While we still have a lot to learn about the human body, researchers and medical experts all agree that nothing in human physiology happens in a vacuum. 

In other words, if one system or organ is not functioning properly, it will most definitely affect other parts of the human machine. 

One area in which this is frequently seen is the association between insulin resistance and mood disorders. While on the surface these two conditions seem to be completely unrelated (one stemming from metabolic dysfunction and the other neurological), they actually have some interesting overlap. 

In fact, research shows that having insulin resistance can double the risk for mood-related issues like major depressive disorder.[1] 

In this article, you'll learn how chronic stress can instigate mood disorders, where insulin and glucose fit into the picture, and how insulin resistance may increase the risk and severity of mood disorders.

The HPA Axis: Where Mood And Metabolism Meet

Your HPA Axis (which stands for hypothalamic-pituitary-adrenal) is a complex neuroendocrine mechanism that mediates your stress response by regulating numerous processes, including metabolism, immunity, and nervous system function.[2]

The wide-ranging effects of the HPA axis make it a fascinating subject for research as the downstream impacts that this system has on your body can reach far and wide. 

The Involvement of You HPA Axis In Mood

The primary way in which your HPA axis is activated is via stress. This can be emotional or physical, but any stressor that tells your body it's time to fight will kick your HPA axis into gear. 

Mood and mental disorders like anxiety and depression act as psychological stressors to your system, knocking on your HPA axis door and setting a cascade of chemical reactions into motion. Ultimately, a class of steroid hormones known as glucocorticoids is released from your adrenal glands, signaling various pathways related to metabolism, digestion, inflammation, immunity, and autonomic nervous system functioning.

Glucocorticoids also directly affect neurotransmitters, sex hormones, and neurotrophic factors (which impact the survival of brain cells). Furthermore, these compounds are able to pass the blood-brain barrier, which grants them access to several areas of the brain related to mood and stress. 

It's well understood that chronic exposure to glucocorticoids can lead to cognitive impairment (like that seen in Alzheimer's disease), affecting memory, decision-making, and behavior.

This is likely due, at least in part, to glucocorticoids' role in inducing or impeding neuroplasticity in the brain – which is also where depression and other mood disorders come into play.

Neuroplasticity is your brain's ability to adapt and reorganize synaptic connections in response to learning, changes in the environment, and injury. When something stressful happens in your life, your brain's neuroplasticity can either kick into gear to help you cope, or shut down, which leaves you feeling stuck, anxious, and depressed. 

When glucocorticoids are chronically high, it impedes your brain's ability to reorganize, and research suggests that this can lead to changes in the hippocampus (brain region) that result in the onset of mood disorders.

Where Insulin and Glucose Come In

As noted, the release of glucocorticoids sets into action a cascade of biochemical reactions. In addition to the impact on neurotransmitters, sex hormones, and your autonomic nervous system, glucocorticoids also elevate circulating glucose levels. 

This adaptive strategy would have greatly benefited your ancestors, whose stress response was primarily reserved for life or death situations – like running from a predator. In those instances, a surge of glucose would help to fuel up your muscles so you could run, fight, climb, and claw your way out of a bad situation. 

Luckily, times have changed, and today's stressors are much less dire. But, unluckily – our physiology hasn't received the message. As a result, when we experience chronic stress (like that experienced with mood disorders), our blood sugar levels remain high for extended periods (hyperglycemia). Over time this dysregulation can lead to insulin resistance, which in turn creates more elevated blood glucose. 

This is one explanation of how mood disorders and insulin resistance are related. But wait – there's more.

On the flip side of this story, research also shows that insulin resistance can serve as a chronic stressor to the body. This means that, you guessed it, insulin resistance on its own can stimulate HPA axis activation and increase susceptibility to mood and metabolic disorders.[3]

In this way, insulin resistance creates a feedback loop that instigates more stress, which instigates more insulin resistance, which creates more stress… and you get it. 

Your brain also has insulin receptors, and there's evidence that insulin resistance in the brain can alter the turnover of dopamine, a "feel-good" hormone. When dopamine isn't functioning properly, it increases anxiety and depressive-like behavior.[4]

Some interesting clinical trials which demonstrate these concepts include:

  • Research in children where the severity of depressive symptoms predicts the development and prevalence of insulin resistance.[5]
  • Research in obese, depressed youths where more pronounced insulin resistance correlates with more worsening symptoms of depression.[6]

Clearly, there is comorbidity between these two conditions, as the incidence of one often results in an increased risk for the other.

Sex Differences In The Stress Response and Insulin Resistance

Research shows that men and women experience differences in their HPA axis response. For instance, women are more susceptible to illnesses that impact the brain, like anxiety and depression, while men are more susceptible to metabolic diseases like insulin resistance, type 2 diabetes, and metabolic syndrome.[7]

This is primarily due to sex hormones' impact on the HPA axis (remember, nothing in the body happens in a vacuum). For example, testosterone can inhibit HPA function, while estradiol can either increase or attenuate its function. Furthermore, sex hormones may influence inflammatory markers differently in men and women, which is an important factor in all states of dis-ease.[3]

Takeaway: A New Perspective On Treating Mood Disorders

Treating mood disorders like depression and PTSD can be very challenging, especially when combined with obesity and metabolic dysfunction. While insulin sensitivity alone is likely not at the root of mood disorders, it's clear that it can play a role in the intensity and progression. 

This gives researchers a new perspective to take on managing these conditions, which are often non-responsive to medications like antidepressants.

While research has yet to uncover the exact pathophysiology of psychiatric disorders like major depression, we do have a handful of therapeutic strategies for insulin resistance and stress-management – many of which overlap. 

For example, exercise is shown to enhance your body's sensitivity to insulin while also reducing stress. Similarly, dietary considerations that focus on whole foods and avoid pro-inflammatory processed foods are known to promote mental health while also improving metabolic biomarkers such as:[8,9,10,11,12]

  • Waist circumference
  • Body mass index
  • Cholesterol
  • Fasting plasma glucose
  • Insulin signaling
  • Triglyceride concentrations

All in all, it seems that reducing risk factors for diabetes may play a powerful role in the treatment of mood disorders while also improving your overall quality of life.

To learn more about diabetes treatment and prevention, check out BioCoach for a range of diabetes care tips and tools.


  1. Watson, Kathleen T., et al. "Incident major depressive disorder predicted by three measures of insulin resistance: a Dutch cohort study." American Journal of Psychiatry 178.10 (2021): 914-920.
  2. Sheng, Julietta A., et al. "The hypothalamic-pituitary-adrenal axis: development, programming actions of hormones, and maternal-fetal interactions." Frontiers in Behavioral Neuroscience 14 (2021): 601939.
  3. Henry, Stefanie S., Rachel A. Ross, and Natalie Rasgon. "Relevance of Sex-Specific Metabolic Phenotypes in Diagnosis and Treatment of Mood Disorders and PTSD." Psychiatric Annals 52.1 (2022): 20-25.
  4. Kleinridders, Andre, et al. "Insulin resistance in brain alters dopamine turnover and causes behavioral disorders." Proceedings of the National Academy of Sciences 112.11 (2015): 3463-3468.
  6. Singh, Manpreet K., et al. "Brain and behavioral correlates of insulin resistance in youth with depression and obesity." Hormones and behavior 108 (2019): 73-83.
  7. Bourke, Chase H., Constance S. Harrell, and Gretchen N. Neigh. "Stress-induced sex differences: adaptations mediated by the glucocorticoid receptor." Hormones and behavior 62.3 (2012): 210-218.
  8. Firth, Joseph, et al. "Food and mood: how do diet and nutrition affect mental wellbeing?." Bmj 369 (2020).
  9. Fechner, Eva, et al. "A whole-diet approach affects not only fasting but also postprandial cardiometabolic risk markers in overweight and obese adults: a randomized controlled trial." The Journal of nutrition 150.11 (2020): 2942-2949.
  10. Moradi, Sajjad, et al. "Ultra-processed food consumption and adult diabetes risk: A systematic review and dose-response meta-analysis." Nutrients 13.12 (2021): 4410.
  11. Borghouts, L. B., and H. A. Keizer. "Exercise and insulin sensitivity: a review." International journal of sports medicine 21.01 (2000): 1-12.
  12. Jackson, Erica M. "Stress relief: The role of exercise in stress management." ACSM's Health & Fitness Journal 17.3 (2013): 14-19.

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