ABSTRACT
A decrease in the activity of the insulin signaling system of the brain, due to both central insulin resistance and insulin deficiency, leads to neurodegeneration and impaired regulation of appetite, metabolism, endocrine functions. This is due to the neuroprotective properties of brain insulin and its leading role in maintaining glucose homeostasis in the brain, as well as in the regulation of the brain signaling network responsible for the functioning of the nervous, endocrine, and other systems. One of the approaches to restore the activity of the insulin system of the brain is the use of intranasally administered insulin (INI). Currently, INI is being considered as a promising drug to treat Alzheimer's disease and mild cognitive impairment. The clinical application of INI is being developed for the treatment of other neurodegenerative diseases and improve cognitive abilities in stress, overwork, and depression. At the same time, much attention has recently been paid to the prospects of using INI for the treatment of cerebral ischemia, traumatic brain injuries, and postoperative delirium (after anesthesia), as well as diabetes mellitus and its complications, including dysfunctions in the gonadal and thyroid axes. This review is devoted to the prospects and current trends in the use of INI for the treatment of these diseases, which, although differing in etiology and pathogenesis, are characterized by impaired insulin signaling in the brain.
Subject(s)
Alzheimer Disease , Brain Injuries , Diabetes Mellitus , Emergence Delirium , Humans , Insulin/metabolism , Emergence Delirium/complications , Emergence Delirium/drug therapy , Emergence Delirium/metabolism , Diabetes Mellitus/metabolism , Insulin, Regular, Human , Brain/metabolism , Alzheimer Disease/metabolism , Cerebral Infarction/drug therapy , Brain Injuries/metabolism , Administration, IntranasalABSTRACT
Postoperative delirium is the most common complication among older adults undergoing major surgery. The pathophysiology of delirium is poorly understood, and no blood-based, predictive markers are available. We characterized the plasma metabolome of 52 delirium cases and 52 matched controls from the Successful Aging after Elective Surgery (SAGES) cohort (N = 560) of patients ≥ 70 years old without dementia undergoing scheduled major non-cardiac surgery. We applied targeted mass spectrometry with internal standards and pooled controls using a nested matched case-control study preoperatively (PREOP) and on postoperative day 2 (POD2) to identify potential delirium risk and disease markers. Univariate analyses identified 37 PREOP and 53 POD2 metabolites associated with delirium and multivariate analyses achieved significant separation between the two groups with an 11-metabolite prediction model at PREOP (AUC = 83.80%). Systems biology analysis using the metabolites with differential concentrations rendered "valine, leucine, and isoleucine biosynthesis" at PREOP and "citrate cycle" at POD2 as the most significantly enriched pathways (false discovery rate < 0.05). Perturbations in energy metabolism and amino acid synthesis pathways may be associated with postoperative delirium and suggest potential mechanisms for delirium pathogenesis. Our results could lead to the development of a metabolomic delirium predictor.
Subject(s)
Postoperative Cognitive Complications/etiology , Postoperative Cognitive Complications/metabolism , Aged , Aged, 80 and over , Aging , Biomarkers/blood , Case-Control Studies , Cohort Studies , Computational Biology/methods , Delirium/etiology , Emergence Delirium/metabolism , Female , Humans , Male , Mass Spectrometry , Metabolomics/methods , Postoperative Complications/metabolism , PrognosisABSTRACT
OBJECTIVE: The aim of this study was to determine risk factors for postoperative delirium after cardiac surgery, specifically associated with the conduct of cardiopulmonary bypass (CPB). DESIGN: Prospective observational study. SETTING: Heart Centre, University Hospital. PARTICIPANTS: The study included 142 patients aged 70 years and older scheduled for elective cardiac surgery with CPB. INTERVENTIONS: Risk factor analysis comprised information collected from the hospital clinical and CPB dedicated databases in addition to the medical chart. Delirium was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision criterion using the Mini Mental State Examination and the Organic Brain Syndrome scale. MEASUREMENTS AND MAIN RESULTS: Assessments of delirium diagnosis were executed preoperatively and on the following first and fourth postoperative days. Delirium occurred in 55% (78/142) of the patients. Patients with delirium were identified with significantly higher body weight and body surface area preoperatively, accompanied with longer CPB time, higher positive fluid balance per CPB, and lower systemic pump flow related to body surface area. Furthermore, the duration of the mixed venous oxygen saturation (SvO2) below 75% was significantly longer during CPB. The result from the multivariable logistic regression analysis included the duration of SvO2 below 75%, fluid balance per CPB and patient age as independent risk factors for postoperative delirium. CONCLUSIONS: The influence of the SvO2 level during CPB, fluid balance, and patient age should be recognized as risk factors for postoperative delirium after cardiac surgery in patients 70 years and older.
