T2DM is characterized by two central pathophysiological defects: pancreatic β-cell dysfunction and insulin resistance (IR). β-cell dysfunction manifests as inadequate insulin secretion or decompensation, ultimately resulting in hyperglycemia. IR refers to diminished responsiveness of peripheral tissues (e.g., skeletal muscle, adipose tissue, liver) to insulin signaling, glucose uptake into these cells becomes inefficient, resulting in its accumulation in the bloodstream and consequent hyperglycemia. To compensate, pancreatic β-cells augment insulin secretion, leading to a state of hyperinsulinemia. These defects mutually reinforce each other, establishing a vicious cycle. Chronic inflammation, ectopic lipid deposition, endoplasmic reticulum stress (ERS), and oxidative stress further exacerbate metabolic dysregulation by impairing insulin sensitivity and/or β-cell function, thereby driving the onset and progression of T2DM and its target organ damage (TOD) (6).

β-cells integrate signals from glucose, free fatty acids (FFA), hormones (e.g., incretins GLP-1/GIP), and neural inputs to dynamically regulate insulin secretion (7). Factors contributing to β-cell failure include: aging and genetic predisposition, incretin resistance/deficiency (e.g., impaired glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP] signaling), lipotoxicity (FFA-induced β-cell apoptosis) and glucotoxicity (chronic hyperglycemia-induced oxidative stress), insulin resistance-induced β-cell stress, islet amyloid deposition (excessive islet amyloid polypeptide [IAPP] aggregation), reactive oxygen species (ROS)-mediated damage and proinflammatory signaling (8).

IR is a multifactorial metabolic disorder marked by reduced responsiveness of insulin-target tissues (liver, adipose tissue, skeletal muscle) to physiological insulin levels. It is closely linked to metabolic syndrome (MS), where obesity, dyslipidemia, and hypertension amplify IR through: proinflammatory cytokine release (e.g., TNF-α, IL-6), ectopic lipid accumulation (hepatic and muscular lipotoxicity), oxidative stress-mediated inhibition of insulin receptor signaling (e.g., PI3K/Akt pathway) (9).

Insulin acts on insulin receptors in the brain to promote neurotransmitter synthesis, synaptic plasticity, and neuronal differentiation—processes critical for learning and memory. Insulin signaling in the brain is essential for normal cognitive function, particularly in key regions such as the hippocampus and prefrontal cortex (25), where it regulates glucose utilization, energy homeostasis, synaptogenesis and long-term potentiation (LTP). It also governs appetite regulation and systemic metabolic balance (26). Brain insulin resistance (BIR) is recognized as a key factor linking metabolic disorders like obesity and T2DM to cognitive decline. It disrupts normal insulin signaling pathways, leading to mitochondrial structural and functional abnormalities, which in turn result in ​​impaired energy metabolism​​ and ​​increased oxidative stress​​. This dysfunction triggers ​​neuronal damage​​ and ​​cognitive deterioration​​, ultimately contributing to ​​cognitive impairment​​ (27).

BIR reduces plasma levels of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) (28), which plays a critical role in promoting structural and functional plasticity in the central nervous system (CNS) (29). Additionally, BIR downregulates the expression of neuronal glucose transporters (e.g., GLUT4), impairing cerebral glucose uptake (30). This energy deficit results in decreased brain glucose utilization, triggering neuronal metabolic dysfunction. Such metabolic disturbances not only compromise synaptic plasticity but may also threaten neuronal survival, contributing to memory deficits and executive dysfunction.

Diabetes mellitus, a chronic metabolic disorder, significantly disrupts systemic and localized inflammatory responses, thereby compromising brain health. The systemic inflammation associated with diabetes promotes increased BBB permeability, neuroinflammation, and subsequent neurodegenerative alterations. These inflammatory processes are mechanistically linked to cognitive impairment and an elevated risk of neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease.

Characterized by chronic low-grade inflammation, diabetes alters the expression of key inflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and C-C motif chemokine receptor 2 (CCR2), which collectively modulate peripheral and central immune responses (31). Activation of inflammatory pathways, particularly those mediated by NF-κB, synergizes with oxidative stress and impaired autophagy to exacerbate neuronal damage and accelerate cognitive decline (32). Dysregulated inflammatory signaling in diabetic individuals amplifies ischemic brain injury.

Diabetes exerts profound detrimental effects on cerebrovascular health, precipitating vascular injury and microvascular pathologies closely associated with cognitive impairment. The relationship between diabetes and cerebrovascular pathology is multifaceted, encompassing both macrovascular and microvascular abnormalities that synergistically contribute to cognitive decline (33).

Accumulating evidence indicates that diabetes independently increases the incidence of cerebral infarctions and vascular brain injuries, both of which are critical determinants of cognitive deterioration (33). Diabetic-induced cerebrovascular damage manifests as endothelial dysfunction, increased arterial stiffness, and thickening of capillary basement membranes (34). These pathological alterations compromise cerebrovascular elasticity and integrity, leading to reduced cerebral blood flow and chronic cerebral hypoperfusion, thereby exacerbating cognitive deficits.

As an established risk factor for cerebrovascular diseases, diabetes is characterized by a higher prevalence of cerebral infarctions, white matter hyperintensities (WMH), and cerebral small vessel disease (CSVD) (33). These pathologies exhibit greater severity in diabetic populations and correlate with an elevated risk of accelerated cognitive decline. Preclinical studies utilizing diabetic rodent models demonstrate that hyperglycemia exacerbates cerebrovascular dysfunction, which parallels observed cognitive impairments, highlighting diabetes-specific vulnerabilities in neurovascular coupling (35).

Chronic hyperglycemia drives oxidative stress, a pivotal mechanism underlying neuronal injury in diabetes. Sustained elevation of blood glucose promotes excessive generation of ROS and reactive nitrogen species (RNS), overwhelming endogenous antioxidant defenses. This redox imbalance critically contributes multifaceted biochemical cascades and cellular dysfunction. Prolonged hyperglycemia activates four major oxidative stress-inducing pathways: the polyol pathway, advanced glycation end-product (AGE) accumulation, protein kinase C (PKC) activation, and dysregulation of the hexosamine pathway (36, 37). These interconnected pathways work synergistically to amplify ROS production, which directly damages neuronal membranes, proteins, and DNA.

Moreover, oxidative stress activates redox-sensitive transcription factors, such as NF-κB, leading to the upregulation of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) (37, 38). These cytokines exacerbate neuroinflammation, creating a vicious cycle in which oxidative stress and inflammation synergistically drive neurodegeneration. Diabetic rodents exhibit elevated oxidative markers (8-OHdG, nitrotyrosine) and increased apoptosis in dorsal root ganglion (DRG) neurons, confirming oxidative damage as a driver of peripheral neuropathy (39).

Emerging evidence reveals significant pathophysiological intersections between diabetes mellitus, particularly T2DM, and neurodegenerative disorders, with Alzheimer’s disease (AD) demonstrating particularly strong associations (40). T2DM has been established as an independent risk factor for accelerated cognitive decline and neurodegeneration, potentially increasing AD susceptibility through shared biological mechanisms. The disease continuum appears driven by overlapping pathways including chronic insulin resistance, systemic inflammation, and mitochondrial dysfunction, which collectively create a neurodegenerative milieu (41, 42). Notably, hallmark AD pathologies – β-amyloid (Aβ) plaque deposition and tau protein hyperphosphorylation – are exacerbated by diabetic metabolic disturbances. Sustained hyperglycemia and impaired insulin signaling in T2DM patients potentiate amyloidogenic processing while compromising tau protein homeostasis, thereby accelerating the neuropathological cascade characteristic of AD progression (43).

The gut-brain axis is a bidirectional communication system between the gastrointestinal tract and the central nervous system that influences cognitive function through various mechanisms (44). In T2DM, significant alterations occur in the composition of the gut microbiota, which affect cognitive abilities. Specific genera (e.g., Parabacteroides and Lactobacillus) have been shown to modulate metabolites, thereby improving cognitive behavior in diabetic models (45). Changes in the gut microbiome directly or indirectly impact brain function through vagal, endocrine, and immune pathways. Metabolites directly activate vagal afferent nerves, transmitting signals to the brain via vagal pathways. In the endocrine pathway, enteroendocrine L cells release gut hormones such as GLP1, peptide YY (PYY), and cholecystokinin (CCK), which subsequently influence learning, memory, and mood. Within the immune pathway, immune cells including helper T cell 1 (Th1), helper T cell 17 (Th17), regulatory T cells (Treg), neutrophils, and macrophages are stimulated (46). Fecal microbiota transplantation has demonstrated potential in alleviating diabetes-related cognitive decline by altering gut microbiota composition and enhancing brain insulin signaling pathways (45).

Although the gut-brain axis plays a significant role in T2DM-related cognitive impairment, it is essential to consider other contributing factors, such as genetic predisposition and lifestyle. The interactions between these factors and the gut-brain axis are complex and require further research to fully elucidate the underlying mechanisms.

The relationship between glycemic control and cognitive performance represents a critical focus in diabetes research, particularly in the context of neurodegeneration. Accumulating evidence indicates that suboptimal glycemic management is strongly associated with accelerated cognitive impairment, whereas rigorous blood glucose regulation may attenuate neurodegenerative progression. In patients with T2DM, chronic hyperglycemia and elevated glycated hemoglobin (HbA1c) levels correlate with measurable declines in global cognitive function. Multiple studies have shown that improving blood sugar control can enhance cognitive function. For example, a systematic review found that antidiabetic treatment can significantly alleviate the decline in cognitive ability in diabetic patients (55).

The potential impact of glucose-lowering drugs on cognitive function is multifaceted, encompassing both adverse effects resulting from drug-induced hypoglycemia and possible cognitive benefits associated with specific drugs. These effects are systematically summarized in Table 1.

As a first-line oral hypoglycemic agent for T2DM, metformin demonstrates bidirectional regulatory effects on cognition. Accumulating evidence suggests its neuroprotective properties through mechanisms including AMPK signaling pathway activation and oxidative stress inhibition, with demonstrated improvements in specific cognitive domains such as verbal learning, working memory, and executive function in diabetic patients (56). Notably, prolonged metformin therapy may induce vitamin B12 deficiency, which has been established as a risk factor for cognitive decline (57, 58). This dual mechanism indicates that while metformin may mitigate diabetes-related neurodegenerative processes, it could paradoxically impair cognitive health in susceptible individuals through nutritional metabolic disturbances. Clinical protocols should therefore incorporate regular serum vitamin B12 monitoring and timely nutritional supplementation to prevent associated complications (59).

Accumulating evidence supports behavioral and lifestyle interventions—including dietary modification, physical exercise, and cognitive training—as promising non-pharmacological strategies to mitigate diabetes-related cognitive decline. T2DM is a well-established independent risk factor for mild cognitive impairment and dementia progression. While current pharmacological interventions remain suboptimal, multimodal lifestyle approaches demonstrate clinically meaningful potential for preserving neurocognitive function in T2DM populations.