评定量表(DRS)-98进行评估。次要目标是胰岛素敏感性，使用胰岛素抵抗稳态模型评估（HOMA-IR）和生物标志物进行评估，包括总骨钙素（tOC），未羧化骨钙素（ucOC）和脑源性神经营养因子（BDNF）。主要结果：与安慰剂相比，鼻内胰岛素显著降低术后5天内谵妄发生率（8例[8.33%]vs 23例[23.23%]，P= 0.004，优势比[OR] = 3.33 [95% CI 1.41 ~ 7.88]）和谵妄严重程度(P0(所有P0， D1和D3（所有P0，但不包括D1和D3（所有P3））（P=0.002）。结论：鼻内胰岛素可显著降低老年关节置换术患者POD的发生率和严重程度，这可能与骨钙素和BDNF水平升高有关。试验注册号：中国临床试验注册中心（ChiCTR2300068073）。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.