Brain-derived neurotrophic factor in diabetes: A promising target for cognitive restoration

Summary

Brain-derived neurotrophic factor (BDNF) plays an essential role in neuronal growth and maturation, as well as in maintaining synaptic plasticity. Dysregulated BDNF levels significantly increase the risk of neurological and metabolic disorders. In type 2 diabetes mellitus, several pathological mechanisms, including prolonged hyperglycemia, oxidative damage, chronic inflammation, and impaired insulin sensitivity, are known to drive neurodegenerative processes and deterioration of cognitive function. Impaired BDNF signaling can result in compromised synaptic transmission and gradual loss of neurons, with the hippocampus being particularly vulnerable. A growing body of evidence points to a strong correlation between diminished BDNF levels and diabetes related cognitive decline. Findings from both human clinical trials and animal studies have consistently reported reduced BDNF concentrations in brain tissues and systemic circulation in diabetic conditions. Therapeutic strategies aimed at upregulating BDNF expression and modulating its downstream signaling pathways hold considerable promise for preventing or mitigating diabetes associated cognitive deficits.

Graphical abstract

Neuroscience

Introduction

Brain-derived neurotrophic factor (BDNF) is vital for the maturation, differentiation, and survival of neurons. It was first extracted from mammalian brains and is the second member of the neurotrophin growth factor family, after nerve growth factor.¹ Several studies have shown that the existence of BDNF is essential for cell proliferation, growth, and axon navigation, dendritic tree development, and synaptic connectivity. It is synthesized from proBDNF, which is subjected to proteolysis by various enzymes.² BDNF is commonly available in the hippocampus, amygdala, and cerebellum. An examination of cell types reveals that BDNF is present in major glutamatergic neurons but is missing in interneurons and astroglial cells, although astroglial production of BDNF is present in cell culture. It has a significant role from infancy to adulthood in the survival, differentiation, and outgrowth of central nervous system (CNS) neurons.³ It also participates in neuronal plasticity and is thus responsible for learning and memory. Studies have found that the level of BDNF in a person with DM is responsible for cognitive impairment, as BDNF has a positive relationship with memory.⁴ The precise mechanism underlying this phenomenon remains unclear; however, a likely explanation is the neuroprotective role of BDNF. BDNF protein not only exists in the nervous system but also in endothelial cells, skin, adipose tissue, and immune cells. Serum and plasma are also rich in BDNF. Peripheral BDNF was shown to be retained in large quantities in platelets; i.e., it is important for preserving the BDNF secreted from other tissues.⁵ Thus, in this evaluation, we discussed the role of BDNF in cognitive impairment associated with DM and its complications. Changes in the BDNF gene, such as the Val66Met variation, have been linked to both helpful and harmful effects on the brain’s function in various nervous system conditions. Another change, called C270T (rs56164415), happens in a part of the BDNF gene that does not code for proteins. This change is connected to a higher chance of developing Alzheimer’s disease later in life, and also makes someone more likely to get multiple sclerosis, and it can affect when the disease starts.⁶

Synthesis, storage and release of BDNF

Initially, BDNF is synthesized in the endoplasmic reticulum as a precursor protein (preproBDNF). The proBDNF is transported to the Golgi, where it is sorted into constitutive secretory vesicles after the signal peptide is cleaved.⁷ ProBDNF can be transformed into mature BDNF in the trans-Golgi by subtilisin-kexin-type endoproteases, including furin. Only secreted mBDNF is known to be biologically active, and proBDNF is found intracellularly and acts as an inactive precursor.⁸ Recent proBDNF secretion findings and their conversion by plasmin and matrix metalloproteases to mBDNF in vitro indicate that proBDNF may have been biologically active, while intracellular cleavage efficiency is problematic and may differ among neuronal cell types.⁹ The intrinsic pathway, which is not dependent on extracellular pathway. The second is the controlled pathway, where the secretory granules merge with the plasma membrane due to an increase in intracellular Ca²⁺. The mature form must be attached to carboxypeptidase E, and the pro-form must be bound with a short linker to deal with the pro-BDNF in the regulated pathway with authorization¹⁰ (Figure 1).

Figure 1.

The diagram illustrates the synthesis, processing, and functional roles of brain-derived neurotrophic factor (BDNF) in synaptic plasticity

Neuronal activity increases Ca²⁺ influx, which stimulates BDNF gene transcription and mRNA production in the nucleus. The translated pre-pro-BDNF enters the endoplasmic reticulum, undergoes signal peptide removal, N-glycosylation, and is processed in the Golgi. Pro-BDNF can be cleaved intracellularly by furin to mature BDNF (mBDNF) or secreted and cleaved extracellularly by MMPs/plasmin. mBDNF activates TrkB receptors to enhance long-term potentiation (LTP) and synaptic plasticity, whereas pro-BDNF preferentially binds p75, promoting long-term depression (LTD) and degenerative signaling.

The intracellular Ca²⁺ concentration mostly determines the release of neurotrophins. When IP3R depolarizes, Ca²⁺ enters through the voltage-gated calcium channels (VGCC) and NMDA receptor, and when the metabotropic glutamate receptor (mGLUR) is activated, Ca²⁺ exits through IP3R, raising the calcium concentration.¹¹ The Ca²⁺ influx triggers the release of Ca²⁺ from Ryanodine (RyR) receptors that enhance the Ca²⁺ rise. Calcium (Ca²⁺) activates CaMKII, promoting the fusion of secretory vesicles via protein kinase A.¹² Secreted neurotrophins enhance intracellular Ca²⁺ production through positive feedback. PKG activation via the nitric oxide (NO) signaling mechanism reduces neurotrophin secretion by desensitizing proteins involved in this method.¹³

BDNF-mediated neurogenesis

BDNF fits well with the idea that the function of the brain changes based on what it is doing. Stress and hormones such as glucocorticoids, which lower the production of new brain cells in the hippocampus, also reduce BDNF levels. On the other hand, physical activity increases BDNF and helps create more brain cells in the hippocampus. BDNF is important because it helps different types of brain cells, including those that use glutamate, to survive and grow. When people exercise, the amount of BDNF mRNA in the hippocampus goes up quickly and stays high for weeks.¹⁴ There is several evidence showing that BDNF is important for new brain cell growth in adults. Studies have found that when BDNF helps make new brain cells in a special type of mouse brain culture, using a medicine that blocks TrkB stops this process. This shows that the BDNF/TrkB system plays a key role in promoting brain cell growth.¹⁵ Giving BDNF directly into the hippocampus of adult rats led to more new neurons being created and also made some extra granule cells appear, which suggests that BDNF affects both the birth of new neurons and their movement to the right place.¹⁶ BDNF helps activate certain pathways in the body, such as MAPK/ERK, PI3K, and PLC-gamma, by working through a receptor called TrkB. TrkB is a main receptor for BDNF. Research shows that these pathways play an important role in creating new brain cells and strengthening connections between brain cells, both in living organisms and in lab tests. Also, studies suggest that when the BDNF/TrkB system does not work properly, it can lead to problems such as brain diseases and mental health issues.¹⁴ In a model of central nervous system injury, when adult rat retinal ganglion cells were studied, it was found that injecting BDNF into the body helped the nerve cells survive. This happened because BDNF activated certain pathways such as TrkB, MAPK, and PI3K-PKB, and stopped a process called apoptosis, which is when cells die. Also, when BDNF was given continuously for 12 days, it helped create new nerve cells in the hypothalamus. In another study, when mice were given less food, their brain cells in the hippocampus grew better, showing that keeping a balance in energy intake can affect how nerves grow.¹⁷

Intracellular signaling pathways of BDNF

Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are found in many parts of the brain during development and in adult mammals. When BDNF binds to TrkB, it starts important signals inside cells that help neurons survive, grow in shape, and adapt. It is known that this binding activates several key pathways, such as the MAPK/ERK, PLCg, and PI3K pathways, and these pathways help neurons function properly. Besides TrkB, another receptor called p75 also plays a role in helping neurons survive and adapt. BDNF can have either positive or negative effects on neurons, depending on which pathways are activated through TrkB or p75.¹⁸ BDNF can activate several important pathways inside cells, such as the mitogen-activated protein kinase pathway, the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, and the phospholipase C gamma pathway. These pathways can help cancer cells grow, survive, multiply, and move, which can affect how cancer develops. When BDNF and its receptor, called tropomyosin receptor kinase B, are missing or not working properly in these pathways, it can make a person more likely to develop brain and heart diseases. Also, lower levels of BDNF in both the brain and the body are connected to different diseases that affect the nervous system, such as neuropathic pain and mental health disorders.¹⁹ Studies show that mBDNF can work as a pair on the TrkB receptor, which starts several signaling paths such as the PI3K/Akt, NF-κB, and mTOR pathways. These paths help control different functions in the nervous system, such as keeping neurons alive, improving connections between brain cells, and helping them grow and mature. In research about antidepressants, it was found that the NF-κB factor is important in how depression works, and it is involved in processes such as creating new brain cells, sending signals between brain cells, and changing these connections. BDNF is very important in most treatments for depression. Some research suggests that the way BDNF and the NF-κB path work together in a positive cycle might help improve the effects of antidepressants.²⁰ In addition, studies also show that BDNF is an important regulator of other signaling pathways in the hippocampus. It was also found that BDNF can play a role in the nervous system through purinergic receptors, and some of these include P2X7R, P2Y11R, and A2BR. Ribeiro et al. found that when P2X7R is blocked, the ventral hippocampus produces more BDNF-AKT-p70 S6 kinase, which has effects similar to antidepressants.²¹ Also, turning on P2X4R influences how BDNF is released via the p38 MAPK pathway, and P2X7 receptors work in a similar way.²² BDNF helps nerves grow and extend, keeps neurons alive, and changes the connections between nerve cells in the brain and spinal cord. It also helps keep nerve networks working properly and makes them flexible. Many studies have shown that BDNF is important for treating and recovering from brain diseases and injuries. By studying how BDNF and its receptor TrkB work, new and better treatment options can be developed.²³

TrkB receptor and intracellular signaling pathway of BDNF

Tropomyosin receptor kinase (TrkB), often referred to as a Tyrosine Receptor kinase B, binds with BDNF/NT-3 growth factors. A “tyrosine kinase” is an enzyme that can modify some tyrosines on the target proteins by adding a phosphate group. A tyrosine kinase receptor is situated in the cell membrane and activated via the ligand binding to the extracellular domain of the receptor.²⁴ This is the catalytic receptor with a strong affinity for many neurotrophins, which are the tiny protein growth factors contributing to the development and differentiation of various cell populations. TrkB-activating neurotrophins are brain-dependent neurotrophic factor (BDNF), neurotrophin-4, and neurotrophin-3 (NT-3). TrkB mediates the diverse functions of these neurotrophic factors, which involve neuronal differentiation and survival.²⁵ Work has shown that TrkB activation will reduce the KCC2 chloride transporter in the CNS. Neurotrophic factors originating from the hippocampus, i.e., BDNF and its receptor, TrkB, are commonly found in adult mammalian brains.²⁶ Intracellular signals activated by BDNF/TrkB are essential for neuronal growth, morphogenesis and plasticity.¹⁸ The binding of BDNF to TrkB contributes to numerous intracellular signaling pathways, such as (MAPK/ERK), C gamma phospholipase, and PI3K phosphoinositide (PI3K) pathways.¹⁴ BDNF has a biological impact on neurons via activation of specific mechanisms. A low-affinity receptor, p75, also leads to neuronal survival and plasticity in response to TrkB. The BDNF has either a beneficial or negative impact on neurons through different intracellular signaling pathways activated through TrkB or p75 activation.²⁷ From a scientific perspective, the functions of BDNF in the pathophysiology of multiple brain illnesses are implicated. The biochemical mechanisms of depression are correlated with stress-induced steroid hormones, glucocorticoids, and BDNF.²⁸ The latest research indicates that glucocorticoids and BDNF/TrkB-mediated signaling could have crosstalk²⁹ (Figure 1). The three main pathways of BDNF actions are as follows.

P13/Akt pathway

PI3K activation alters the inositol phospholipid composition of the plasma membrane’s inner leaflet, enabling the translocation of Akt/protein kinase B to the membrane.³⁰ Stimulated Akt supports cell viability and protein production. The TrkB-PI3K-AKT pathway enhances translation by activating mTOR, a key regulator of protein synthesis.³¹ Akt is regulated by TSC2 tuberous sclerosis complex downregulation, which creates a complex with TSC1. This complex further inhibits Rheb, a usual mTOR activator. P70S6 kinase and 4E-BP1 are phosphorylated by active mTOR, which allows mRNA translation.³² The PI3K-Akt system controls synaptic protein transport. This route plays an important role in sustaining synaptic plasticity over the long term through the translation and transport of synaptic proteins.³³

MEK/Erk pathway

In this MEK/Erk pathway, the Shc protein is transferred to TrkB and phosphorylated at another TrkB phosphorylation site. In return, Shc joins forces with Grb2, an adapter protein that activates the guanine nucleotide exchange factor SOS. To bind and activate GTP, SOS promotes the removal of Ras GDP.³⁴ Ras stimulates B-RAF, MEK, and MAPK/Erk downstream kinases. MEK-MAPK/Erk signaling affects transcription activities such as CREB transcription factor activation.³⁵ This increases the phosphorylation of eukaryotic initiation factor 4E, which binds to 4E-BP1 protein and ribosomal protein S6, thus regulating protein production-based plasticity. MAPK/Erk pathway, therefore, plays a crucial role in protein-production-dependent plasticity³⁶ (Figure 2) concept reproduced from Schirò G et al., 2022).

Figure 2.

The signaling pathways of mBDNF and proBDNF

The diagram illustrates BDNF signaling through its receptors TrkB and p75NTR. Binding of mature BDNF to TrkB induces receptor autophosphorylation at key tyrosine residues, activating PI3K-Akt-mTOR, Ras-Raf-MEK-ERK, and PLCγ pathways. These cascades converge on CREB in the nucleus to regulate gene transcription involved in dendritic growth, cytoskeletal remodeling, protein synthesis, synaptic plasticity, neuroprotection, and myelination. PLCγ generates DAG and IP3, leading to PKC activation and Ca²⁺ signaling via CaMKII. In contrast, pro-BDNF binding to p75NTR activates NF-κB and JNK pathways, which can promote apoptotic signaling.

PLC/PKC/IP3 pathway

There are two components involved in tyrosine phosphorylation that are located outside of the TrkB kinase activation domain. Phosphatidylinositol 4,5-bisphosphate generates diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) via phospholipase C (PLC) activation. DAG activates protein kinase C (PKC), and IP3 causes the release of intracellular Ca²⁺.³⁷ The main use of BDNF is that it contributes to strong calcium transients at postsynaptic sites in the formation of hippocampal neurons.³⁸ The BDNF-induced release of intracellular Ca²⁺ in combination with DAG stimulates a plasma-membrane-transient receptor function canonical subfamily channel (TRPC3/6), which leads to BDNF-induced Ca²⁺ increases at growth cones and synapses.³⁹ Several studies directly relate the PLC pathway of BDNF-stimulated Ca²⁺ to synaptic plasticity.⁴⁰

BDNF and diabetes

BDNF supports glucose metabolism and prevents pancreatic depletion in diabetic mice by preserving and regenerating insulin-secreting β cells.⁴¹ These actions of BDNF indicate that pancreatic β cells can be protected by BDNF.¹ This cytoprotective activity of BDNF could be related to a potential mechanism(s) for its binding to the receptor TrkB that results in the induction of proteins that cause IRS, PI3K, and protein kinase B (Akt) activation.⁴² Such steps stimulate one or more transcription factors that control gene expression of proteins that engage in synaptic plasticity, stress tolerance, and cell survival.⁴³ Therefore, the downstream signaling pathways of BDNF and IGF-I are consistent with both p-CAMK I (calcium/calmodulin protein kinase II) signaling, which facilitates cell survival through a dual pathway involving post-translational modification, and inhibition of cell death machinery.⁴⁴ It also increases pro-survival gene transcription. Thus, BDNF inhibits the progression of DM and acts as an anti-diabetic agent.⁴⁵

BDNF dysregulation in diabetes

BDNF and its receptor TrkB are abundantly expressed and secreted in various nuclei of the hypothalamus and hippocampus, where they play a crucial role in regulating glucose and energy balance.¹⁷ Activation of the melanocortin-4 receptor (MC4-R) is widely recognized to suppress appetite while enhancing energy expenditure. Moreover, evidence suggests that BDNF functions as a key downstream effector of the melanocortinergic signaling pathway, particularly in the ventromedial hypothalamus, where its expression is regulated by MC4-R signaling.⁴⁶ BDNF plays a central role in controlling appetite and maintaining body weight homeostasis. Experimental studies have confirmed that BDNF administration reduces food intake. In particular, chronic central administration of BDNF over three weeks resulted in marked, dose-dependent suppression of appetite and significant weight loss in rodents’ models. This effect was proposed to be mediated through serotonergic pathways within the hypothalamus.⁴⁷ In addition to its role in appetite control, BDNF is also closely involved in the regulation of glucose homeostasis. Tonra et al.⁴⁸ and colleagues demonstrated that systemic BDNF administration lowered non-fasting blood glucose levels in obese diabetic mice, independent of significant changes in food intake relative to body weight. Likewise, intermittent BDNF treatment for three weeks significantly reduced blood glucose and glycated hemoglobin (HbA1c) in the db/db mouse model, a model of obesity and type 2 diabetes characterized by leptin receptor deficiency.⁴⁹ Krabbe et al.⁵⁰ reported significantly lower circulating BDNF levels in individuals with T2DM compared to nondiabetic subjects. Furthermore, BDNF levels showed an inverse correlation with fasting plasma glucose and the Homeostatic Model Assessment of Insulin Resistance (HOMA2-IR) score, which is an indirect measure of insulin resistance. These findings suggest that elevated plasma glucose may negatively regulate circulating BDNF concentration. Recently, studies have demonstrated reduced serum levels in patients with T2DM compared to healthy controls. Li et al. further observed that decreased serum BDNF levels were inversely associated with body mass index (BMI), insulin resistance, fasting glucose, and disease duration. They also found an inverse relation of serum BDNF level to fasting glucose and duration of illness. Chronic inflammation is a critical contributor to the development of insulin resistance and T2DM. However, studies clearly demonstrated that alterations in the immune system are commonly observed in both obesity and T2DM. These changes are particularly evident in adipose tissue, liver, and circulating leukocytes and associated cytokine and chemokine profiles.⁵¹ Elevated levels of inflammatory mediators such as interleukin-1β (IL-1β), IL-6, and acute phase markers, such as C-reactive protein (CRP), are predictive components in patients with T2DM.⁵² Several studies have identified a strong association of plasma BDNF levels with inflammatory conditions.⁵³ Activated T cells and B cells, and monocytes are known to produce BDNF along with pro-inflammatory cytokines such as IL-6 and TNF-α linsing immune activation with neuronal changes.⁵⁴ Huang et al.⁵⁵ reported that peripheral blood mononuclear cells from obese individuals produce higher levels of BDNF, which are associated with increased IL-6 responses. These findings indicate that inflammatory conditions may enhance BDNF and IL-6 expression in immune cells. Moreover, plasma BDNF levels have been positively correlated with inflammatory markers such as C-reactive protein (hs-CRP) and interferon gamma (IFN-γ) in patients with hemodialysis. This observation may suggest that plasma BDNF reflects the uremic inflammatory condition in patients undergoing hemodialysis.⁵⁶ Krabbe et al.⁵⁰ found a significant association between decreased BDNF concentration and CRP in T2DM independently of obesity. Despite this, no association was found between BDNF and CRP in participants without T2DM. T2DM is characterized by a hypercoagulable state and is linked to increased platelet reactivity. The causes of elevated platelet reactivity are multifaceted, involving metabolic imbalances, high blood sugar levels, and concurrent inflammation.⁵⁷ Patients who have experienced a myocardial infarction showed higher serum BDNF levels, which were associated with P-selectin, a marker of platelet activation and inflammation.⁵⁸ In addition to insulin and glucose, it has been noted that leptin regulates BDNF expression in the hypothalamus. Research has demonstrated that administering BDNF can improve hyperphagia and hyperglycemia in a leptin receptor-deficient db/db animal model.^59,60 It is possible that BDNF has a role in leptin-resistant obesity and T2DM. Maekawa et al.⁶¹ have shown that reduced BDNF expression in the ventromedial hypothalamus correlates with blood glucose levels, elevated leptin secretion, and increased visceral fat mass in a T2DM rat model. T2DM is marked by hyperglycemia due to impaired insulin secretion, insulin action defects, increased hepatic glucose production, and reduced peripheral glucose utilization.⁶² Some studies have indicated changes in BDNF levels with antidiabetic drugs in in vitro, animal, and human models.⁶³ To explore metformin’s effect on BDNF levels, Ma et al.⁶⁴ examined its impact on Schwann cells under hypoxic conditions and discovered a significant decrease in BDNF mRNA levels. Furthermore, to verify the link between metformin and BDNF levels, Yoo et al.⁶⁵ administered K252a, a strong inhibitor of TrkB and TrkC receptors, to mice. The administration of K252a to the group treated with metformin notably counteracted the improvement in neuroblast differentiation reduction caused by a high-fat diet.

Risk factors involving T2D to cognitive impairment

Hyperglycemia

Chronic hyperglycemia increases the production of advanced glycation end products (AGEs) and stimulates oxidative stress and inflammatory signaling. By cross-linking with proteins and lipids, these AGEs cause neuronal dysfunction, increased inflammation, and accelerated neurodegeneration.⁶⁶ Apoptosis-related markers, including Bcl-2, Bcl-xl, Bax, and caspase 3, have been found to be significantly elevated in the hippocampus tissue of diabetic animal models in a number of preclinical investigations.⁶⁷ La Sala et al. found a significant correlation between glycemic abnormalities and circulating miR-21 levels, providing crucial information about the molecular process causing impaired glucose tolerance (IGT). People with IGT were shown to have higher levels of circulating miR-21. Additionally, the formation of reactive oxygen species (ROS) and indicators of insulin resistance were favorably connected with miR-21 levels and postprandial glucose.⁶⁸

Vascular damage

Vascular dementia and Alzheimer’s disease with vascular involvement are among the many types of cognitive decline linked to vascular risk factors and cerebrovascular pathology, collectively referred to as vascular cognitive impairment.⁶⁹ One important mechanism linking type 2 diabetes (T2D) to dementia and cognitive decline is vascular damage. Persistent hyperglycemia and insulin resistance in type 2 diabetes (T2D) lead to endothelial dysfunction, blood-brain barrier (BBB) impairment, and macrovascular damage, which eventually lowers cerebral perfusion and raises the risk of ischemic injury.⁶⁶ Additionally, diabetes can exacerbate diseases including atherosclerosis and cerebral amyloid angiopathy (CAA), increasing the risk of stroke and hastening neurodegenerative processes.⁷⁰

Hypoglycemia

Normal cognitive function is acutely at risk from hypoglycemia. The International Hypoglycemia Study Group (IHSG) defines blood glucose levels below 3.0 mmol/L as “level 2 hypoglycemia” because of their strong correlation with rapid cognitive impairment.⁷¹ A number of counterregulatory mechanisms are triggered to restore normal glucose levels at the onset of hypoglycemia, including suppression of insulin secretion from pancreatic β-cells and enhanced glucagon release from α-cells, mediated by ATP-sensitive potassium (KATP) channel and glucokinase activity. Additionally, activation of the sympathoadrenal system stimulates the adrenal medulla to release catecholamines such as norepinephrine and cortisol.⁷² Intensive treatment was linked to a 3-fold increased risk of severe hypoglycemia as compared to usual care, according to a randomized controlled trial in patients with type 1 diabetes. In this trial, insulin was administered three or more times a day as part of intensive therapy, while one or two injections per day were part of normal treatment.⁷³

Comorbidities

Overlapping metabolic, vascular, and inflammatory processes, comorbid disorders linked to type 2 diabetes significantly contribute to cognitive deterioration. T2D is often accompanied by hypertension, which exacerbates cerebrovascular injury and causes micturition, white matter abnormalities, and small vessel disease, all of which impair cognitive function.⁷⁴ Patients with diabetes and cerebrovascular illness may benefit from therapeutic approaches targeted at reducing dyslipidemia as their cognitive decline progresses. The production of amyloid β (Aβ) is influenced by the activity of two important enzymes, β and γ-secretases, which are involved in the processing of amyloid precursor protein (APP). Because β and γ-secretases are membrane-associated enzymes, increased cholesterol in lipid rafts may facilitate their interaction with APP, increasing activity. The cleavage of APP into amyloidogenic Aβ peptides is facilitated by this interaction.⁷⁵ Coexisting hypertension is frequently closely linked to cerebrovascular problems in diabetics.

Insulin resistance

Insulin resistance in the brain reduces the brain’s ability to absorb glucose, which results in energy shortages. Neurons become physiologically impaired as a result of decreased glucose consumption and synaptic plasticity. Neuronal insulin resistance lowers levels of brain-derived neurotrophic factor (BDNF), which contributes to neurodegenerative alterations, and interferes with long-term potentiation (LTP), a crucial process for learning and memory.⁷⁶ A reduced capacity of insulin to promote glucose absorption and utilization in a particular tissue is known as insulin resistance. It is a key factor in the onset of prediabetes and type 2 diabetes. It has been identified as a potentially controllable factor in AD and cognitive impairment in more recent times. Indices such as the Homeostatic Model Assessment for Insulin Resistance (HOMA) are frequently used in clinical practice to evaluate insulin resistance. These approaches are validated and useful substitutes for more intricate gold-standard methods, such as the euglycemic-hyperinsulinemic clamp.⁷⁷ The anti-inflammatory impact of BDNF is depicted in Figure 3. The IGF axis is a collection of insulin-like peptides (ILPs) that are involved in insulin signaling. Among these, insulin-binding proteins and insulin-like growth factors 1 and 2 (IGF-1, IGF-2) are very important in addition to insulin itself. Insulin has significant neurotrophic effects on the brain. In a similar vein, IGF and its receptors are thought to have two functions in cellular growth and metabolic control.⁷⁸ Reduced cell survival and compromised anti-apoptotic mechanisms result from disruption of insulin/IGF signaling pathways in the brain. Pro-apoptotic factors such as BCL2-associated agonist of cell death (BAD 11q13.1) are regulated differently as a result. Additionally, it is linked to elevated activation of signaling molecules such as NF-κB, FoxO1, and glycogen synthase kinase 3β (GSK-3β). Furthermore, disruption of the GSK-3β/β-catenin/Wnt signaling pathway impairs synaptic plasticity.⁷⁹

Figure 3.

The diagram illustrates the central role of brain-derived neurotrophic factor (BDNF) in regulating neuronal survival, plasticity, and cognitive function, while counteracting dementia-associated pathology

BDNF activates TrkB signaling to promote neural regeneration, synaptic plasticity, neuron health, and memory, and to reduce glutamate-induced neurotoxicity and epilepsy. Through Ras-PI3K-Akt pathways, BDNF enhances neuronal survival and limits neuroinflammation. In contrast, hyperglycemia, aging, amyloid-β, S100β, and HMGB1 activate RAGE signaling, leading to oxidative stress, pro-inflammatory cytokine release, vascular damage, and cognitive decline. BDNF acts as a protective modulator against these detrimental processes.

Gut dysbiosis

Recent studies have found that the microbiota, which is the community of microbes in the gut, may play a role in cognitive problems linked to diabetes. But the exact connection between gut bacteria and cognitive issues as type 2 diabetes progresses is still not clear. Cognitive problems related to diabetes, known as diabetic cognitive dysfunction, are a serious complication of type 2 diabetes. These problems can make it harder for older people to manage their blood sugar levels and can greatly reduce their quality of life. In the past, research on cognitive problems has mainly looked at issues with brain cells, such as the buildup of a protein called beta-amyloid outside the cells and the overactivity of another protein called tau inside the cells. There is also growing evidence that changes in the gut bacteria and the chemicals produced by gut bacteria are connected to several metabolic diseases, including diabetes. An imbalance in gut bacteria can help cause and worsen several diabetes-related health problems.⁸⁰ The gut bacteria help control how the body uses energy and manage the immune system. In people with type 2 diabetes, when the gut bacteria become unbalanced and the protective lining of the intestines is damaged, it can hurt several organs. This happens because harmful substances from the gut enter the bloodstream, which disrupts how the body uses insulin, processes sugar, keeps the immune system balanced, creates harmful chemicals, and causes inflammation. These changes can harm gut health and affect the brain through the vagus nerve, which connects the gut and the brain (known as the gut-brain axis). The vagus nerve is influenced by certain chemicals made by gut bacteria and helps control inflammation by using a pathway called the cholinergic anti-inflammatory pathway (CAIP). This pathway may play a role in reducing inflammation, which could be important in certain types of brain diseases that involve inflammation.⁸¹It is well known that an imbalance in the gut microbiota, called gut dysbiosis, plays a role in the development of type 2 diabetes. This happens because the imbalance increases the production of harmful substances made by gut bacteria, such as trimethylamine-N-oxide (TMAO), secondary bile acids, and lipopolysaccharides. At the same time, it decreases the production of beneficial substances such as short-chain fatty acids and metabolites made from the amino acid tryptophan.^82,83 SCFAs⁸⁴ and indole derivatives⁸⁵ are valuable for maintaining intestinal epithelial barrier function whereas LPS promotes the intestinal permeability. The loss of gut integrity allows the leakage and transfer of metabolites to the distant organs,⁸⁶ promoting the translocation of endotoxic metabolites into circulation and triggering the systemic inflammation.⁸⁷ Systemic inflammation can turn on enzymes such as c-Jun N-terminal Kinase (JNK), IΰB Kinase (IKK), and Protein kinase R (PKR). These enzymes then go after the insulin receptor substrate (IRS-1) and add a type of change called serine inhibitory phosphorylation. This action can block the normal chain of signals that insulin uses to work properly.⁸⁸ Gut dysbiosis can also modify the abundance of neurotransmitters and stimulate the CNS via the vagus route.⁸⁹ In short, mitochondria in neurons, microglia, and astrocytes react to signals from microbiota metabolites and neurotransmitters. If these microbiota metabolites or nerve signals are disrupted, it can affect the shape and function of mitochondria, which in turn can lead to the development of type 2 diabetes through brain inflammation and metabolic problems.^90,91(Figure 3).

Therapeutic interventions: Counteract diabetes associated cognitive impairment

Lifestyle intervention

Integrated lifestyle therapies that combine dietary modifications, physical activity, cognitive exercises, and other techniques may provide synergistic neuroprotective benefits and enhance overall general brain health.⁹² According to recent research, specific dietary approaches can significantly improve cognitive outcomes in people with type 2 diabetes by altering metabolic, vascular, and neurodegenerative pathways. Following a Mediterranean diet, which is strong in polyphenols and omega-3 fatty acids, has been associated with improved memory and decreased hippocampus atrophy. Its strong anti-inflammatory and antioxidant qualities are primarily responsible for these advantages.⁹³ Particularly useful for maintaining cognitive function are multimodal exercise regimens. Large-scale clinical investigations, such as the Look AHEAD research, have shown that higher levels of physical exercise are linked to a slower rate of cognitive deterioration. Additionally, a number of pathogenic pathways in T2D-related cognitive impairment are attenuated by physical activity. Reducing oxidative stress, improving cerebrovascular function, and decreasing Aβ buildup are some of these outcomes.⁹⁴ There is growing evidence that social engagement techniques and cognitive training can mitigate cognitive deterioration in people with type 2 diabetes. It is believed that these therapies enhance compensatory mechanisms and brain resilience. Participating in social activities, such as cognitively demanding tasks and group interactions, may offer further advantages. These kinds of activities can improve cognitive reserve while reducing cortisol levels linked to stress. Long-term, meaningful social contacts play a major role in mediating these advantages.⁹⁵

Remote digital technologies for interventions

Reducing the progression of cognitive impairment in people with diabetes requires early detection and prompt intervention. Cognitive changes can be difficult to recognize in their early stages and often develop gradually. Early diagnosis and intervention can help halt and sometimes even reverse cognitive decline, while maintaining functional abilities and quality of life. Cognitive screening and monitoring should be part of routine diabetes care, especially for those who are at high risk. Early detection makes it possible to implement relevant interventions in a timely manner, such as cognitive training, lifestyle changes, and, when necessary, pharmaceutical approaches.⁹⁶ For controlling cognitive loss in diabetic populations, remote digital health technologies—often referred to as “eHealth”—offer scalable, affordable, and accessible solutions. These platforms use wearable technology, cellphones, tablets, and web-based systems to provide cognitive monitoring, assessment, and therapies right at home.⁹⁷ Computerized cognitive tests are interactive, verified instruments that are used with digital equipment to evaluate areas including processing speed, executive function, memory, and attention. Digital biomarkers, such as keystroke dynamics, speech analysis, and gait analysis, use passively gathered data from wearables and smartphones to assess cognitive state.⁹⁸ Asynchronous communication between patients and healthcare providers is made possible via secure messaging systems. Through RPM systems, clinicians may connect data from wearables, CGMs, and cognitive apps, allowing care teams to keep an eye on a patient’s general health and take preemptive measures.⁹⁹ Different digital devices can be used to give active digital evaluations in clinical or home settings in a variety of formats, such as clinician-guided or self-administered techniques. When compared to traditional paper-based cognitive evaluation methods, these computerized instruments involve less time, money, and staff.¹⁰⁰ Many neurological and metabolic disorders, including type 2 diabetes, are known to cause motor deficits. To evaluate motor functions, mobile applications make use of smartphone sensors including the touch screen, accelerometer, magnetometer, and gyroscope. These instruments allow for the quantitative assessment of manual dexterity, balance, gait, and coordination. Digital evaluations of gait, balance, and finger tapping can be used to track treatment outcomes, gauge the severity of a condition, and correlate with accepted clinical metrics.^101,102 According to a study that compared older persons with and without type 2 diabetes, temporal speech features such as utterance length, overall pause duration, and pause patterns may be sensitive markers of early cognitive impairments. However, more research is needed to confirm and broaden the application of speed-based markers for T2D early cognitive decline identification.¹⁰³ In contemporary healthcare, telemedicine and remote patient monitoring have become crucial tools, especially for managing diabetes. Through the use of digital technologies, telemedicine improves clinical outcomes and individualized care by allowing medical professionals to perform distant evaluations, provide diagnoses, and carry out treatment plans.¹⁰⁴

Pharmacological treatment

The potential of stem cell-based and regenerative techniques to encourage neurogenesis, aid neural repair, and restore functional outcomes in the diabetic brain is currently being studied.¹⁰⁵ Research developments demonstrate the increasing interest in regenerative medicine as a means of enhancing neuronal regeneration and recovery in neurodegeneration associated with diabetes. Stem cell-based interventions may involve either transplantation of external stem cells or activation of resident neural stem cells to replace damaged neurons.¹⁰⁶ Metformin treatment has been linked to better cognitive outcomes in people with type 2 diabetes, according to analysis of data from the global AD Neuroimaging Initiative (ADNI).¹⁰⁷ Antidiabetic drugs called SGLT2 inhibitors lessen the renal tubules’ ability to reabsorb glucose. According to recent research, these substances may also improve cognition through a variety of neuroprotective pathways.¹⁰⁸ It has been demonstrated that engeletin increases BDNF levels, which improves cognitive function. Additionally, it protects microglial cells, which enhances cognitive performance.¹⁰⁹ Engeletin also suppresses important inflammatory signaling pathways, including as NF-κB, c-Jun N-terminal kinase (JNK), and the phosphorylation of signal transducers and activators of transcription 1 and 3 (STAT1/3). By modifying the IκB kinase/NF-κB, mitogen-activated protein kinase 7/JNK, and Janus kinase 2/STAT1 pathways, these actions improve cognitive performance by reducing inflammation.¹¹⁰

GLP-1 receptor agonists (GLP-1RAs) promote neuronal function, regulate microglial activity, and improve vascular integrity. By reducing neuroinflammation and modulating the PI3K/AKT pathway, these agents have neuroprotective effects.¹¹¹ In the hippocampal CA1 region, liraglutide has been shown to lessen damage to synaptic and neuronal ultrastructure. Additionally, it increases the expression of markers such as LC3-II and beclin 1, which improve autophagy. According to in vitro research, liraglutide inhibits mTOR signaling while activating AMP-activated protein kinase (p-AMPK). It has been demonstrated that melatonin inhibits microglial activation. Additionally, it decreases the generation of cytokines that promote inflammation.¹¹²

Research has demonstrated that melatonin (MLT) inhibits microglial activation and reduces the production of pro-inflammatory cytokines. Studies indicate that MLT decreases the expression of TLR4, phosphorylated Akt (p-Akt), and mTOR. This suggests that its anti-inflammatory and anti-apoptotic effects may be linked to the inhibition of the TLR4/Akt/mTOR pathway. Melatonin-treated rats showed better learning and memory in animal trials, as seen by shorter escape latency and more time spent in target zones. Melatonin-treated rats stayed in the target quadrant longer and had shorter escape latencies than HFD-fed and STZ-treated rats. Melatonin reduced the induction of astrogliosis, synaptogenesis, and neurogenesis. Additionally, it reinstated the expression of the insulin receptor and melatonin, as well as their downstream signaling pathway.^113,114 It has been demonstrated that the S1PR1 modulator fingolimod modulates and decreases microglial polarization, which helps to ameliorate cognitive impairment. Research indicates that fingolimod improves cognitive impairments in people with type 2 diabetes. Suppression of proinflammatory cytokine production is the main mechanism by which these effects are mediated.¹¹⁵

Role of BDNF as a therapeutic target for cognitive impairment

The BDNF protein is important for short-term memory function and long-term changes in brain morphology (e.g., plasticity). Indeed, the significance of BDNF for cognitive output is a work line that has gained significant interest.¹¹⁶ The effects of BDNF on cognitive function were mainly focused on memory tasks. The hippocampus is known as the main region of BDNF expression and is widely recognized as crucial to memory function.²⁸ Numerous experiments have strongly shown that BDNF plays a vital function in long-term potentiation (LTP), which is a long-term improvement in the synaptic effectiveness of learning and memory.¹¹⁷ Convergent research also strongly shows that BDNF signal deficiencies lead to the pathogenesis of a variety of significant diseases and illnesses, such as Huntington’s disease, Alzheimer’s disease, and depression.¹¹⁸ The BDNF has shown considerable interest in the process of learning and memory, as it appears that it contributes to behavior-dependent synaptic plasticity.¹¹⁹ The function relies on the hippocampus, which is important for other types of long-standing retention in humans and animals. Quick and selective activation of BDNF appearance in the hippocampus has been reported in contextual learning, and functional blocking BDNF antibodies, BDNF deletion, forebrain trkbsignalling, and over-expression of trkB in mice cause harm to spatial memory.¹²⁰ Among humans, there has been a valine-to-methionine polymorphism correlated with impaired incident memory in vitro neurons transfected with met-BDNF-GFP, which showed decreased BDNF secretion. Thus, this study confirmed that BDNF deficiency is responsible for impaired memory.¹²¹

BDNF is a component that allows cellular metabolism to be regulated in low-oxygen environments and facilitates neuronal survival. This protein is essential for neuronal proliferation and synaptic interaction during neurogenesis.¹²² Potential defensive mechanisms of BDNF contribute to the capacity of this protein to bind to its receptor, that is the TrkB-FL receptor, and trigger intracellular signaling cascades. (NF-kB) protein complex activator is one of the signaling pathways that is related to cell survival during hypoxia.¹²³ Through the application of a particular NF-kB inhibitor, the homo- or heterodimeric complex of NF-kB is typically inactive and found in the cytoplasm. NF-kB reacts to the expression of the Bcl2 and IAP (apoptosis inhibitors) families. Research indicates that BDNF can activate NF-kB. Therefore, it is possible to identify increased NF-kB mRNA synthesis, which is brought on by BDNF, as one of the possible mechanisms to alter cell metabolism in response to low oxygen levels. The PLC, MAPK, and phosphatidylinositol 3-kinase (PI3 K) pathways are further pathways.¹²⁴ The PI3K pathway activates Protein Kinase B (Akt), which in turn promotes the expression of anti-apoptotic proteins such as BcL2 and ultimately aids cell survival by inhibiting the illness. Additionally, pro-apoptotic proteins and pro-caspase-9, which support nerve cell survival, are eliminated as a result of Akt activation.¹²⁵ A common single-nucleotide polymorphism in the pro-region of the human BDNF gene, resulting in a valine-to-methionine substitution (Val66Met), has been associated with the susceptibility, incidence, and clinical features of several neurodegenerative disorders.¹²⁶ A naturally occurring variation in the human BDNF gene causes an amino acid change from valine (Val) to methionine (Met) at the 66^th position in the BDNF pro-region, leading to a functional single-nucleotide polymorphism (SNP) that may affect BDNF’s activity-dependent secretion.¹²⁷ The connection between this BDNF polymorphism and various neuropsychiatric disorders has been thoroughly examined.¹²⁸ Numerous studies have been conducted to explore the potential link between this polymorphism and neurodegenerative disorders of the central nervous system (CNS).The discovery of an SNP in the BDNF gene, which results in a valine (Val) to methionine (Met) substitution at codon 66 (Val66Met, c.196G>A, dbSNP: rs6265), has significantly advanced the understanding of BDNF function in humans. In individuals carrying this Met variant, specifically BDNF Val/Met heterozygotes and Met/Met homozygotes, the gene’s pro-domain structure is modified. Although this change does not necessarily affect the inherent biological activity of the mature BDNF protein, the polymorphism can lead to incorrect protein folding and diminished binding of mature BDNF to its receptor TrkB, resulting in impairments in hippocampal function.¹²⁹ BDNF has important roles in synaptic plasticity and in the processes of learning and memory, so it is an important target for developing therapies for cognitive deficits associated with Alzheimer’s disease, depression, and traumatic brain injuries.¹⁰² BDNF cannot be administered directly because it does not cross the BBB and is rapidly degraded. Gene therapy has recently been developed in which viral vectors transport the BDNF gene to target neurons, and it has been shown to result in improved cognitive function in animal studies. Additionally, some small molecules and peptides have been developed that enhance the body’s own BDNF production or mimic its behavioral effects. For example, TrkB agonists, which selectively activate the tropomyosin-related kinase B (TrkB) BDNF receptor, promote the formation of new nerve cells and the strengthening of synapses, and have improved pharmacokinetics compared to BDNF. Emerging drug delivery technologies such as nanoparticles and exosomes are being developed to facilitate BBB crossing and targeted release. These innovative methods collectively aim to safely amplify BDNF-TrkB signaling to restore cognitive function. BDNF is a key neurotrophin that regulates memory-related neuroplasticity by supporting synaptic growth, proliferation, and cell survival in the central nervous system. BDNF induces LTP, which is essential for learning and memory. Inhibiting BDNF through gene knockout can impair spatial learning and memory.¹³⁰ Various Experiments have recently found thatBDNF level is decreased in cognitive dysfunction-related disorders such as Huntington’s, Alzheimer’s disorders, and mild neurological impairments.¹³¹ In addition, hypothalamic upregulation was connected to increased cognitive function and memory. Studies found that BDNF was negatively correlated with both fasting levels of glucose and DM duration, indicating that reduced BDNF levels in T2DM might be associated with higher levels of glucose and longer duration of hyperglycemia.¹³² A substantial correlation between elevated blood glucose and low plasma BDNF in T2DM has also been seen in recent research. Elevated amounts of leptin, but not insulin, have been shown to adversely affect brain BDNF production.¹³³ Reduction in BDNF levels in the brain of various animal models of type 2 diabetes mellitus (T2DM) has also been observed. All of these findings suggest that poor glucose metabolism may be associated with low BDNF levels; hence, reduced BDNF may be a pathogenetic factor in type 2 diabetes.⁵⁰ Recent research shows that levels of serum BDNF have been favorably associated with the cognitive performance of aged adults, but the specific mechanism for this association is not defined. The neuroprotective role of BDNF may explain the positive association between BDNF and cognition.¹³⁴ BDNF is elicited as the neurophysiological framework for learning and memory, particularly the early and late-stage LTP. Animal studies with BDNF knockout mice have shown substantially diminished LTP.¹³⁵ However, this deficiency may be improved by BDNF upregulation or recombinant BDNF therapies. BDNF is also implicated in insulin tolerance in animals. BDNF increases the consumption of food and decreases blood glucose in overweight diabetic mice.¹³⁶ BDNF’s hypoglycemic impact is not only because of its hypophagia influence but also because BDNF has positive effects on glucose homeostasis and improves insulin tolerance in db/db mice. The contribution of BDNF in uptake is confirmed by experiments on BDNF-deficient mice, which can easily progress obesity and hyperphagia.¹³⁷ However, in normal rats, BDNF has little impact on blood glucose levels, suggesting that BDNF has its effects by increasing insulin sensitivity. In turn, BDNF stimulates many insulin-activated signaling pathways.¹³⁸ Preclinical data are available in Table 1, which contains information about the role of BDNF in DM and cognitive impairment in different animal models.

Table 1.

Preclinical evidence of various drugs used in cognitive impairment associated with DM via increased expression of BDNF

Sr. No.	Animal used	Animal model	Drug used	Molecular target	Pharmacological actions	References
1.	adult male Wister rats	STZ-induced Type 1 Diabetes Mellitus (100 mg/kg)	pioglitazone and Exendin-4 (EX-4)	Up-regulation of the (CREB/BDNF) pathway cAMP response-element-binding protein/brain-derived neurotrophic factor	PIO and Ex-4 may showed neuroprotective effects in T1DM by modulating SIRT-1 signaling	Tork et al.139
2.	adult male Wister rats	STZ-induced Type 1 Diabetes Mellitus (50 mg/kg)	2-aminoethoxydiphenyl borate (2-APB)	CREB-Ser133 pathway and BDNF	Gene expressions of memory-associated proteins (CREB) and BDNF were upregulated.	Thapak et al.140
3.	male Sprague-Dawley rats	STZ-induced Type 1 Diabetes Mellitus (60 mg/kg)	celecoxib	BDNF and TrkB signaling pathway	Celecoxib treatment upregulated BDNF and TrkB phosphorylation, which enhanced memory.	Yang and Gao141
4.	male Wistar rats	STZ-induced Type 1 Diabetes Mellitus (60 mg/kg)	deferoxamine	Neuro-inflammation and cognitive dysfunction due to iron accumulation	DFO effectively increases BDNF levels, combats memory dysfunction, and achieves this by restoring iron balance, reducing neuroinflammation, and mitigating oxidative stress.	Zeinivand et al.142
5.	adult male and female Sprague-Dawley rats	STZ-induced Type 1 Diabetes Mellitus (90 mg/kg)	berberine	mRNA-BDNF	Berberine increased the mRNA-BDNF level in the sciatic nerve due to neuroprotective activity.	Zhou et al.143
6.	male Sprague-Dawley rats	1% STZ at a dosage of 35 mg/kg after three months of a high-carb and high-fat diet	irisin	mRNA-BDNF	Irisin upregulated BDNF expression and attenuated mild cognitive impairment.	Huang et al.144
7.	six-week-old male Wistar rats	streptozotocin (65 mg/kg)	fluvoxamine	mRNA-BDNF/sigma-1 receptor	Disturbed S1R-BDNF signaling in the brain plays a relevant role in DM-induced depression.	Lenart et al.145
8.	8-week-old male Sprague-Dawley rats	for four weeks, a high-fat diet was given, and then 30 mg/kg of STZ was injected.	rolipram	CREB/BDNF/Arc pathway	Levels of CREB, BDNF, and Arc proteins were increased, improving cognitive impairment.	Zhong et al.146
9.	male C57BL/6 J mice and db/db (C57BLKS/J) mice	high-fat diet (60 Kcal)	docosahexaenoic acid	GPR40 and BDNF	DHA improved cognitive function in diabesity via GPR40 agonism and increased the level of BDNF	Sona et al.147
10.	male Wistar rats	STZ-induced cognitive dysfunction (3 mg/kg)	chromium picolinate	IRS-1/PI3K/AKT/GSK-3β pathway	BDNF expression was increased, and cognitive impairment was improved	Akhtar et al.148
11.	4-week-old male ICR mice	an injection of 60 mg/kg of STZ was given following a 4-week high-fat diet.	geniposide	BDNF/CREB signaling pathway	Increased BDNF levels reduced cognition impairment	Liu et al.149
12	4-week-old male C57BL/6J mice	a diet high in sugar and fat for 8 weeks, followed by STZ (100 mg/kg) for 3 days.	dihydromyricetin (DHM)	mRNA-BDNF and oxidative stress mediators (SOD, MDA, CAT, GSH-PX)	DHM increases working memory by increasing mRNA levels of BDNF and suppressing oxidative stress	Ling et al.150
13.	2-month-old male Swiss mice	STZ-induced T2DM (200 mg/kg)	4-4′-dichlorodiphenyldiselenide (p-ClPhSe)2	BDNF/TrkB signaling	(p-ClPhSe)2 modulated theBDNF/TrkB signaling pathway and improved cognitive deficits	Zborowski et al.151
14.	male Wistar rats	STZ-induced T2DM (50 mg/kg)	cilostazol (CLZ)	Selective phosphodiesterase III inhibitor Increase BDNF expression	BDNF level was increased along with antioxidant effects that enhanced memory	Rababa’h et al.152
15.	male Sprague-Dawley rats	STZ-induced T2DM (50 mg/kg)	vitamin D	CREB/BDNF pathway	Vitamin D enhanced CREB phosphorylation in the hippocampus; however, there were no significant changes in serum and hippocampal BDNF levels, nor in TrkB and BDNF gene expression.	Nadimi et al.153
16.	C57BL/6J mice	provided a high-sugar and high-fat diet with an intraperitoneal (i.p.) injection of streptozotocin (STZ) at a dose of 100 mg/kg/day.	dihydromyricetin (DHM)	Increased mRNA expression of BDNF	Mitigating oxidative stress, boosting BDNF-driven neuroprotection, and enhancing cognitive function are essential for optimal brain health and performance.	Ling et al.150
17.	leptin-deficient (db/db) and C57/bl6 male mice	genetic model (insulin receptor knockout) of DM	rosiglitazone	Activation of PPARγ (Peroxisomes proliferator activator receptor) that further increases BDNF expression	Improve synaptic plasticity, neurogenesis andDM-mediated cognitive impairment.	Kariharan et al.154
18.	male albino Wistar rats	High fat, high fructose diet (HFFD)-fed rats	apigenin (4′,5,7-trihydroxyflavone	BDNF-CREB signaling pathway Insulin-mediated Akt/PKB pathway	Apigenin could modulate brain insulin signaling during calorie excess by upregulating BDNF signaling through its ability to enhance GLP-1.	Kalivarathan et al.155
19.	male Wistar albino rats	STZ-induced type 2 diabetic model	exendin-4	Increase BDNF expression and decrease visfatin level in the brain	Through their control of inflammation, oxidative stress, neuro-degeneration, and synaptic function, BDNF and brain visfatin were discovered to contribute to the neuroprotective action	Abdelwahed et al.156
20.	60 prepubertal, 28-days-old male, Sprague-Dawley rats	Intraperitoneal STZ	Insulin + Noopept	Serum LH, FSH, hippocampal NGF-BDNF levels	Noopept may have positive effect in treatment of pubertal diabetes	Gürbüz et al.157
21.	male Wistar rats	high-fat diet/streptozotocin-induced (HFD/STZ) model	MCC950	NLRP3 inflammasome inhibition, which increases BDNF expression	Prevent neurovascular remodeling and cognitive decline	Ward et al.158
22.	obese diabetic db/db mice	Genetic model	BDNF	Enhances glucose metabolism and safeguards against pancreatic exhaustion	Enhance cognitive function in individuals with DM, promote neurogenesis in the hippocampus, and prevent apoptotic responses in the hippocampus.	Yamanaka et al.159
23.	female ICR mice	High-fat diet and streptozocin-induced diabetic mice	ERα and Erβ	The activation of the PI3K/Akt pathway, along with CREB and BDNF in the hippocampus, plays a crucial role in enhancing cognitive function and promoting neuroplasticity.	ERα and ERβ are involved in the cognitive impairment in type 2 diabetes, and that activated ERs	Tang et al.160
24.	male Wistar rats	Sreptozotocin-induced diabetic rat model	resveratrol	reduce oxidative stress and increase neurotrophin expression	Vasculoprotective and neuroprotective effects improve cognitive decline	Gocmez et al.161
25.	male Wistar rats (210–230 g)	Streptozotocin (STZ)-induced diabetic rats	naringin	Elevated SOD and reduced MDA levels significantly lower inflammatory markers, IL-1β, IL-6, and TNF-α while enhancing PPARγ expression.	Improve diabetes-associated cognitive decline (DACD) Antioxidant	Liu et al.162

Reported clinical data

T2DM is correlated with cognitive dysfunction, such as learning, memory, and understanding in humans. Wide population-based research findings show that the cognitive impairment risk is rising among seniors with T2DM.¹⁶³ People with T2DM have a high incidence of mental illness, and approximately 11% and 15% meet the conditions of severe depression. Vascular disease and changes in leptin, insulin, and amyloid beta metabolism are pathways that clarify the association between DM and neuropsychiatric disorders.¹⁶⁴ Several studies have recently found that BDNF serum concentrations in patients with cognitive disorders are substantially decreased, including Huntington’s, Alzheimer’s disorder, and moderate cognitive impairment (MCI).¹⁶⁵ In comparison, the hippocampus upregulation of BDNF was associated with enhanced cognitive performance, including memory. In Table 2, various clinical studies show the relationship of BDNF with DM-associated cognitive impairment. From these studies, it is concluded that BDNF has a positive correlation with cognitive function. This means that when the level of BDNF is increased, the cognitive function of the individual also increases, and vice versa. These studies show that BDNF is not only related to cognitive impairment but also plays an important role in depression. In patients with depression, the level of BDNF is reduced. Thus, BDNF is also an important biomarker for the treatment of depression. It is also clarified that BDNF has a negative relation with age. As the age of humans increases, the level of BDNF decreases; therefore, this can be one of the factors responsible for cognitive impairment in older people. The purpose of the interventional study (NCT05526131) was to evaluate the relationship between the occurrence of depression in people with type 2 diabetes and brain derived neurotropic factor and the val66met polymorphism of the BDNF gene.¹⁷³ Another interventional trial (NCT03670186) investigates whether the Val66Met genetic variation of the BDNF gene affects the physiological and cognitive advantages of exercise in sedentary but otherwise healthy participants after a six-week training period.¹⁷⁴ According to clinical investigations, including one study, SGLT2 inhibitor medication significantly lowers body weight, systolic and diastolic blood pressure, and HbA1c levels (NCT05341388).¹⁷⁵

Table 2.

Clinical evidence of BDNF’s role in DM and cognitive impairment associated with DM

Sr. No.	Type of Study	Condition	No. of participants	Inclusion criteria	Objective	Outcomes	References
1.	single-blinded randomized clinical trials (Interventional study)	obesity leads to DM	304 participants	inactive post-pubertal adolescents aged 14–18 years with BMI > 95th percentile.	to measure the impact of weight exercise, cardiovascular activity, aerobic and resistance training on total body fat.	Improvements in specified DM risk outcomes have been related to increased serum BDNF concentrations in obese adolescents.	Walsh et al.166
2.	randomized controlled cross-over study (Interventional study)	T2DM	14 patients	male patients having T2DM performed no physical exercise more than once a week.	to evaluate the effects of sustained neuromuscular electrical stimulation in patients with T2DM on metabolic profile and cognitive-related blood parameters.	In patients with T2DM, the NMES training system increases plasma BDNF, which lessens neurological issues.	Miyamoto et al.167
3.	observational study	T2DM	715 patients	individuals with T2DM aged from 30 to 75 years	to evaluate the function of BDNF serum concentrations on the mild cognitive impairment (MCI) pathophysiological process	Higher serum BDNF concentrations were linked to decreased risk of MCI and may be useful in recognizing patients with dementia-prone diabetic for early preventive strategies	Sun et al.168
4.	cross-sectional observational study	mild cognitive impairment associated with DM	1833 participants	elderly type 2 patients with diabetic aged 60 years or older	to examine the relation between plasma DPP4 action to the BDNF ratio (DBR) and MCI in old patients with T2DM.	A higher risk of moderate cognitive impairment (MCI) in the elderly is linked to both decreased peripheral circulation levels of brain-derived neurotrophic factor (BDNF) and increased dipeptidyl peptidase-4 (DPP4) activity.	Zheng et al.169
5.	observational study	T2DM	208 patients	patients have T2DM and have taken metformin and repaglinide but have not taken insulin.	to assess the relationship between BDNF and cognitive decline in people with type 2 diabetes	The etiology of cognitive impairments, including delayed memory in type 2 diabetes, is significantly influenced by BDNF.	Zhen et al.170
6.	observational studies	MCI associated with T2DM	326 patients	old and having T2DM	to investigate the relationship between MCI and the GSK-3β/BDNF ratio in older patients with T2DM	Higher GSK-3β/BDNF ratio indicates poorer cognitive performance.	Du et al.171
7.	interventional study	T1DM	14 patients	patients (aged 26.9 years) with or without T1DM participated	to assess how two distinct exercise regimens—intermittent and continuous—affect blood glucose, BDNF, IGF-1, and inflammatory cytokine responses in young adults with and without type 1 diabetes.	Exercise has a positive impact on serum levels of IGF-1 and BDNF. Patients with type 1 diabetes may benefit more from high-intensity intermittent exercise in lowering their chance of developing glycemic problems	Żebrowska et al.172

Recent studies

BDNF’s role in diabetes-related cognitive impairment is well supported by recent experimental and clinical research. One study¹⁷⁶ showed that by altering neurotransmitter levels and lowering inflammation and apoptosis, pinoresinol diglucoside mitigated the cognitive impairment caused by streptozotocin in rats. The NF-κB/BDNF/CREB/caspase-3 pathway was regulated to mediate these effects. These mechanistic linkages were further confirmed by supporting data from molecular docking research. Another study¹⁷⁷ found that in a T2D rat model, a ketogenic diet improved cognitive function. The activation of BDNF-related neuroprotective signaling pathways was partially responsible for this improvement. A clinical investigation found that SGLT2 inhibitor therapy was linked to changes in circulating BDNF levels and enhanced cognitive performance in patients with T2D.¹⁷⁸ Another study assessed the combined effects of semaglutide, a glucagon-such as peptide-1 receptor agonist, and high-intensity interval exercise (HIIE) on diabetes-related cognitive impairment.¹⁷⁹ Exogenous β-hydrobutyrate has been shown to improve cognitive outcomes and BDNF signaling in both insulin-resistant mice and people with type 2 diabetes.¹⁸⁰ The results showed that Elderberry (EB) supplementation reduced blood sugar following DM induction. However, the body weights of the DM and EB groups were lower than those of the control group. However, following DM, the EB diet improved memory and learning while reducing anxiety and despair. Electrophysiological recording showed that the EB diet improved long-term potentiation (LTP) more than the DM group.¹⁸¹ Diabetes-related cognitive impairment appears to benefit from early pharmaceutical management. In one study, mice with diabetes-induced cognitive impairment (DCI) showed a substantial reduction in brain shrinkage and cognitive abnormalities when Sig-1R was activated.¹⁸² BDNF and acetylcholinesterase (AChE) were highlighted in a study that assessed the subchronic effects of HgCl₂ on neuroinflammation and cognitive function in a rat model of type 2 diabetes. The findings demonstrated that the fasting blood glucose levels of the diabetes and HgCl₂-treated groups were significantly higher than those of the control group.¹⁸³ Another study investigated whether the combined administration of insulin and lemon peel essential oil (EO) could mitigate learning and memory impairments associated with chronic hyperglycemia by normalizing oxidative stress, attenuating neuroinflammation, enhancing BDNF expression, and restoring acetylcholinesterase (AChE) activity in streptozotocin (STZ)-induced type 1 diabetic rats.¹⁸⁴ Another study investigated the combined effects of selenium nanoparticles (SeNPs) and high-intensity interval training (HIIT) on cognitive function and neuroprotection in diabetic rats. The findings demonstrated that all treatment groups significantly improved learning and memory, enhanced cell viability, and modulated the expression of GLUT4, BDNF, and irisin.¹⁸⁵

Future prospect

Regarding the BDNF’s involvement in the pathophysiology of DM associated cognitive impairment, there is still evidence translation gaps. Most of the existing studies are preclinical, while human studies lean more toward a clinical-observational methodology that is not adequate enough to show causation. There is also not enough evidence to demonstrate the involvement of polymorphisms (Val66Met), the degree of insulin resistance, the presence of inflammation, and the variability of glycemia. Future studies should concentrate on more longitudinal and interventional clinical studies that are combined with neuroimaging, metabolic biomarkers and cognitive testing in order to confirm the mechanistic studies. This should also be the case for the development of TrkB selective agonists that have a good safety profile, small molecules that are based on gene therapy, and other similar approaches.

Advancing selective TrkB agonists, sharpening the precision medicine approach, developing reliable biomarker panel systems for patient stratification and treatment monitoring, and developing blood-brain barrier-crossable delivery systems with combinations including lifestyle-based BDNF modulators such as exercise or dietary BDNF homeostasis shifting, blood-based BDNF and neuroplasticity modulatory research are proposed to support viable clinical-translatable strategies.

Conclusion

BDNF is a key neurotrophic factor that plays a role in many cognitive processes, metabolic regulation, and neuroprotective mechanisms. Through activation of TrkB, which in turn modulates PI3K/Akt, MAPK/ERK, and PLC pathways, BDNF brings together synaptic plasticity, neurogenesis, insulin sensitivity, and inflammatory modulation, which in turn places it at the crossroads of DM and cognitive impairment. Preclinical data report that restoration of BDNF signaling improves memory performance, reduces oxidative stress, and increases neuronal survival. Also, clinical settings report a positive correlation between circulating BDNF levels and cognitive outcomes in diabetic populations. However, while great progress has been made in the mechanics of it all, translation into effective clinical application is still very limited. Most current data come from animal models and cross-sectional human studies, which in turn limit our ability to make cause-and-effect claims. Also, large-scale variability in the measurement between periphery and center for BDNF, which in turn is also affected by genetic factors such as the Val66Met, and also the fact that a large variety within diabetic populations presents a problem. Future research will put forward the development of selective BDNF TrkB modulators, which we think will improve therapeutic results and at the same time reduce off-target effects.

Data and code availability

No data were generated during this study.

Acknowledgments

The authors are thankful to the School of Pharmaceutical Sciences, Lovely Professional University, Punjab, India, for providing necessary facilities. The authors also extend their appreciation to the Deanship of Research and Graduate Studies at King Khalid University for funding this work through a Large Research project under grant number RGP 2/595/47. The authors would also like to acknowledge BioRender.com, an online image creation platform.

Declaration of interests

The authors declare no competing interests.