Research inspiration for this post:
Fanelli, G. et al. The interface of depression and diabetes: treatment considerations. Transl Psychiatry 15, 22 (2025). https://doi.org/10.1038/s41398-025-03234-5
While not every person with depression as an inflammatory component, it is part of the assessment when working with an integrative psychiatrist. How do we address inflammation in patients with depression and pre-diabetes or diabetes? Let's dive in!
How Depression and Diabetes Are Linked
The connection between depression and diabetes is far from coincidental—it stems from a complex interplay of biological, emotional, and lifestyle factors that mutually reinforce one another:
Chronic Inflammation: Both conditions are associated with persistent, low-grade inflammation, which impairs insulin sensitivity and disrupts mood regulation.
Stress and Cortisol: Chronic stress elevates cortisol, a hormone that raises blood sugar levels and exacerbates insulin resistance.
Brain Insulin Resistance: Insulin resistance in the brain disrupts neurotransmitter function, contributing to mood changes and cognitive issues.
Lifestyle Factors: Poor dietary choices, physical inactivity, and sleep disturbances fuel a vicious cycle that worsens both depression and diabetes.
In functional medicine psychiatry, we treat the interconnected systems of the body, including hormonal balance, immune regulation, and nervous system health.
Why Inflammation Matters
Chronic inflammation is a key factor linking depression and diabetes. One significant contributor is lipopolysaccharides (LPS)—molecules released when the gut lining becomes "leaky." These molecules enter the bloodstream, triggering widespread inflammation that worsens mental health and disrupts blood sugar control.
Key Nutrients to Improve Blood Sugar and Mood
The review from Basiri et al. (2023) highlights several nutrients that support both mental health and blood sugar regulation:
Omega-3 Fatty Acids: Found in fatty fish (think: salmon), omega-3s lower inflammation, enhance brain health, and improve insulin sensitivity.
Vitamin D: Deficiency in vitamin D is common in both diabetes and depression. Supplementation improves insulin sensitivity, reduces inflammation, and boosts mood.
L-Methylfolate: An active form of folate, it aids neurotransmitter production and reduces inflammation. It is especially beneficial for individuals with genetic variants that hinder folate metabolism. Doses found to be most effective for depression are 15 mg/day. (There is a prescription form of this called Deplin but buying it over the counter is cheaper - pick a reputable source that is third-party tested).
Magnesium: Essential for glucose metabolism, magnesium improves insulin sensitivity and helps alleviate depression symptoms.
Zinc and Selenium: These trace minerals enhance insulin function, provide antioxidant protection, and support cognitive and emotional well-being.
The Role of Continuous Glucose Monitors (CGMs)
For individuals with diabetes or prediabetes, managing blood sugar is vital for both physical and mental health. A Continuous Glucose Monitor (CGM) is a small wearable device that provides real-time tracking of blood sugar levels. These can now be accessed through a prescription or purchased over the counter without a prescription.
How It Helps: A CGM offers insights into how meals, stress, and daily habits affect blood sugar.
Benefits: Stabilizing blood sugar can lead to fewer mood swings, improved focus, and reduced inflammation.
Tip: People often wear these for a short period of time (2-4 weeks) to get a sense of how foods they eat impact their blood sugar levels in a truly personalized approach.
Lifestyle Changes for Dual Management
Adopting small, sustainable changes can have a profound impact on managing both diabetes and depression:
Healthy Eating
Replace refined carbs with low-glycemic foods (e.g., quinoa, sweet potatoes, leafy greens). Common examples of refined carbs include candies, cookies, pastries, desserts, white bread, white rice, white pasta, sodas, fruit juices, energy drinks, chips, crackers, and processed breakfast cereals.
Introduce meal balancing with protein and healthy fats.
Add anti-inflammatory foods, such as fatty fish, leafy greens, and nuts.
Support your gut health with fermented foods (e.g., yogurt, kimchi) and prebiotic fibers (e.g., garlic, onions).
Gentle Movement
Physical activity enhances insulin sensitivity and releases mood-boosting endorphins.
Post-meal walks to reduce glucose peaks.
Stress Reduction
Chronic stress exacerbates inflammation and disrupts blood sugar regulation. Strategies to reduce stress include:
Meditation: Just 10 minutes a day can lower cortisol levels.
Breathing exercises: Simple practices can stabilize mood and reduce stress.
Sleep Hygiene
Poor sleep impacts blood sugar control and emotional regulation. To improve sleep:
Maintain a consistent bedtime.
Get assessed for obstructive sleep apnea if snoring or poor sleep are an issue.
Avoid screens at least one hour before bed.
Consider magnesium supplements or herbal teas to promote relaxation.
Hot and Cold Practices
Incorporating hot and cold therapies into your routine can have profound benefits for managing both depression and diabetes. These approaches, supported by emerging research, target inflammation, improve metabolic health, and support emotional well-being.
Cold Water Therapy
Cold water therapy, including cold water immersion (CWI) and whole-body cryotherapy (WBC), has shown promise in managing depression, diabetes, and inflammation-related conditions:
Depression:
Cold exposure activates the sympathetic nervous system and increases the release of beta-endorphins and noradrenaline, chemicals that enhance mood.
Research highlights that adapted cold showers and WBC, when used alongside traditional treatments, can significantly improve depressive symptoms and quality of life.
Diabetes:
Cold exposure has been found to improve insulin sensitivity and reduce fasting glucose levels. Animal studies and human trials suggest that mechanisms such as enhanced plasma-derived extracellular vesicles contribute to these effects.
Inflammation-Related Depression:
CWI and WBC reduce systemic inflammation by lowering cortisol levels and modulating pro-inflammatory pathways. This is particularly beneficial for depression associated with chronic inflammation.
How to Incorporate Cold Therapy: Start with manageable practices like short cold showers or localized cold packs, gradually progressing to full immersion or professional cryotherapy sessions.
Heat Therapy: Sauna and Whole-Body Hyperthermia
Heat therapy, including sauna use and whole-body hyperthermia (WBH), offers a range of metabolic and psychological benefits:
Blood Sugar Regulation:
Regular sauna sessions have been shown to reduce glycated hemoglobin (HbA1c) by 1%, improve fasting glucose, and enhance insulin sensitivity.
These effects are mediated by increased production of heat shock protein 70 (HSP70) and nitric oxide, both of which reduce inflammation and support glucose metabolism.
Inflammation Reduction:
WBH decreases systemic inflammation by modulating pathways such as NF-κB and IL-6, offering therapeutic benefits for conditions like diabetes and inflammation-driven depression.
Mental Health:
Heat exposure stimulates the release of endorphins, promoting relaxation and mood improvement, and alleviating depressive symptoms.
How to Incorporate Heat Therapy: Research suggests 2–3 sauna sessions per week for 20–30 minutes. Proper hydration and professional guidance are recommended, particularly for individuals with pre-existing cardiovascular conditions.
Medications with Anti-Inflammatory Effects for Comorbid Depression and Diabetes
Since we are taking an integrative lens, it is important to discuss the role of medications. Medications that target inflammation may actually help with both of these conditions. Below is an overview of medications with potential anti-inflammatory effects that are being explored or utilized in this context:
Antidepressants with Anti-Inflammatory Effects
Selective Serotonin Reuptake Inhibitors (SSRIs):
Examples: Fluoxetine, sertraline, escitalopram.
Effects: May decrease pro-inflammatory cytokines (e.g., IL-6, TNF-α) and modulate inflammatory pathways, contributing to improved glucose regulation and reduced depressive symptoms.
Considerations: Monitor for potential weight gain and long-term risk of Type 2 Diabetes Mellitus (T2DM) with certain SSRIs.
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs):
Examples: Duloxetine, venlafaxine.
Effects: Generally neutral regarding glucose regulation but may indirectly reduce inflammation by alleviating depressive symptoms.
Tricyclic Antidepressants (TCAs):
Examples: Amitriptyline, nortriptyline.
Effects: Potential anti-inflammatory benefits, though their high affinity for histamine receptors may contribute to weight gain and hyperglycemia.
Considerations: Use cautiously due to metabolic side effects.
Antidiabetic Medications with Anti-Inflammatory Properties
Metformin:
Effects: Inhibits inflammatory pathways (e.g., NF-κB) and normalizes gut microbiota. May have modest effects on reducing depressive symptoms in some individuals.
Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs):
Examples: Liraglutide, semaglutide, dulaglutide.
Effects: Anti-inflammatory, neuroprotective, and anti-obesity effects. May reduce TNF-α and increase brain-derived neurotrophic factor (BDNF). Emerging evidence suggests potential mood benefits.
Considerations: Monitor for rare psychiatric side effects, including suicidality.
Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors:
Examples: Empagliflozin, dapagliflozin.
Effects: Reduce low-grade inflammation, improve oxidative stress, and increase BDNF levels. Early evidence suggests they may improve depressive symptoms in patients with T2DM.
Thiazolidinediones (e.g., Pioglitazone):
Effects: Activates PPAR-γ to reduce inflammation and improve insulin sensitivity. Some studies show improvements in depressive symptoms, particularly in individuals with insulin resistance.
Considerations: Risk of weight gain, edema, and other side effects may limit use.
Other Anti-Inflammatory Agents
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):
Examples: Aspirin, salsalate.
Effects: Inhibit NF-κB and other inflammatory pathways. Limited evidence suggests benefits in improving depressive symptoms in individuals with systemic inflammation.
Statins:
Examples: Atorvastatin, rosuvastatin.
Effects: Reduce systemic inflammation and may lower the risk of depressive symptoms in patients with diabetes.
Monoclonal Antibodies Targeting Cytokines:
Examples: Anti-TNF-α agents, IL-1 antagonists (e.g., anakinra).
Effects: Specifically target inflammatory cytokines implicated in insulin resistance and depression.
Considerations: Use is limited due to high costs and potential immunosuppressive side effects.
Did you know? Those with type 2 diabetes mellitus and depression are more likely to experience what we call atypical depression. These are specific depressive symptoms such as anhedonia (loss of interest in doing things that were once pleasurable), sleeping too much, and fatigue.
Biomarkers for Depression, Blood Sugar Dysregulation, and Inflammation
Blood Sugar and Metabolic Health
Hemoglobin A1c (HbA1c)
A long-term marker of blood sugar control over 2–3 months.
Fasting Insulin
Assesses insulin resistance and early metabolic dysfunction.
Fasting Glucose
Provides baseline glucose levels.
Continuous Glucose Monitoring (CGM)
Tracks blood sugar fluctuations in real-time to identify triggers like food, stress, or sleep disruption.
Cortisol and Adrenal Function
4-Point Cortisol Saliva or Dried Urine Test
Evaluates diurnal cortisol patterns (morning peak, daytime dips, and evening lows).
DHEA-S (Included with Genova Adrenocortex Profile Lab)
Monitors adrenal reserves and cortisol/DHEA balance.
Optimal ratio: Higher DHEA relative to cortisol in healthy individuals.
Inflammation and Gut Health
High-Sensitivity C-Reactive Protein (hs-CRP)
Functional medicine target: <1.0 mg/L for low inflammation.
Zonulin
A marker of intestinal permeability ("leaky gut").
Comprehensive Stool Analysis
Evaluates microbiome diversity, short-chain fatty acids (SCFAs), inflammation markers (calprotectin, lactoferrin), and gut pathogens.
Calprotectin
Marker of gut inflammation, often tied to leaky gut and LPS.
Secretory IgA (sIgA)
Reflects mucosal immunity and gut barrier function.
Nutrient Deficiencies
Vitamin D (25-Hydroxy)
Magnesium (RBC Magnesium)
Functional focus is on intracellular magnesium, not serum levels.
Omega-3 Index
Measures EPA/DHA levels in red blood cells to assess anti-inflammatory balance.
Vitamin B12 (Methylcobalamin) and Folate (RBC Folate)
Iron Panel with Ferritin
Both deficiency and excess of ferritin can drive inflammation).
Homocysteine
Elevated levels indicate poor methylation or inflammation.
Hormonal and Thyroid Health
Thyroid Panel
Includes TSH, Free T4, Free T3, Reverse T3, and Thyroid Antibodies (TPO)
A kind reminder: This blog post is designed as a general guide. This is not a substitute for personalized medical advice, nor is a patient-physician relationship established in this blog post.
References:
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