Luo C, Yu XM, Zeng MQ, Duan CZ, Xu SY, Zhu CY, Zheng ZG, Sun D, Fang J, He DJ. Breaking the diabetes-depression cycle: Exploring shared mechanisms, neuroinflammation, and emerging interventions for metabolic-mood comorbidities. World J Diabetes 2025; 16(7): 107406 [DOI: 10.4239/wjd.v16.i7.107406]
Corresponding Author of This Article
Dong-Juan He, MD, Chief Physician, Deputy Director, Department of Endocrinology, The Second People’s Hospital of Quzhou, No. 338 Xin’an Avenue, Qujiang District, Quzhou 324002, Zhejiang Province, China. hedongjuan1247@wmu.edu.cn
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
Letter to the Editor
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Cheng Luo, Cheng-Zheng Duan, Shi-Yu Xu, Chun-Yan Zhu, Department of Endocrinology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou 324000, Zhejiang Province, China
Xian-Mei Yu, Dong-Juan He, Department of Endocrinology, The Second People’s Hospital of Quzhou, Quzhou 324002, Zhejiang Province, China
Mei-Qi Zeng, Zhi-Gang Zheng, Department of Ophthalmology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou 324000, Zhejiang Province, China
Da Sun, Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325000, Zhejiang Province, China
Jian Fang, Department of Hepatobiliary Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou 324000, Zhejiang Province, China
Co-corresponding authors: Jian Fang and Dong-Juan He.
Author contributions: Luo C and Yu XM contributed to conceptualization and writing of the original draft, they contributed equally as co-first authors; Zeng MQ and Duan CZ contributed to formal analysis and data validation; Xu SY and Zhu CY contributed to methodology and investigation; Zheng ZG and Sun D contributed to supervision and project administration; Fang J and He DJ contributed to reviewing, editing, and final approval of the manuscript, they contributed equally as co-corresponding authors; and all authors participated in drafting the manuscript and have read, contributed to, and approved the final version of the manuscript.
Supported by the Quzhou Science and Technology Plan Project funded by the Quzhou Municipal Science and Technology Bureau, No. 2022K67, No. 2022K69, and No. 2024K076.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dong-Juan He, MD, Chief Physician, Deputy Director, Department of Endocrinology, The Second People’s Hospital of Quzhou, No. 338 Xin’an Avenue, Qujiang District, Quzhou 324002, Zhejiang Province, China. hedongjuan1247@wmu.edu.cn
Received: March 24, 2025 Revised: April 9, 2025 Accepted: May 15, 2025 Published online: July 15, 2025 Processing time: 114 Days and 23.7 Hours
Abstract
This article explores the bidirectional relationship between type 2 diabetes mellitus (T2DM) and depression, focusing on their shared pathophysiological mechanisms, including immune-inflammatory responses, gut-brain axis dysregulation, metabolic abnormalities, and neuroendocrine modulation. Research indicates that T2DM contributes to anxiety and depression through chronic low-grade inflammation, insulin resistance, gut microbiota imbalance, and hyperactivation of the hypothalamic-pituitary-adrenal axis. Conversely, depression may increase the risk of T2DM via lifestyle disruption, immune activation, and neurotransmitter imbalance. Additionally, metabolic pathway disturbances - such as reduced adiponectin, impaired insulin signaling, and altered amino acid metabolism - may influence mood regulation and cognition. The article further examines emerging therapeutic strategies targeting these shared mechanisms, including anti-inflammatory treatments, gut microbiota modulation, hypothalamic-pituitary-adrenal axis interventions, metabolic therapies (e.g., glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors), and multidisciplinary integrative management. Emphasizing the multisystem nature of diabetes-depression comorbidity, this work highlights the importance of incorporating mental health strategies into diabetes care to optimize outcomes and enhance patient quality of life.
Core Tip: Type 2 diabetes mellitus and depression share a bidirectional relationship driven by immune inflammation, gut-brain axis dysfunction, metabolic abnormalities, and neuroendocrine dysregulation. Chronic low-grade inflammation, insulin resistance, gut microbiota imbalance, and overactivation of the hypothalamic-pituitary-adrenal axis contribute to both conditions. Emerging treatments targeting these shared mechanisms include anti-inflammatory therapies, gut microbiota modulation, regulation of the hypothalamic-pituitary-adrenal axis, and metabolic interventions such as glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors. A multidisciplinary, integrative approach is essential for effective management, emphasizing the need for comprehensive metabolic-mental health strategies to improve patient outcomes and quality of life.
Citation: Luo C, Yu XM, Zeng MQ, Duan CZ, Xu SY, Zhu CY, Zheng ZG, Sun D, Fang J, He DJ. Breaking the diabetes-depression cycle: Exploring shared mechanisms, neuroinflammation, and emerging interventions for metabolic-mood comorbidities. World J Diabetes 2025; 16(7): 107406
The intricate interplay between type 2 diabetes mellitus (T2DM) and psychiatric disorders has garnered increasing attention in recent years. Borovcanin et al[1] previously outlined this bidirectional relationship, underscoring how T2DM may function as a risk factor, comorbidity, or consequence of psychiatric conditions through mechanisms such as inflammation, oxidative stress, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, gut-brain axis dysfunction, and endothelial impairment. Building upon this foundation, the present analysis integrates findings published since 2020 to further delineate the multifaceted links between T2DM and mood disorders, particularly depression and anxiety. Recent literature highlights emerging immune-inflammatory pathways [e.g., toll-like receptor 4 (TLR4) signaling, advanced glycation end-products (AGEs)], microbiota-mediated neuroimmune interactions, and novel therapeutic approaches including glucagon-like peptide-1 receptor agonists (GLP-1RAs), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and microbiota-targeted strategies. Collectively, these advances bridge mechanistic insights with clinical perspectives, offering a more comprehensive understanding of T2DM-psychiatric comorbidities and informing future intervention development.
Bidirectional relationship between diabetes and depression
Borovcanin et al[1] appropriately highlighted the frequent coexistence of diabetes and depression. Indeed, epidemiological data confirm this bidirectional relationship: Individuals with T2DM have a significantly higher prevalence of depression, while those with depression are at an increased risk of developing T2DM[2]. This reciprocal influence is driven by a combination of biological and behavioral factors. Chronic stress and depression can lead to hyperglycemia through elevated cortisol and catecholamine levels, unhealthy lifestyle choices, and poor adherence to diabetes care[3,4]. Conversely, the burden of diabetes management, diabetes-related complications, and psychosocial stressors - such as stigma or the psychological impact of diagnosis - may trigger or exacerbate anxiety and depressive disorders[2,5]. Notably, anxiety symptoms in T2DM patients often overlap with diabetic neuropathy and fear of hypoglycemia, further complicating diagnosis and treatment[6].
We appreciate that this review incorporates a broad spectrum of psychiatric conditions into the bidirectional model, ranging from cognitive impairment and dementia to schizophrenia. The fact that depression is approximately twice as prevalent in individuals with T2DM compared to the general population, and that depression increases the future risk of T2DM (and vice versa), underscores the necessity of integrated medical management. Recent cohort studies and Mendelian randomization analyses have further reinforced the argument for a bidirectional causal relationship between these two conditions[2,7]. Therefore, we fully agree with Borovcanin et al[1] that addressing this dual disease burden is essential for improving patient outcomes.
Immune system and inflammation as a shared mechanism
Growing evidence suggests that immune-inflammatory pathways are key mediators linking diabetes with anxiety and depression. Borovcanin et al[1] described how T2DM induces chronic low-grade inflammation, where hyperglycemia activates the nuclear factor kappa B signaling pathway, upregulating pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6, thereby promoting insulin resistance (IR)[1]. These cytokines can cross a compromised blood-brain barrier, triggering neuroinflammation, synaptic dysfunction, and neuronal damage. In fact, elevated circulating cytokine levels in T2DM patients have also been implicated in the pathophysiology of major depressive disorder, a concept known as the “cytokine hypothesis”[8,9].
Recent studies have further elucidated specific immune-mediated mechanisms. For instance, increased intestinal permeability in T2DM can lead to lipopolysaccharide (LPS)-mediated metabolic endotoxemia, which damages pancreatic beta cells and activates TLR4 on microglia, exacerbating neuroinflammation[10]. Research by Campello-Costa et al[10] demonstrated that diabetic animal models exhibit hippocampal TLR4 overexpression and display more severe depressive behaviors upon LPS stimulation, further linking peripheral immune activation to central depressive phenotypes[10]. Additionally, AGEs, generated by chronic hyperglycemia, act as danger signals by binding to receptors for AGEs and TLR4 on immune and glial cells, amplifying inflammation and oxidative stress. This cascade not only promotes IR and vascular damage but also contributes to mood and cognitive impairments, such as “diabetic encephalopathy” and vascular depression[1]. It is important to emphasize that diabetes-related inflammation is systemic, affecting the pancreas, vasculature, and brain, and may lead to hyperactivation of the HPA axis, reduced neurotrophic support, and disrupted neurotransmitter metabolism. These findings are consistent with studies in patients with depression, where up to 50% exhibit HPA axis overactivation and elevated cortisol levels - features also observed in T2DM patients with poor glycemic control[10]. Overall, immune dysregulation represents a core shared mechanism: T2DM establishes a pro-inflammatory environment that predisposes individuals to depression, while depression-related inflammation (and associated behavioral changes) may further deteriorate glycemic control, creating a vicious cycle[2].
From a clinical perspective, elevated inflammatory markers in diabetes patients, such as increased C-reactive protein or IL-6 levels, should prompt clinicians to assess for depressive symptoms, and vice versa. Our recent research supports this immune connection, showing that the burden of comorbidities in T2DM, as measured by the Cumulative Illness Rating Scale (CIRS), is independently associated with increased depression severity[11]. Patients with a higher number of chronic comorbidities or inflammation-related conditions have a significantly greater risk of depression, suggesting that systemic inflammatory load may impact mental health[7]. These findings, in conjunction with other studies, further underscore the importance of comprehensive assessment - evaluating both physical comorbidities and inflammatory biomarkers is crucial for a more holistic approach to diagnosing and managing psychological health in T2DM patients (Table 1).
Table 1 Common immune-inflammatory mechanisms of type 2 diabetes and depression.
Mechanism
Manifestation in T2DM
Manifestation in depression
Shared pathways/outcomes
Cytokine dysregulation
Elevated TNF-α, IL-1β, IL-6; activation of NF-κB pathway; reduction in anti-inflammatory cytokines
Cumulative inflammatory burden; systemic effects; dysregulation of multiple systems
The gut-brain axis: Microbiota and metabolic signaling
It is notable that Borovcanin et al[1] emphasized the role of the gut-brain axis in diabetes-psychiatric comorbidities, describing it as a “novel therapeutic avenue”. In recent years, the gut microbiota has been recognized as a crucial regulator of metabolism, immunity, and brain function. Patients with T2DM often exhibit gut microbiota dysbiosis, which refers to a disruption in microbial balance and function. Instead of relying on vague definitions such as the ratio of aerobic to anaerobic bacteria, dysbiosis is now increasingly assessed using advanced tools such as 16S rRNA gene sequencing and metagenomics, which allow for more accurate characterization of microbial diversity and function. Conventional culture-based methods are limited in scope, as they fail to detect non-culturable or low-abundance organisms, potentially underestimating microbial shifts. This dysbiosis, along with increased intestinal permeability (so-called “leaky gut”), facilitates the translocation of bacterial metabolites such as LPS into the systemic circulation, thereby initiating inflammatory cascades[1]. These endotoxins can activate immune responses, leading to IR and beta-cell stress, while also directly affecting the brain by inducing neuroinflammation[1]. For instance, short-chain fatty acids, beneficial metabolites produced by healthy gut bacteria, are reduced in dysbiosis, and their depletion may compromise the intestinal barrier and disrupt neurotransmitter systems involved in mood regulation.
Recent studies have further deepened our understanding of this gut-brain connection. Tan[12] described the microbiota-gut-brain axis as a bidirectional pathway, where stress and depression can alter gut microbiota composition, while microbial metabolites influence central neurotransmitter signaling and inflammatory responses. In the context of diabetes, chronic hyperglycemia itself can modify gut microbiota and mucosal immune function[10]. Mázala-de-Oliveira et al[10] demonstrated that dysregulation of the adrenal-gut-brain axis exacerbates depressive symptoms in diabetes: Hyperglycemia and hypercortisolemia, resulting from overactivation of the HPA axis, disrupt gut microbiota, leading to dysbiosis and intestinal barrier dysfunction, allowing inflammatory bacterial products to enter the bloodstream and ultimately reach the brain[10]. At the same time, within the central nervous system, diabetes is associated with reduced brain-derived neurotrophic factor and altered neurotransmitter levels, which, together with gut-induced neuroinflammatory signaling, worsen depressive symptoms[10]. We support this model and recognize the potential of microbiota-targeted interventions. Emerging evidence suggests that modulating gut microbiota can influence both metabolic and mental health[10,13]. Clinical trials on probiotics in T2DM patients have shown improvements not only in glycemic control and inflammatory markers, but also in depressive symptom scores[10]. Moreover, prebiotics such as inulin-type fructans and dietary fiber may enhance intestinal barrier integrity and promote the growth of beneficial bacteria[10], contributing to reduced endotoxemia and mood stabilization[13]. Additionally, fecal microbiota transplantation has emerged as a promising approach to restore gut microbial balance and modulate systemic inflammation, although its use in diabetes-related mood disorders requires further validation[10]. These microecological strategies represent a novel and integrative avenue for treating T2DM with comorbid anxiety or depression. For example, clinical trials on probiotics in T2DM patients have reported improvements in glycemic control and inflammatory markers, along with reductions in depression scores[10]. Furthermore, specific dietary fibers and prebiotics may restore gut microbial balance (symbiosis) and strengthen the intestinal barrier, thereby reducing endotoxemia[10]. This conceptual framework underscores the multi-organ nature of diabetes-depression comorbidity, involving the gut microbiota, immune system, and neuroendocrine stress axis.
The gut-brain axis also provides a pathophysiological explanation for diabetes-associated anxiety. Gastrointestinal symptoms, which are common in diabetes and often arise from autonomic neuropathy, can relay distress signals to the brain via vagal pathways, potentially triggering anxiety. Additionally, the gut microbiota can produce or regulate neurotransmitters such as gamma-aminobutyric acid and serotonin, which are implicated in anxiety-related behaviors[13]. Therefore, treating gastrointestinal issues and optimizing gut microbiota may help alleviate anxiety symptoms in diabetes patients. Future research should focus on characterizing the gut microbiome in T2DM patients with depression or anxiety to identify specific microbial markers or metabolic products linked to mental health. For instance, certain Clostridium species that produce butyrate or Gram-negative Proteobacteria that generate LPS may play critical roles. These insights could aid in developing novel probiotics or dietary interventions tailored to diabetes-psychiatric comorbidities (Table 2).
Table 2 Role of the gut-brain axis in type 2 diabetes mellitus and depression comorbidity.
Component
Changes in T2DM
Impact on mental health
Potential intervention measures
Gut microbiota composition
Dysbiosis (microbial imbalance); reduction in beneficial bacteria; increase in pathogenic bacteria
Changes in neurotransmitter production; immune activation; vagus nerve signal dysregulation
Vagus nerve stimulation; management of gastrointestinal symptoms; autonomic nervous system regulation
Metabolic pathway abnormalities and “diabetic distress”
As highlighted in the review, the inherent metabolic dysregulation in diabetes - including IR, hyperglycemia, and dyslipidemia - can have adverse effects on brain function (Table 3). Here, we further explore key metabolic pathways and their associations with mental health.
Table 3 Metabolic pathway abnormalities in type 2 diabetes mellitus and their impact on mental health.
Metabolic pathway
Abnormalities in T2DM
Neuropsychiatric effects
Biomarkers/evidence
Insulin signaling
Peripheral and central insulin resistance; insulin receptor dysfunction; PI3K/Akt signaling alterations
IGF-1 has neurotrophic effects; IGF-1 reduction associated with depression/cognition; neuroplasticity changes
Correlation with metabolic parameters; targeting key pathways; diagnostic potential
Microvascular function
Small vessel disease; endothelial dysfunction; insufficient tissue perfusion
White matter lesions; “vascular depression”; cognitive dysfunction; neuropathic pain
Related to retinopathy/nephropathy; cerebral small vessel disease; complication burden
IR and neurotransmitter regulation: Insulin plays a crucial role not only in glucose uptake in peripheral tissues but also in regulating neurotransmitter signaling and neuroplasticity in the brain. IR in T2DM may impair insulin signaling in the brain, leading to cognitive dysfunction and mood disturbances. Borovcanin et al[1] noted that pro-inflammatory cytokines can induce IR, and conversely, IR can exacerbate inflammation, forming a vicious cycle. Studies suggest that IR is associated with reduced serotonin transporter function and decreased dopaminergic activity in the central nervous system, which mechanistically links IR to depression. Moreover, central IR may influence anxiety and reward processing. Thus, therapies that improve insulin sensitivity may have antidepressant or anxiolytic effects. Notably, recent Mendelian randomization studies have provided evidence of a causal relationship: Depression can increase T2DM risk through lifestyle and neuroendocrine pathways, while genetic predisposition to hyperglycemia may also elevate the risk of depression[7,14].
Adipokines and endocrine crosstalk: In obesity and T2DM, adipose tissue secretes adipokines and cytokines - such as leptin, adiponectin, and TNF-α - that influence mood regulation. Low adiponectin levels and leptin resistance have been linked to depression[15]. Chronic stress can promote visceral fat accumulation through cortisol, thereby connecting psychological stress to poorer metabolic health, a key feature of metabolic syndrome. Our research team has extensively investigated the relationship between metabolic syndrome components and mental health. Sun et al[16] demonstrated that patients with metabolic syndrome exhibit an altered amino acid profile compared to healthy controls, with elevated levels of branched-chain amino acids and aromatic amino acids, such as leucine, tyrosine, and tryptophan. Many of these amino acids serve as neurotransmitter precursors or modulators - for instance, tryptophan is a precursor of serotonin. Excess large neutral amino acids in plasma may compete for transport across the blood-brain barrier, thereby reducing central nervous system uptake of tryptophan and limiting serotonin synthesis, which may contribute to depressive symptoms. In T2DM, metabolic inflexibility and disrupted nutrient signaling may further impact brain chemistry. Additionally, amino acid imbalances reflect IR and metabolic dysfunction[16], reinforcing the close link between metabolic and mood disorders.
Lin et al[17] further elucidated a molecular mechanism: In patients with metabolic syndrome, urinary levels of microRNA miR-29a-3p are elevated and correlate with key metabolic parameters, such as body mass index, insulin levels, and high-density lipoprotein cholesterol, targeting the insulin-like growth factor-1 (IGF-1) signaling pathway. IGF-1 plays a crucial role in insulin signaling and has neurotrophic effects in the brain. Reduced IGF-1 activity has been associated with depression and cognitive decline. Since miR-29a-3p downregulates IGF-1, this finding suggests that metabolic syndrome - and by extension, T2DM - may contribute to emotional vulnerability through gene regulatory mechanisms[17]. In summary, abnormal metabolic pathways - including IR, adipose tissue inflammation, and alterations in amino acid and microRNA profiles - may collectively contribute to the development of depression and anxiety in diabetes. These studies further highlight that metabolic control is not only essential for preventing diabetes complications (such as nephropathy and retinopathy) but may also have a significant impact on mental health.
Microvascular complications and neuropathology: Diabetes causes microvascular damage (to small blood vessels) which can affect the brain and nerves. Depression in diabetes has been linked to the presence of microvascular complications such as retinopathy, nephropathy, and neuropathy[7]. For instance, cerebral small vessel disease due to diabetes could manifest as white matter lesions or silent infarcts, which are associated with late-life depression and cognitive impairment. Peripheral neuropathy may lead to chronic pain, worsening depression/anxiety and reducing quality of life. Additionally, the concept of “diabetic distress” - the psychological demoralization specifically related to living with diabetes and its complications - is an important consideration. High glycated hemoglobin and long duration of diabetes (often proxies for greater metabolic derangement and complication burden) correlate with elevated diabetes distress and depressive symptoms[7]. Our research using the CIRS suggests that the sheer number of comorbid conditions in a diabetic patient (e.g. hypertension, cardiovascular disease, arthritis, etc.) can predict depressive outcomes[11], likely because each additional illness adds inflammatory load and psychosocial stress. We agree with Borovcanin et al[1] that metabolic syndrome is the common soil for both diabetes and mental disorders. We encourage clinicians to take note of metabolic red flags (e.g., significant weight gain, poor glycemic control, blood pressure spikes) in patients with depression, as these might herald the development of diabetes. Conversely, in patients with T2DM, vigilance for cognitive changes or mood symptoms is warranted, especially if metabolic parameters worsen. Early intervention in this metabolic-mental crosstalk could potentially halt a progression to full syndrome depression or difficult-to-control diabetes.
Emerging therapeutic targets and comprehensive interventions
Understanding these shared mechanisms is crucial as it provides opportunities for developing novel interventions that simultaneously improve both metabolic and mental health (Table 4). We support the multifaceted intervention approach proposed in the review and would like to emphasize the following potential therapeutic strategies.
Table 4 Treatment strategies for type 2 diabetes-depression comorbidity.
Clinical trials show improvements in glycemic control, inflammation, and depression scores in T2DM patients; FMT is a promising intervention under investigation; safety and long-term psychiatric efficacy remain to be confirmed
Multidisciplinary approach; increases endorphins and myokines; anti-inflammatory diet; social support
Proven effective for chronic diseases; exercise as insulin sensitizer and antidepressant; omega-3, vitamins (D, folate); focus on “whole-patient” concept
Anti-inflammatory and immunomodulatory therapies: Given the pivotal role of inflammation in diabetes-depression comorbidity, anti-inflammatory drugs have gained attention in depression treatment, including low-dose acetylsalicylic acid, cytokine inhibitors, and the antibiotic minocycline. One promising therapeutic avenue is targeting the NOD-like receptor pyrin domain-containing 3 inflammasome, a key immune complex implicated in both IR and depression[1,10]. NOD-like receptor pyrin domain-containing 3 inhibitors are currently under development and may alleviate both hyperglycemia and depressive symptoms by reducing IL-1β and IL-18 levels. Similarly, pentoxifylline, a TNF-α inhibitor, has demonstrated antidepressant effects in small-scale studies and may be beneficial for patients with diabetes-related depression and elevated inflammatory markers. Additionally, modulating the gut-immune axis through probiotics, as previously discussed, or even fecal microbiota transplantation is an emerging approach under investigation.
Neuroendocrine and HPA axis modulation: Since chronic stress and hyperactivation of the HPA axis are shared mechanisms underlying diabetes-related depression, interventions aimed at reducing stress responses may have therapeutic benefits. From a psychological perspective, mindfulness-based stress reduction and cognitive-behavioral therapy have been shown to reduce perceived stress and may improve diabetes management and depressive symptoms by lowering cortisol levels[18]. In terms of pharmacological interventions, mifepristone - a glucocorticoid receptor antagonist - has been used in the treatment of psychotic depression and may be beneficial for treatment-resistant depression characterized by HPA axis overactivation[19]. Given that diabetes-related depression often presents with excessive HPA axis activation, this drug may hold therapeutic potential. Moreover, melatonin receptor agonists such as agomelatine not only help regulate circadian rhythms and improve sleep - common issues in both diabetes and depression - but also exert beneficial effects on HPA axis regulation and insulin sensitivity[10]. Due to its multi-target action, agomelatine presents a promising therapeutic option for diabetes-depression comorbidity.
Metabolic therapies with mental health benefits: Notably, certain diabetes medications may exert beneficial effects on the brain. For example, metformin not only lowers blood glucose but also possesses anti-inflammatory and neurogenic properties. Recent studies have shown that metformin effectively alleviates depressive symptoms even in non-diabetic individuals. Furthermore, its use in patients with polycystic ovary syndrome - a condition often associated with IR - has been linked to a reduced risk of depression[10,20-22]. Another class of medications garnering attention is GLP-1RAs, such as liraglutide and semaglutide. These agents can cross the blood-brain barrier and have demonstrated neuroprotective effects in animal models of Alzheimer’s and Parkinson’s diseases. Some studies suggest that GLP-1RAs may improve mood and anxiety symptoms in diabetes by reducing neuroinflammation and modulating appetite-reward pathways, although recent pharmacovigilance data indicate some controversy regarding their psychiatric effects[23].
In a meta-analysis conducted by our team, Luo et al[24] found that liraglutide significantly improved health parameters in patients with T2DM, particularly by reducing urinary protein levels and systolic blood pressure, suggesting a role in vascular function improvement. Enhanced endothelial function and reduced microvascular damage (e.g., decreased urinary protein levels) may contribute to better cerebral perfusion, potentially lowering the risk of vascular depression[1]. While the direct antidepressant effects of GLP-1RAs remain under investigation, their multifaceted benefits in metabolism, vascular health, and inflammation position them as promising therapeutic options for patients with comorbid diabetes and depression. Additionally, SGLT2i, such as empagliflozin, have demonstrated anti-inflammatory properties and have been shown to reduce anxiety-like behaviors in diabetic mouse models, potentially through ketone-mediated neuroprotection[25,26]. These findings further blur the distinction between metabolic and psychiatric treatments, suggesting that diabetes medications may hold potential for repurposing in mental health management.
Integrated psychosocial interventions: Beyond biological treatments, integrated care models are essential for managing comorbid diabetes and psychiatric disorders. Diabetes self-management education, when combined with mental health support - such as problem-solving therapy targeting diabetes distress - can lead to simultaneous reductions in glycated hemoglobin and depressive symptoms[1]. The collaborative care model has been demonstrated to be effective in managing depression in chronic diseases[27,28]. In this approach, care managers and psychiatrists work alongside endocrinologists or primary care physicians to provide multidisciplinary support, optimizing the overall treatment strategy for patients. Encouraging regular physical activity is also a cost-effective and beneficial intervention. Exercise not only enhances insulin sensitivity but also exerts antidepressant effects by promoting the release of endorphins and anti-inflammatory myokines. Furthermore, exercise may directly modulate the gut microbiota, benefiting both metabolic and mental health[28,29]. Nutritional guidance is equally important. Diets rich in omega-3 fatty acids, vitamins (such as folate and vitamin D), and dietary fiber have been shown to alleviate depression and improve metabolic control. A 2022 study found that vitamin D deficiency in T2DM patients was associated with poor glycemic control and cognitive dysfunction, suggesting that vitamin D supplementation may concurrently benefit metabolism and brain function[30].
Personalized and holistic management strategies: Any intervention strategy should be both holistic and personalized[31]. As Borovcanin et al[1] pointed out, the bidirectional relationship between diabetes and psychiatric disorders necessitates an integrated approach to managing both conditions rather than treating them in isolation. Our research team strongly advocates for the “Four-Early” strategy in managing diabetes-psychiatric comorbidities: Early screening, early identification, early prevention, and early treatment. Routine use of the Self-Rating Anxiety Scale and Self-Rating Depression Scale in diabetes outpatient clinics can help identify patients with psychological distress at an early stage. Additionally, our findings suggest that incorporating CIRS assessments in hospitalized diabetes patients to screen for high comorbidity burden, coupled with comprehensive interventions - including optimized pharmacotherapy, psychological education, and counseling - yields better outcomes than standard care. This aligns with the concept of integrated psycho-metabolic therapy, emphasizing that only by embedding mental health care into diabetes management (and vice versa) can the vicious cycle between hyperglycemia and psychological stress be effectively broken[32].
Key clinical insights: (1) Comorbid T2DM and depression require integrated care addressing both metabolic and psychiatric drivers; (2) Systemic inflammation, HPA axis dysregulation, and microbiota imbalance represent common pathophysiological targets; (3) Anti-inflammatory and gut-targeted therapies may hold promise beyond glucose control; (4) Routine mental health screening (e.g., Self-Rating Depression Scale, Self-Rating Anxiety Scale) in diabetes care settings is recommended; and (5) Multidisciplinary collaboration is essential for breaking the diabetes-depression cycle.
Conclusion and future directions
The relationship between diabetes and anxiety/depression is a highly intertwined and bidirectional system - a dynamic interplay between the pancreas and brain, immunity and emotions, microbiota and behavior. We commend Borovcanin et al[1] for addressing this critical issue and have built upon their discussion by further exploring recent research findings on shared mechanisms: Chronic inflammation as a core driver, the gut-brain axis as a key communication network, and the deep interconnection between metabolic dysregulation and neuropsychiatric changes. These insights have paved the way for innovative therapeutic approaches, including anti-inflammatory cytokine modulation, gut microbiota interventions, HPA axis regulation, and integrated metabolic-brain therapies[10]. Multidisciplinary collaboration is essential - endocrinologists, psychiatrists, psychologists, and nutritionists must work together to adopt a patient-centered approach. For example, in patients with diabetes and comorbid depression, both antidepressant and insulin therapies should be considered simultaneously. Conversely, in patients with depression at risk for diabetes, GLP-1RAs or lifestyle interventions may be viable strategies.
Future research should explore the mechanisms and interventions for diabetes-depression comorbidity at multiple levels. On one hand, it remains to be determined whether early stress management or anti-inflammatory interventions can reduce the risk of depression in individuals with prediabetes. Longitudinal studies tracking microbiome alterations and inflammatory biomarkers in diabetes patients may also help identify triggers for depression[33]. On the other hand, genetic and epigenetic studies could help identify shared susceptibility genes, such as circadian rhythm regulators (CLOCK, basic helix-loop-helix ARNT like 1) and immunometabolic genes (TNF-α, IL-6), and investigate their dynamic regulation in response to environmental factors[34,35]. Furthermore, comprehensive treatment strategies need further optimization, particularly in assessing the effects of diabetes medications (such as GLP-1RAs and SGLT2i) on depression and evaluating the role of psychological interventions in improving glucose metabolism. These questions should be addressed through multidisciplinary clinical trials[36-39]. The central challenge for future research is integrating precision prediction, biological mechanism elucidation, and personalized interventions to achieve effective management of diabetes-depression comorbidity.
We fully recognize that the identification and management of diabetes and anxiety/depression are crucial for improving patient outcomes and quality of life. Only through comprehensive interventions targeting immune dysfunction, gut microbiota imbalance, metabolic abnormalities, and psychosocial stress can we break this bidirectional vicious cycle. As researchers and clinicians, we must build upon the foundation laid by Borovcanin et al[1] and other scholars, striving to achieve seamless integration of endocrinology and psychiatry[40-42]. Our team has been actively engaged in this field, with recent studies covering clinical prediction models for depression in T2DM patients and biochemical mechanisms underlying metabolic syndrome[11,16,17]. Finally, we thank the authors of this review for initiating this important discussion and hope that our work provides additional valuable perspectives. Through collective efforts, we can move closer to unraveling the “diabetes-depression puzzle” and bring better health and well-being to the millions affected worldwide.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Endocrinology and metabolism
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade A, Grade B, Grade B, Grade B, Grade B
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