Insulin Resistance

Chronic stress is a major contributor to metabolic and inflammatory dysregulation, both of which can have profound effects on brain function and emotional health. Conditions such as insulin resistance (IR), affecting nearly 40% of adults in the United States (1), often arise under sustained psychosocial stress and impaired metabolic control. IR is characterized by a diminished ability to utilize glucose and dispose of excess circulating blood sugar and has been closely linked to depression and related mood disturbances. Individuals with elevated IR tend to experience more severe and persistent depressive symptoms (2, 3), and prospective data suggest that IR may also predict the development of major depressive disorder (MDD). For instance, one large cohort study found that individuals with higher levels of IR were more than twice as likely to develop MDD over a 7-year follow-up period (4), underscoring the role of metabolic dysfunction in stress-related vulnerability to mood disorders.

IR appears to be associated more with the current state of depression rather than with past or remitted episodes, suggesting that it may reflect an active biological process rather than a fixed trait (5). This observation is clinically significant, as it opens the door to targeted interventions aimed at reversing IR and mitigating its adverse effects on brain function and mood regulation (5, 6).

Pharmacologic agents targeting metabolic inflammation are an emerging area of interest. Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, such as pioglitazone, have shown anti-inflammatory effects and the potential to reduce both systemic and neuroinflammation associated with chronic stress. These agents may help restore mood and cognitive function, especially in individuals with persistent depressive symptoms and comorbid IR (6). Further trials are needed to clarify the mechanisms and subgroups most likely to benefit (6).

Links to Stress

Chronic stress, particularly when coupled with metabolic strain, can disrupt neural systems involved in mood regulation. Insulin receptors are widely distributed in the brain, particularly in the hippocampus and prefrontal cortex—regions that are highly sensitive to stress hormones and inflammatory cytokines (7, 8). Experimental studies demonstrate that brain-specific insulin resistance in these areas impairs neuroplasticity, reduces neurogenesis, and alters dendritic structure, which together contribute to depressive-like behaviors (8, 9). Moreover, human neuroimaging studies suggest that individuals with higher IR exhibit reduced hippocampal and prefrontal volumes and altered reward-related connectivity, which correlate with greater depression severity, particularly under conditions of chronic stress (10).

Stress-related metabolic dysfunction is also associated with increased production of pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β. This chronic low-grade inflammation has been consistently implicated in the onset and persistence of depression (11, 12, 13). Rodent models combining high-fat diet exposure with chronic stress show synergistic elevations in brain inflammation and behavioral despair, offering causal support for the inflammation–mood link (11). In humans, stress-induced immune dysregulation and impaired glucocorticoid signaling can lead to an amplified and prolonged inflammatory state, creating a feedback loop that exacerbates depressive symptoms (12, 13).

These inflammatory signals also disrupt the hypothalamic-pituitary-adrenal (HPA) axis. Under conditions of chronic stress, the HPA axis becomes overactive, leading to prolonged elevations in cortisol and impaired feedback regulation (14, 15, 16). Glucocorticoid receptor resistance prevents cortisol from dampening the immune response, allowing inflammatory mediators to persistently circulate and enter the brain. This process can interfere with the synthesis and metabolism of key neurotransmitters—particularly serotonin, dopamine, and norepinephrine—via mechanisms such as altered monoamine oxidase activity and tryptophan shunting through the kynurenine pathway (15, 17). As a result, chronic stress produces a neurochemical profile marked by heightened emotional reactivity, reduced reward sensitivity, and diminished resilience to future stressors.

Measurement Reliability and Feasibility

Insulin resistance is frequently used as a biomarker of metabolic stress and dysfunction. The gold standard method for assessing IR is the euglycemic hyperinsulinemic clamp technique, which is resource-intensive but highly accurate (18). Alternatives such as the steady-state plasma glucose (SSPG) test or insulin suppression protocols offer valid options (19). More commonly used in large-scale studies are fasting insulin and glucose measures, which can be combined into indices like the homeostasis model assessment of insulin resistance (HOMA-IR) (18). While not as precise as gold-standard techniques, these methods provide practical estimates of IR and are especially useful when evaluating the role of metabolic dysfunction in psychiatric populations (3, 4).

Conclusion

The intersection of stress, inflammation, and metabolic dysfunction provides a compelling framework for understanding the development and persistence of mood disorders. Insulin resistance and related inflammatory changes in the brain may serve as state markers of chronic stress exposure and offer actionable targets for intervention. Future research should continue to explore the biological mechanisms underlying this relationship and test interventions—pharmacologic, behavioral, or dietary—that mitigate the harmful effects of stress-induced metabolic dysfunction on mental health (13, 17).

Below is a review on IR in relation to mood more broadly:

Clinical Relevance

Insulin resistance (IR) is a significant metabolic inflammatory condition that affects around 40% of adults in the United States (1). It is characterized by a reduced ability to utilize blood glucose for cellular activity and a decreased capacity to dispose of excess glucose. Extensive evidence links IR to depression. Individuals with higher IR often experience greater severity and chronicity of depression (2, 3). Moreover, IR has been shown to predict the onset of major depressive disorder (MDD). A recent study demonstrated that higher levels of IR more than doubled the risk of developing incident MDD over a 7-year follow-up, highlighting the importance of metabolic health in preventing mood disorders (4). People with depression and IR are more resistant to treatments such as antidepressants and lithium, suggesting that IR may exacerbate neurobiological dysfunction associated with depression or impede the body's ability to counteract it (2, 5). However, IR is primarily associated with the current state of MDD rather than with remitted MDD, indicating that it is a state marker rather than a trait marker for depression. The modifiability of IR presents promising opportunities for potential interventions and treatments (5, 6).

One promising intervention involves using peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists. These agents act as anti-inflammatory mediators and may combat the general inflammation associated with IR and stress response, both of which are associated with neuronal degradation. Pioglitazone, a PPAR-γ agonist, has shown potential in improving mood in patients with non-remitted depressive disorders and IR (6,12). Further research is necessary to fully understand the efficacy of pioglitazone and other PPAR-γ-related interventions (6, 12).

Mechanism Linking IR to Mood Disorders

IR may contribute to mood disorders through multiple mechanisms. Insulin receptors are widely distributed in the brain, particularly in areas involved in mood regulation, such as the hippocampus and prefrontal cortex. IR may lead to impaired insulin signaling in the brain, which can affect neurotransmitter systems, neuroinflammation, and neurogenesis, all of which are implicated in the pathophysiology of mood disorders (7,8).

Moreover, IR is associated with increased production of pro-inflammatory cytokines. Chronic low-grade inflammation is a recognized factor in the development of depression. Elevated cytokines can alter brain function by increasing the activity of the hypothalamic-pituitary-adrenal (HPA) axis, leading to higher levels of cortisol. This increased HPA activity, is, in turn, linked to depression and anxiety. Additionally, IR can affect the metabolism of neurotransmitters such as serotonin, dopamine, and norepinephrine, further contributing to mood disturbances (9, 10).

Measurement Reliability and Feasibility

The gold standard for measuring insulin resistance is the euglycemic clamp technique, which involves maintaining a constant blood glucose level by infusing glucose and insulin simultaneously, making it both time- and resource-intensive. (11). An alternative is steady-state plasma glucose (SSPG) concentration, a measure derived from an insulin suppression test that assesses how effectively insulin can lower blood glucose levels during a controlled insulin infusion. Less intensive methods include the oral glucose tolerance test and single-blood measures, such as the triglyceride/HDL ratio (12). Fasting glucose and fasting insulin can be combined to calculate the homeostatic model of insulin resistance (HOMA-IR), which, while not as sensitive or specific as the euglycemic clamp technique or SSPG, can approximate IR when other tests are impractical (13, 14).

Conclusion

The connection between IR and mood disorders highlights the importance of metabolic health in psychiatric conditions. Understanding and addressing IR may offer new avenues for treating mood disorders, particularly depression. Future research should continue to explore the mechanisms underlying this relationship and the potential benefits of interventions targeting IR (8, 9, 15).

Author(s) and Reviewer(s):

Prepared by Katie Tamara Watson, Ph.D.

Version July 2025. Waiting for Review.

References (Stress and IR):
1. National Health and Nutrition Examination Survey (NHANES).

2. Kan, C., Geerlings, M. I., Collard, R. M., Huisman, M., Comijs, H. C., & Penninx, B. W. (2013). Depressive symptoms and incidence of type 2 diabetes: the effect of characteristics of depression. American Journal of Psychiatry, 170(8), 978–985.

3. Watson KT, Simard JF, Henderson VW, Nutkiewicz L, Lamers F, Rasgon N, Penninx B. Association of Insulin Resistance With Depression Severity and Remission Status: Defining a Metabolic Endophenotype of Depression. JAMA Psychiatry. 2021 Apr 1;78(4):439-441. doi: 10.1001/jamapsychiatry.2020.3669. PMID: 33263725; PMCID: PMC7711568.

4. Watson, K. ., Simard, J. F., Henderson, V. W., Nutkiewicz, L., Lamers, F., Nasca, C., Rasgon, N., & Penninx, B. W. J. H. (2021). Incident Major Depressive Disorder Predicted by Three Measures of Insulin Resistance: A Dutch Cohort Study. American Journal of Psychiatry, 178(10), 914–920. https://doi.org/10.1176/appi.ajp.2021.20101479

5. Rasgon, N. L., & McEwen, B. S. (2016). Insulin resistance—a missing link no more. Molecular Psychiatry, 21(12), 1648–1652.

6. Kemp, D. E., Schinagle, M., Gao, K., Conroy, C., Ganocy, S. J., Ismail-Beigi, F., ... & Calabrese, J. R. (2014). PPAR-γ agonism as a modulator of mood: proof-of-concept for pioglitazone in bipolar depression. CNS Drugs, 28(6), 571–581.

7. Nguyen, T. T. L., Chan, L. C., La Via, M. C., et al. (2018). A review of brain insulin signaling in mood disorders: From biomarker to clinical target. Neuroscience & Biobehavioral Reviews, 92, 7–15. https://doi.org/10.1016/j.neubiorev.2018.05.014

8. Loyo-Rosado, F. Z., Macht, V. A., & Grillo, C. A. (2021). Hippocampal-specific insulin resistance elicits behavioral despair and hippocampal dendritic atrophy. Neurobiology of Stress, 15, 100354. https://doi.org/10.1016/j.ynstr.2021.100354

9. Kleinridders, A., Cai, W., Cappellucci, L. A., et al. (2015). Insulin resistance in brain alters dopamine turnover and causes behavioral disorders. Proceedings of the National Academy of Sciences, 112(11), 3463–3468. https://doi.org/10.1073/pnas.1500877112

10. Singh, M. K., Jo, B., Gebral, S., et al. (2018). Brain and behavioral correlates of insulin resistance in youth with depression and obesity. Hormones and Behavior, 108, 73–83. https://doi.org/10.1016/j.yhbeh.2018.03.009

11. Wang, W., Yang, J., Xu, J., et al. (2022). Effects of high-fat diet and chronic mild stress on depression-like behaviors and inflammatory cytokines in the hippocampus and prefrontal cortex of rats. Neuroscience, 480, 178–193. https://doi.org/10.1016/j.neuroscience.2021.11.015

12. Hassamal, S. (2023). Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories. Frontiers in Psychiatry, 14, 1130989. https://doi.org/10.3389/fpsyt.2023.1130989

13. Ouakinin, S. R. S., Barreira, D. P., & Gois, C. J. (2018). Depression and obesity: integrating the role of stress, neuroendocrine dysfunction and inflammatory pathways. Frontiers in Endocrinology, 9, 431. https://doi.org/10.3389/fendo.2018.00431

14. Miller, A. H., & Raison, C. L. (2016). The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature Reviews Immunology, 16(1), 22–34. https://doi.org/10.1038/nri.2015.5

15. Correia, A. S., Vale, N., & Correia-Neves, M. (2022). Tryptophan metabolism in depression: a narrative review with a focus on serotonin and kynurenine pathways. International Journal of Molecular Sciences, 23(15), 8493. https://doi.org/10.3390/ijms23158493

16. Pariante, C. M., & Miller, A. H. (2001). Glucocorticoid receptors and depression. Biological Psychiatry, 49(5), 391–404. https://doi.org/10.1016/S0006-3223(00)01088-6

17. Herman, J. P., McKlveen, J. M., Ghosal, S., et al. (2016). Regulation of the hypothalamic-pituitary-adrenocortical stress response. Comprehensive Physiology, 6(2), 603–621. https://doi.org/10.1002/cphy.c150015

18. Muniyappa, Ranganath, et al. "Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage." American Journal of Physiology-Endocrinology and Metabolism 294.1 (2008): E15-E26.

19. Matthews, D. R., Hosker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F., & Turner, R. C. (1985). Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28(7), 412–419.

References (Mood and IR):
1. National Health and Nutrition Examination Survey (NHANES).

3. Musi, N., & DeFronzo, R. A. (2002). Metabolic and molecular effects of insulin on human skeletal muscle. Diabetologia, 45(5), 657-673.

4. Watson, K. T., Simard, J. F., Henderson, V. W., Nutkiewicz, L., Lamers, F., Nasca, C., Rasgon, N., & Penninx, B. W. J. H. (2021). Incident Major Depressive Disorder Predicted by Three Measures of Insulin Resistance: A Dutch Cohort Study. American Journal of Psychiatry, 178(10), 914-920. DOI: 10.1176/appi.ajp.2021.20101479.

5. Rasgon, N. L., & McEwen, B. S. (2016). Insulin resistance—a missing link no more. Molecular Psychiatry, 21(12), 1648-1652.

7. Craft, S., & Watson, G. S. (2012). Insulin and neurodegenerative disease: shared and specific mechanisms. The Lancet Neurology, 11(6), 489-498.

8. Miller, A. H., & Raison, C. L. (2016). The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature Reviews Immunology, 16(1), 22-34.

9. Matthews, D. R., Hosker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F., & Turner, R. C. (1985). Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28(7), 412-419.

10. Lebovitz, H. E. (2001). Insulin resistance: definition and consequences. Experimental and Clinical Endocrinology & Diabetes, 109(Suppl 2), S135-S148.

11. Golden, S. H., Lazo, M., Carnethon, M., Bertoni, A. G., Schreiner, P. J., Diez Roux, A. V., ... & Lyketsos, C. (2008). Examining a bidirectional association between depressive symptoms and diabetes. JAMA, 299(23), 2751-2759.

12. Kohen, D., Burgess, E., Catalán, J., & Lant, A. (1998). The role of anxiety and depression in quality of life and symptom reporting in people with diabetes mellitus. Quality of Life Research, 7(3), 197-204.

13. Pan, A., Lucas, M., Sun, Q., van Dam, R. M., Franco, O. H., Willett, W. C., & Hu, F. B. (2010). Bidirectional association between depression and type 2 diabetes mellitus in women. Archives of Internal Medicine, 170(21), 1884-1891.

14. Musselman, D. L., Betan, E., Larsen, H., & Phillips, L. S. (2003). Relationship of depression to diabetes types 1 and 2: epidemiology, biology, and treatment. Biological Psychiatry, 54(3), 317-329.

15. Cusi, K., & DeFronzo, R. A. (1998). Metformin: a review of its metabolic effects. Diabetes Reviews, 6(2), 89-131.