Abstract

Postoperative cognitive dysfunction (POCD) and postoperative delirium (POD) are common perioperative neurocognitive disorders, particularly affecting individuals with diabetes, who show a disproportionately higher susceptibility. Diabetic patients are at higher risk due to blood sugar fluctuations, vascular changes, and inflammation that can affect brain function. This review explores how diabetes contributes to POCD and POD, the role of biomarkers in identifying those at risk, and strategies to prevent and manage these complications. A thorough analysis of current studies highlights that factors such as hyperglycemia, glycemic variability, and diabetes-related complications significantly increase the likelihood of cognitive problems after surgery. While several tools exist to assess cognition and delirium, none reliably detect early changes on their own, underscoring the need for integrated approaches that combine biomarkers and clinical assessment. Interventions like tight blood sugar control, careful perioperative monitoring, and cognitive rehabilitation may help reduce these risks. Overall, understanding the link between diabetes and postoperative cognitive complications and implementing personalized care plans are key to improving recovery and quality of life for diabetic patients. Future research should prioritize the standardization of diagnostic criteria, the clinical validation of perioperative biomarkers, and the development of targeted preventive and therapeutic strategies for patients at increased perioperative neurocognitive risk.

1 Introduction

Following surgery, older adults and individuals with diabetes are at increased risk of perioperative neurocognitive disorders, particularly postoperative delirium (POD), characterized by acute and fluctuating disturbances in attention and consciousness, and postoperative cognitive dysfunction (POCD), which involves more prolonged impairments in memory and executive function (1, 2). These complications can prolong hospitalizations and worsen long-term outcomes. Diabetes may heighten susceptibility to POD and POCD through chronic hyperglycemia, vascular injury, autonomic dysfunction, and impaired cerebral metabolic resilience, which reduce the brain’s ability to tolerate perioperative stress (3). Recognizing these risks is essential for early identification and management, which can improve recovery and prevent long-term cognitive decline (4). POD generally arises between hours to days following surgery, presenting as an abrupt and variable impairment in attention and consciousness, frequently resolving within days to weeks. Conversely, POCD entails a more nuanced and enduring deterioration in memory, attention, and executive function, potentially lasting from weeks to months. Major operations, including gastrointestinal, orthopedic, or cardiac procedures, can precipitate these complications, particularly in patients with diabetes due to their pre-existing metabolic and vascular vulnerabilities (5). Large observational and cohort studies have quantified this increased risk, demonstrating that diabetes is associated with approximately a 1.3–2.0-fold higher incidence of postoperative delirium and postoperative cognitive dysfunction compared with non-diabetic patients, with risk magnitude influenced by age, surgical type, and perioperative glycemic control (1, 6). Poor long-term glycemic control, reflected by elevated HbA1c, and perioperative hyperglycemia have consistently been identified as independent predictors of postoperative neurocognitive complications. Nevertheless, the majority of existing evidence is observational, and residual confounding from comorbidities, baseline cognitive status, and perioperative variables constrains clear causal inference.

Prospective studies are still needed to provide standard risk levels and routes.

Complicating diagnosis and treatment are comorbidities like pre-existing cognitive impairment, microvascular disease, neuropathy, and hypoglycemia, which may mask or mimic POCD and POD symptoms. Early detection of these abnormalities is essential to enhance surgical care, alleviate cognitive decline, and facilitate long-term recovery (7). Validated diagnostic tools differentiate these entities: CAM and DRS are commonly used for the assessment of POD, exhibiting excellent sensitivity and specificity, whereas MMSE and MoCA are used for screening for POCD, despite the possibility of overlooking modest abnormalities (8). Emerging techniques, including EEG, ERP, PET, and fMRI, along with biomarkers of inflammation and oxidative stress, provide mechanistic insights and may enhance early detection (9). Although these advanced approaches have great potential, their complexity, cost, and variability of postoperative care make them not generally used in clinical practice. Recent advances in AI and machine learning offer non-invasive, cost-effective approaches for early detection and risk stratification of POD and POCD in diabetic patients. AI-driven cognitive evaluations, predictive analytics, and automated screenings could enhance individualized perioperative management by incorporating patient-specific metabolic, vascular, and cognitive risk factors. (4). This review synthesizes current evidence on the mechanisms, biomarkers, and management strategies for POD and POCD in adults with diabetes, highlighting validated diagnostic instruments, emerging biomarker-driven approaches, and innovative AI-supported risk-prediction tools. By integrating mechanistic understanding with clinical frameworks, it aims to identify research gaps and support evidence-based strategies to optimize perioperative neurocognitive outcomes in this high-risk population (10).

This article is presented as a narrative review synthesizing current evidence on the mechanisms, biomarkers, and perioperative management of postoperative cognitive dysfunction (POCD) and delirium (POD) in adults with diabetes. Relevant literature was identified through searches of major scientific databases, including PubMed and Google Scholar, using combinations of keywords such as diabetes, postoperative delirium, postoperative cognitive dysfunction, neuroinflammation, and biomarkers. Priority was given to recent clinical studies, systematic reviews, and key experimental research addressing mechanistic pathways and clinical implications. As a narrative synthesis, this review does not follow a formal systematic review protocol but aims to provide an integrative overview of this evolving field.

2 The pathophysiology of postoperative cognitive dysfunction and delirium2.1 Mechanisms of postoperative cognitive dysfunction

Particularly in diabetic patients, postoperative cognitive dysfunction (POCD) is mostly associated with neuroinflammation. One aspect of diabetes is chronic inflammation, which increases the brain’s sensitivity in patients with diabetes strong inflammatory reaction following surgery. Pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β, are produced in response to surgical damage during the perioperative period (11). By passing the blood-brain barrier (BBB), these cytokines can activate microglia, the brain’s innate immune cells. This stimulation triggers an inflammatory response that disrupts normal brain function and causes cognitive problems. For patients with diabetes, raised baseline inflammation brought on by underlying metabolic dysregulation aggravates their illness and increases their vulnerability to additional brain injury. Important processes for learning and memory, neuroinflammation disturbs synaptic plasticity and neurogenesis. Therefore, patients with diabetes are more prone to get POCD following surgery (12). Moreover, inflammatory mediators disrupt neurotransmitter systems, including dopamine, serotonin, and glutamate, all of which are vital for cognitive function (13). Hyperglycemic states, frequent in patients with diabetes, aggravate neuroinflammation in POCD by inducing oxidative stress and advanced glycation end-products (AGEs), thereby triggering immunological responses and activating immune receptors. These inflammatory mediators greatly influence microglia in the brain, which are vital for immune monitoring in the central nervous system (CNS) (14). Chronic low-grade neuroinflammation reduces the capacity of neurons to adjust to cognitive tasks, therefore affecting executive function and memory consolidation. Extensive studies on the molecular etiology of POCD and potential preventive strategies have been conducted. The molecular mechanisms by which sevoflurane induces POCD may provide insight into treatment and prevention strategies (15). Animal models used in clinical research help clarify POCD diagnosis criteria and the processes involved in sevoflurane-induced POCD, potentially improving preventive and treatment approaches for the disorder (16).

Additionally, another study explored the inflammatory processes of the CNS, highlighting how changes in peripheral circulation and pathogenic interactions between peripheral circulation and the CNS could exacerbate POCD. These efforts aim to enhance the understanding of POCD’s onset, development, and effective preventive measures. For those with diabetes, POCD is largely driven by neurodegeneration. Persistent hyperglycemia and insulin resistance increase neurodegenerative processes in the brain, making individuals with diabetes more likely to experience cognitive impairment after surgery (4). Elevated oxidative stress and inflammation in patients with diabetes promote the formation of amyloid plaques and tau protein phosphorylation, characteristics of neurodegenerative diseases like Alzheimer’s. These processes lead to synaptic malfunction and cell death in regions of the brain crucial for cognitive functions, such as the hippocampus and prefrontal cortex (17), Figure 1.

The influence of oxidative stress on multiple organs and systems, particularly in individuals with diabetes. It underscores the role of oxidative stress in the development of complications such as diabetic retinopathy, nephropathy, and cardiovascular diseases, positioning it as a critical contributor to the progression of diabetes-related pathological conditions.

Evidence supporting the role of neuroinflammation and oxidative stress in POCD is derived primarily from well-established animal models and observational human studies, whereas direct causal links between diabetes-related neurodegeneration (e.g., amyloid-β accumulation and tau hyperphosphorylation) and POCD in surgical patients remain emergent and are supported mainly by experimental and translational data (18). Surgery and anesthesia accelerate neurodegenerative changes by raising oxidative stress, causing mitochondrial dysfunction, and disrupting pro-survival and pro-apoptotic signaling pathways inside neurons. These factors contribute to cognitive decline typical of POCD by promoting cellular death and weakening synaptic connections (19). Moreover, oxidative stress exacerbates diabetes-related neurotoxicity, further emphasizing the need for early identification and intervention in this at-risk population. In patients with diabetes, poor glucose metabolism causes excess glucose to combine with oxygen, generating reactive oxygen species (ROS), which damage proteins, lipids, and DNA, impairing neuronal integrity. This oxidative damage accelerates neurodegenerative processes, especially in sensitive brain regions such as the prefrontal cortex (important for executive functioning) and the hippocampus (vital for memory storage) (20).

Neurodegeneration in POCD is also linked to the accumulation of improperly folded proteins like tau and amyloid β. This results in defective neural connections, leading to executive cognition and memory deficits. A study evaluating the correlation between postoperative delirium (POD) and POCD found that neurovascular changes are often associated with the development of both conditions (21). High HbA1c readings, which indicate poor glycemic control, may increase the risk of POCD in patients with diabetes, highlighting the need for further research on how glycemic management impacts POCD risk in both diabetic and non-diabetic patients. Diabetes complicates POCD due to its co-occurrence with vascular abnormalities, chronic inflammation, and neurodegenerative alterations. These factors increase the brain’s vulnerability to the physiological and metabolic demands of anesthesia and surgery (1).

While these hormones are part of the body’s adaptive stress response, excessive levels can negatively affect cognitive function. In patients with diabetes, insulin resistance and hyperglycemia elevate pro-inflammatory cytokines such as TNF-α and IL-6, further promoting neuroinflammation and cognitive decline (22). Additionally, hypotension and hypoxia during anesthesia can compromise cerebral perfusion, increasing the risk of ischemic injury to sensitive brain regions, such as the hippocampus, which is crucial for memory and learning. Anesthetic drugs and perioperative stress create a vicious cycle that exacerbates cognitive loss in patients with diabetes, as their pre-existing vascular dysfunction, inflammation, and metabolic abnormalities make the brain more sensitive to anesthesia-induced neurotoxicity (23). Further research into postoperative neurocognitive dysfunction (PND) emphasizes that similar molecular mechanisms are involved in both PND and POCD, with aging individuals being particularly vulnerable.

Research has also explored how diabetes mellitus (DM) may contribute to POCD, as minor cognitive impairment associated with diabetes can increase the likelihood of postoperative cognitive dysfunction. Specifically, type 2 diabetes worsens early postoperative cognitive dysfunction (POCD), with diabetic patients showing more significant impairment in initial cognitive capacities compared to non-diabetic individuals after laparoscopic surgery(Seven et al., 2022b). Additionally, diabetes-induced neuropathy and vascular changes significantly impact cognitive function. These changes, which are present before and after surgery, directly impair brain structure and function. Moreover, sensorimotor neuropathy interferes with sensory information processing, which is essential for cognitive integration and processing. This increases the susceptibility of memory and executive function control centers to further damage during the perioperative period, exacerbating cognitive decline (24–26).

Vascular changes in patients with diabetes, including microvascular and macrovascular disease, significantly impact cognitive function. Hyperglycemia and insulin resistance lead to endothelial dysfunction, increased blood-brain barrier permeability, and reduced cerebral perfusion. Vascular complications such as atherosclerosis and stroke increase the risk of cognitive changes during and after surgery (27). Furthermore, chronic cerebral hypoperfusion due to vascular changes accelerates the buildup of amyloid plaques and tau hyperphosphorylation, both of which are associated with neurodegenerative diseases like Alzheimer’s and POCD study (28). A study by A. Moheet et al. clarified how diabetes affects brain structure and function, revealing that cognitive decline is linked to both type 1 and type 2 diabetes. The study emphasizes the need for comprehensive interventions to address the multifactorial nature of diabetes-related cognitive decline (29).

2.2 Pathophysiology of delirium in diabetic adults

Delirium, characterized by sudden disorientation, fluctuating consciousness, and impaired attention, is a common and serious postoperative complication in adult diabetic patients. Neuroinflammation, vascular restrictions, and metabolic abnormalities are complex underlying factors contributing to delirium in this population. Improper management of diabetes leads to chronic low-grade inflammation, increasing the brain’s vulnerability to perioperative stressors such as surgery and anesthesia (30).

Diabetes-related vascular problems, including microvascular and macrovascular disorders, limit cerebral blood flow and raise the risk of delirium and cerebral hypoperfusion. Variability in glucose levels, between hyperglycemia and hypoglycemia, aggravates cognitive problems by causing oxidative stress and disturbances in neurotransmitter production (31). Adults with diabetes are particularly vulnerable to delirium due to the combination of these factors, highlighting the need for early detection and treatment to improve postoperative outcomes (32). Kris van Keulen and colleagues’ study attempted to determine whether glucose variability is impacted during delirium versus non-delirious times in critically ill patients in the intensive care unit (ICU), both with and without diabetes. The study found that delirium and hypoglycemia are positively correlated in critically ill diabetic patients. However, delirium is not associated with greater glucose fluctuations. The findings suggest that diabetic patients with delirium should have their blood sugar levels monitored more frequently to prevent hypoglycemic episodes (33, 34). Two key features of diabetes that contribute to delirium in diabetic adults undergoing surgery are hyperglycemia and insulin resistance. Particularly during the perioperative period, hyperglycemia greatly raises the risk of delirium by encouraging the production of pro-inflammatory cytokines such as TNF-α and IL-6, which aggravate neuroinflammation (35), Figure 2. By crossing the blood-brain barrier and triggering microglia, these cytokines cause persistent inflammation that reduces cognitive ability.

The sequence where the release of cortisol and catecholamines induces hyperglycemia, which in turn activates the immune system, triggering the release of cytokines. This cascade leads to neuroinflammation and disruptions in normal neuronal activity, ultimately resulting in the development of delirium.

Moreover, aggravating oxidative stress, hyperglycemia damages neurons, compromises synaptic integrity, and lowers neuroplasticity. Typical delirium symptoms, acute disorientation and concentration issues, can result from damage to hippocampus neurons necessary for memory and cognition (36).Furthermore, aggravating cerebral hypoperfusion caused by hyperglycemia is endothelial dysfunction resulting from diabetes, which increases delirium susceptibility. A feature of type 2 diabetes, insulin resistance, is clearly important in the onset of delirium. Reduced insulin sensitivity throws off the brain’s control of glucose and preservation of energy balance (37–39). This metabolic mismatch reduces glucose metabolism in the brain, therefore raising surgical sensitivity to ischemia.

Particularly, lower acetylcholine synthesis, which is essential for cognitive functions like attention, helps to explain cognitive deficits and raises the delirium risk. Rising levels of inflammatory cytokines including TNF-α, IL-6, and, which aggravate neuroinflammation and delirium, have also been associated with insulin resistance (40), Figure 2. Furthermore, increased free fatty acids linked with insulin resistance could cause neurodegenerative alterations, thereby increasing the risk of delirium and postoperative cognitive dysfunction (POCD) in patients with diabetes. Surgery activates the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis, triggering the release of stress hormones like cortisol and catecholamines (41) Figure 2. By means of dietary changes, physical exercise, and pharmaceutical therapies (e.g., metformin and insulin sensitizers), one can improve glucose management and insulin sensitivity, therefore breaking out this vicious cycle and lowering the chance of delirium.

Improving cognitive outcomes following surgery depends on early identification of diabetes patients at risk for delirium and the application of appropriate treatments (42). The interaction of hyperglycemia, insulin resistance, and neuroinflammation greatly increases the delirium risk in diabetic patients. Reducing the risk of delirium in this vulnerable population mostly depends on efficient blood glucose control and raising insulin sensitivity. Furthermore, delirium has been associated with stress hyperglycemia. Interestingly, patients with HbA1c levels below 6.5% indicating no chronic hyperglycemia, are more likely to experience delirium, independent of their stress hyperglycemia ratio (SHR) (43). One proposed mechanism is that individuals with lower baseline glucose tolerance may experience a more pronounced physiological stress response, resulting in acute hyperglycemia that disrupts cerebral metabolism and exacerbates neuroinflammation, both of which are implicated in delirium pathogenesis.

This study suggests that the initial SHR upon admission could serve as a valuable predictor of delirium, and incorporating this parameter into clinical prediction algorithms may enhance risk stratification (44). Although associations between acute hyperglycemia, hypoglycemia, and postoperative delirium are corroborated by numerous clinical and ICU studies, the predictive significance of glucose variability indices, such as the stress hyperglycemia ratio, remains investigational and necessitates validation in extensive, prospective perioperative cohorts (45). The risk of postoperative delirium (POD) is much raised by disturbance of the neurotransmitter balance required for appropriate cognitive capacity. Particularly in those with poor blood glucose control, metabolic dysregulation, neuroinflammation, and visual alterations affect neurotransmitter systems in diabetic patients, therefore increasing their risk of delirium (46). Especially during the perioperative phase, hyperglycemia alters the production, release, and receptor-mediated actions of neurotransmitters. Particularly affecting the dopaminergic, serotonergic, and cholinergic systems, too high glucose levels produce excessive reactive oxygen species (ROS) that damage neuronal membranes and neurotransmitter pathways. Hyperglycemia reduces acetylcholine receptor sensitivity, causing cognitive problems, particularly in short-term memory and attention. Diabetes increases sensitivity to delirium resulting from cholinergic deficits and heightened glutamate excitotoxicity, which impairs neuroplasticity and neurotransmission (47).Insulin resistance significantly affects neurochemical abnormalities related to delirium. It reduces the brain’s ability to use glucose effectively, disrupting synaptic activity and neurotransmitter balance. Reduced glucose uptake by neurons leads to decreased neurotransmitter synthesis and cognitive decline. One of the most disrupted systems is the glutamatergic system, which is crucial for synaptic plasticity and learning (48). Elevated glutamate levels can lead to excitotoxicity, damaging neurons and impairing cognitive ability. Neuroinflammation, which exacerbates neurotransmitter imbalance and delirium, is often connected to the body’s response to surgical stress and diabetes. Inflammatory cytokines like TNF-α and IL-1β reduce neurotransmitter synthesis by activating microglia, impairing synaptic function and cognition (49).

Diabetes exacerbates inflammatory responses by inducing chronic low-grade inflammation, increasing the brain’s susceptibility to postoperative delirium.

Hyperglycemia, insulin resistance, and neuroinflammation all disrupt key neurotransmitter systems necessary for cognitive regulation, leading to typical delirium symptoms that impair executive function, memory, and attention (35).

Neuroinflammatory, neuronal aging, oxidative stress, neurotransmitter deficiency, neuroendocrine, diurnal dysregulation, and network disconnectivity theories have been proposed to explain delirium. These mechanisms, including neuroinflammation and neurotransmitter imbalances, are linked to delirium’s development in ICU patients (50). Additionally, recent studies suggest that delirium may be caused by disturbances in neural pathways and neurotransmitter systems. In longstanding diabetes, autonomic neuropathy, a common complication, compromises the autonomic nerves controlling physiological processes like blood pressure, heart rate variability, and vascular tone. This dysfunction can impair blood flow control, particularly in the brain, worsening cerebral hypoperfusion during surgery (51). Autonomic dysfunction exacerbates the brain’s vulnerability to delirium by impeding its ability to respond appropriately to circulatory demands during surgery. Autonomic dysfunction and neuroinflammation are closely linked in diabetic delirium. Dysfunction of the autonomic nervous system can lead to an inappropriate immune response. People with diabetes already have chronic low-grade inflammation due to insulin resistance and hyperglycemia, but autonomic dysfunction exacerbates this inflammatory state. This imbalance activates the sympathetic nervous system, which releases more pro-inflammatory cytokines, promoting neuroinflammation and increasing the risk of delirium (52) Figure 2.

Additionally, autonomic dysfunction impairs the brain’s ability to control its inflammatory response to perioperative stress. The parasympathetic nervous system typically helps reduce excessive inflammation, but diabetes-related autonomic imbalance impairs this process, leading to uncontrolled neuroinflammation and neuronal damage (53). A study by Jannik Stokholm et al. investigated the relationship between autonomic function and delirium, using measures such as palmar skin conductance level (SCL) and pupillometry to assess changes in autonomic nervous system activity during delirium. The study found that autonomic modulation is altered during delirium episodes in acute stroke patients and noted a higher prevalence of diabetes among those experiencing mental disturbances (54). Despite growing evidence linking diabetes to postoperative neurocognitive disorders, several limitations of the existing literature should be acknowledged. Most available studies are observational in design, limiting causal inference, and many rely on heterogeneous definitions of POCD and delirium, variable cognitive assessment instruments, and relatively short follow-up durations. Moreover, diabetic populations are frequently inadequately categorized by disease duration, glycemic control, or the existence of microvascular complications, thereby obscuring reported relationships. These constraints underscore the necessity for consistent diagnostic criteria and well-constructed prospective trials.

3 Factors for POCD and delirium in diabetic adults3.1 Diabetes-related risk factors

Persistently high blood glucose levels, or chronic hyperglycemia, are a hallmark of poorly managed diabetes and have been identified as a significant independent risk factor for both postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) (55). Prolonged hyperglycemia promotes oxidative stress, vascular dysfunction, and neuroinflammation, all of which increase the brain’s vulnerability to cognitive deterioration following surgery. In diabetic individuals, microvascular damage and reduced cerebral blood flow, both signs of chronic hyperglycemia, inhibit normal brain function and significantly worsen postoperative outcomes. Glycemic variability (GV), including episodes of both hyperglycemia and hypoglycemia, leads to the production of reactive oxygen species (ROS), which trigger inflammation and neuronal damage (56). Fluctuating glucose levels also affect the autonomic nervous system (ANS), disrupting cerebral blood flow regulation and contributing to cognitive impairment. Recent findings indicate GV may be a more predictive marker for long-term diabetic complications than traditional measures like HbA1c. GV has been linked with vascular damage and the progression of atherosclerosis, suggesting it should be a key target in diabetes management. Diabetic neuropathy, especially autonomic neuropathy, is another common complication that significantly impacts cognitive outcomes (57). Chronic hyperglycemia damages peripheral and autonomic nerves, impairing the brain’s control of blood flow and its integration of sensory information. This leads to deficits in memory, attention, and executive functioning, making diabetic patients more susceptible to POD and POCD (58). Diabetic retinopathy, though primarily affecting the eyes, reflects widespread microvascular dysfunction throughout the body, including the brain. This can compromise blood-brain barrier (BBB) integrity and reduce cerebral circulation, allowing inflammatory cytokines and neurotoxins to enter the brain more easily. This promotes neurodegeneration, especially in the hippocampus and prefrontal cortex, regions vital to memory and cognitive control (59). Emerging studies, such as those by Yiwen Li et al., have found consistent patterns among diabetic peripheral diseases (DPDs), showing shared molecular pathways and risk factors. This reinforces the need for integrated care strategies that address neuropathy, nephropathy, and retinopathy collectively, rather than in isolation (60). Early vascular interventions and stringent glucose control are essential to reduce cognitive complications. Additionally, the association between diabetic retinopathy (DR) and nephropathy (DN) suggests that DR may serve as a non-invasive predictor of broader neurological and vascular complications in diabetic individuals. Inadequate diabetes control is a key factor in the development of both POD and POCD.

Uncontrolled blood glucose whether persistently high or fluctuating induces neuroinflammation, damages cerebral vasculature, and increases BBB permeability (61) (Figure 3). These mechanisms impair cerebral perfusion and allow pro-inflammatory agents and toxins into the brain, thereby worsening cognitive function. During surgical stress, these effects are amplified (62). High blood sugar levels contribute to further vascular damage, impair synaptic plasticity, and elevate the risk of neurodegenerative processes. Hypoglycemia, on the other hand, can cause acute neuronal injury, especially in memory-critical areas like the hippocampus. The brain’s extreme sensitivity to glucose fluctuations underscores the importance of consistent glycemic management, particularly in the perioperative period (63).

Surgery and anesthesia contribute to Postoperative Cognitive Dysfunction (POCD) and Postoperative Delirium (POD) by inducing neuroinflammation through mechanisms such as systemic inflammation, anesthetic agents, gut microbiota alterations, circadian rhythm disruption, and exosomal signaling.

Non-compliance with diabetes medications further exacerbates cognitive decline. Irregular glycemic control, combined with untreated vascular conditions like hypertension and dyslipidemia, compromises cerebral blood flow and increases the risk of both acute and chronic cognitive impairments. Patients undergoing surgery must maintain strict adherence to prescribed regimens to preserve cognitive function and avoid the compounding effects of neuroinflammation and vascular stress (64, 65).

3.2 Age and comorbidity

Particularly in patients with diabetes, aging significantly reduces cognitive resilience and increases susceptibility to postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) (66). Age-related changes in brain structure and function, including decreased neuroplasticity, impaired synaptic function, and reduced neuronal regeneration, diminish the brain’s ability to recover from the stress of surgical procedures (67). As people age, the likelihood of experiencing cognitive decline, characterized by memory loss, reduced attention span, and slower processing speed, increases. These challenges are compounded by diabetes-related issues such as neuroinflammation and vascular damage (68). The ageing brain loses capacity to control the physiological demands of anesthesia and surgery and is less able to withstand these stresses. Furthermore, age-related alterations in neurovascular function reduce cerebrovascular reserve, rendering the aging brain more vulnerable to hypoperfusion, particularly during surgical procedures in which anesthesia and surgical stress can induce fluctuations in cerebral blood flow (69, 70) (Figure 3). In elderly individuals with diabetes, vulnerability to postoperative cognitive disorders is amplified by diabetes-related vascular and metabolic dysfunction. The interplay between age-associated neurodegeneration and persistent hyperglycemia generates a compounded risk for postoperative delirium (POD) and postoperative cognitive dysfunction (POCD). Hyperglycemia and glycemic variability induce oxidative stress, endothelial dysfunction, and neuroinflammation, leading to microvascular injury and blood–brain barrier disruption. These processes are associated with elevated inflammatory biomarkers including, IL-6, TNF-α, CRP, S100B, NSE, and impaired neuronal insulin signaling, which compromise synaptic plasticity and cognitive reserve. Neuroimaging studies further demonstrate diabetes-related structural and functional brain alterations, including increased white matter lesion burden and hippocampal atrophy, that predispose patients to perioperative cognitive impairment. (71–73). By raising neuroinflammatory responses, reducing cerebral perfusion, and increasing blood-brain barrier (BBB) permeability, glycemic swings and persistent hyperglycemia aggravate the consequences of ageing on neurovascular function. These elements render the brain less suited to the physiological demands of surgery, which causes long-term cognitive loss connected to POCD (74). Older patients with diabetes are more susceptible to unexpected cognitive problems like delirium. Furthermore, the incidence of comorbid diseases like cardiovascular disease, hypertension, and chronic kidney illness rises with ageing. These disorders further affect neurocognitive capacities and vascular integrity, therefore increasing the likelihood of cognitive problems after surgery. Older diabetic patients’ risk of delirium and POCD is much raised by age-related changes in neuroplasticity, neurovascular function, and cognitive processing (75). This is especially relevant when comorbidities connected to diabetes aggravate the condition: hyperglycemia, vascular dysfunction, and neuroinflammation. During surgery, fluctuations in blood pressure and cardiac output further exacerbate pre-existing vascular conditions, complicating the brain’s ability to maintain an adequate supply of oxygen and nutrients.

This hinders cognitive performance, particularly in regions of the brain that govern executive function, memory, and attention (76). Additionally, cardiovascular medications commonly prescribed to diabetic patients, such as beta-blockers and ACE inhibitors, may impair cognitive performance by causing electrolyte imbalances or hypotension during the postoperative phase. Renal impairment, often seen in patients with diabetes due to diabetic nephropathy, is another significant comorbidity that impacts cognitive function during the perioperative phase (77). Renal dysfunction can lead to the accumulation of uremic toxins in the bloodstream, which can cross the BBB and have neurotoxic effects on the central nervous system. Dialysis patients and those with chronic kidney disease (CKD) often experience cognitive impairment and delirium due to the elevated amounts of uremic toxins in their brains. Dialysis, while essential for renal failure treatment, can also contribute to cognitive deficits due to fluid balance changes, electrolyte imbalances, and hypotension, all of which affect brain oxygenation and perfusion (78). Hypertension and electrolyte imbalances, common in renal disease, exacerbate vascular dysfunction and cerebral ischemia, further increasing the risk of delirium and POCD. Patients with renal dysfunction also tend to have longer recovery times as their impaired ability to eliminate waste results in slower clearance of anesthetics and medications, leading to prolonged cognitive impairment after surgery.

Chronic depression, frequently associated with reduced hippocampal volume, further complicates recovery (79). Depression impairs memory and learning, both of which are critical for cognitive recovery post-surgery. Depressed patients often have poor glycemic control, contributing to elevated inflammation and an increased risk of cognitive decline (68). Additionally, depression affects the autonomic nervous system, increasing the risk of delirium and weakening cerebral blood flow regulation. Sleep disturbances and fatigue, frequently noted in individuals with depression, might intensify postoperative cognitive impairment by hindering synaptic plasticity, obstructing memory consolidation, and enhancing neuroinflammatory signaling, as indicated by increased IL-6 and TNF-α levels. Disruption of circadian rhythms and stimulation of the hypothalamic–pituitary–adrenal (HPA) axis exacerbate vulnerability to postoperative cognitive dysfunction (POCD) and postoperative delirium (POD) during the recovery phase (80–82). Consequently, the regulation of diabetes and the management of depression are crucial for enhancing cognitive results post-surgery in diabetic individuals (83).

3.3 Surgical and anesthetic factors

Particular surgical categories, such as cardiac and non-cardiac surgery, and the classification of surgical procedures, including major and minor surgeries, have a substantial impact on cognitive outcomes in individuals with diabetes. The development of postoperative cognitive dysfunction (POCD) and postoperative delirium (POD) is significantly influenced by these factors (84). Moreover, the complexity and severity of surgical procedures are closely linked to neurological stress responses, neuroinflammatory processes, and vascular function, all of which play a critical role in cognitive recovery (85). The type of surgery performed is a key contributing factor to these adverse outcomes, particularly in patients with diabetes, who are more susceptible to postoperative cognitive decline due to pre-existing vascular and metabolic impairments. The duration and level of invasiveness of surgical operations have a considerable impact on the severity of postoperative cognitive impairment (86). deep general anesthesia, substantial blood loss, and elevated systemic stress are associated with major surgical procedures, such as abdominal, cardiac, or vascular surgeries. These factors can worsen neuroinflammation and cerebral hypoperfusion in patients with diabetes. Surgical procedures that worsen cognitive impairment might result in increased oxidative stress, decreased cerebral blood flow, and more pronounced fluctuations in glucose levels (87). In order to reduce the risk of postoperative cognitive dysfunction (POCD) and delirium (POD) in individuals with diabetes, anesthetic techniques and pharmaceutical drugs are essential. Cognitive outcomes can be strongly impacted by the choice of anesthetic materials, the type of anesthesia (general or regional), and the management of anesthesia during the perioperative period, either improving or worsening them (88–90). Because they already have vascular impairments, neuropathy, and metabolic abnormalities, diabetic patients are more vulnerable to the effects of anesthesia. Therefore, to successfully reduce postoperative cognitive problems, it is essential to understand how specific anesthetic techniques affect the central nervous system (CNS) in individuals with diabetes. General anesthesia is commonly used after major surgery and can have a significant impact on brain function, particularly in diabetic people. Studies reveal that the use of volatile anesthetics, such as isoflurane and sevoflurane, can impair neuroplasticity and synaptic transmission (91, 92). Cerebral hypoperfusion could arise from these anesthetics’ disruption of neurotransmitter systems and reduction of cerebral blood flow (93) Figure 3. Compromised vascular function, which is typified by endothelial dysfunction and microvascular damage, exacerbates these effects in patients with diabetes and makes it more difficult for the brain to guarantee an adequate supply of oxygen and nutrients during surgical procedures. However, localized anesthetic techniques like nerve, spinal, or epidural blocks are linked to fewer cases of cognitive impairment during the recuperation phase (94). By eschewing the use of volatile anesthetics, regional anesthesia may reduce the effects on brain function. Localized (regional) anesthesia can help maintain cerebral perfusion by avoiding the hypoperfusion and blood pressure fluctuations commonly associated with general anesthesia (95–97). In diabetic patients, close monitoring of blood glucose levels and fluid balance remains essential even when regional anesthesia is used to support optimal cognitive outcomes. The choice of anesthetic agents also plays a critical role, as some volatile anesthetics have been linked to delirium and postoperative cognitive dysfunction (POCD), likely due to their effects on neurotransmission and neuroinflammatory pathways (98). Because of their rather constant effects on cerebral blood flow and their anti-inflammatory qualities, intravenous medicines including propofol, usually used in general anesthesia, may be linked with a lower risk of cognitive impairment. Particularly compared with other volatile anesthetics, experimental investigations indicate that propofol exhibits antioxidant and neuroprotective properties, which could help reduce the incidence of postoperative cognitive dysfunction (POCD) (99). Large clinical studies have not clearly shown its superiority, particularly in diabetic individuals who may be more prone to cognitive problems; the evidence still seems suggestive rather than decisive.

4 Detection and screening tools of POCD and delirium4.1 Cognitive screening tools

Standardized cognitive tests help to evaluate postoperative cognitive dysfunction (POCD) in diabetic patients especially prone to cognitive decline resulting from metabolic irregularities, vascular damage, and neurological issues connected with diabetes. Importantly, POCD refers to a more subtle cognitive decline that usually develops days to weeks after surgery and may persist for months, which is different from postoperative delirium (POD), an acute fluctuating condition occurring within hours to days. These tests measure important cognitive skills including executive function, memory, processing speed, and attention, all of which could be affected following surgery especially in people with pre-existing diabetes-related problem (29). Both the MMSE (Mini-Mental State Examination) and MoCA (Montreal Cognitive Assessment) are brief cognitive screening tools used to assess cognitive function. However, referring to them as providing an insightful analysis overstates their purpose and capability. These tools were not originally designed specifically for diabetic patients, though they are often employed in broader clinical populations, including those with diabetes, due to the increased risk of cognitive impairment in this group (100). Evaluating general cognitive ability is mostly dependent on the MMSE. This quick, organized test assesses orientation, attention, memory, language, and computation among other cognitive areas. Although the MMSE is good in identifying early symptoms of dementia and POCD, especially in older diabetic patients, it may not be sensitive enough to find modest cognitive impairment (MCI) or mild cognitive changes following surgery, meaning that its sensitivity for subtle POCD can be limited, even if its specificity is higher for more advanced impairment (101). In contrast, the MoCA is generally considered more sensitive in detecting mild cognitive impairment and early postoperative cognitive decline, making it more useful for identifying subtle POCD changes. It is especially restricted in identifying executive function and processing speed deficiencies, which patients with diabetes commonly compromise. Notwithstanding its shortcomings, the MMSE is nevertheless a useful instrument for spotting notable cognitive decline in diabetes patients following surgery.

Conversely, the MoCA is a useful tool for evaluating POCD in diabetic patients since it is more appropriate for identifying small cognitive deficits and MCI (102).

Common in patients with diabetes, executive dysfunction and attentional problems are especially delicate to it. Although the MMSE provides a rapid assessment of more severe cognitive deficits, the MoCA is more skilled at spotting subtle cognitive changes and MCI particularly common in diabetes individuals. Combining both tests can provide a more whole evaluation of the cognitive condition of a diabetic patient following surgery (103). The MMSE and MoCA do, however, have limits in evaluating cognitive deterioration in diabetic individuals. As various research, particularly in populations with lower literacy levels, have shown, the MoCA, for example, may not be generally relevant across all demographic groups within the diabetic population due of cultural and educational biases (104). Moreover, although the MMSE is extensively investigated and applied, it might not be very sensitive in identifying mild cognitive decline in patients with diabetes, especially those with attention and executive function problems.

Identification of diabetic individuals at higher risk for postoperative deliriu