Can a drug replace the benefits of exercise?

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A new drug, still under investigation and not yet FDA approved is reported to provide the benefits of exercise in humans. The drug is called ATX304 and has been studied in humans in phase II clinical trials. It works by decreasing the degradation of a master energy controller called AMPK (AMP-activated protein kinase) By decreasing the degradation, it increases the amount of AMPK which has multiple favorable metabolic effects. When we exercise our muscles utilize ATP (adenosine triphosphate) the major energy source for our cells. When ATP is broken down the levels of AMP (adenosine monophosphate) increase and that increase signals AMPK to increase. ATX304 produces the same rise in AMPK experienced with exercise. The result is that muscle cells uptake glucose from the circulation without the need for insulin (non insulin dependent glucose uptake), the same occurs with exercise. With exercise the effect can last for 16 hours. Thus blood sugar is better controlled with both exercise and with ATX304. Along with better blood sugar control, insulin sensitivity is maintained and improved by avoiding pancreatic beta cell stress (beta cells produce insulin). ATX-304 also improves blood vessel flow, cardiac pump function, and as a result improved delivery of oxygen and nutrients to muscle and all parts of the body.

ATX304 also increases the uptake of fatty acids by the mitochondria (the organelle in our cells that produce energy in the form of ATP), facilitating energy production through the burning of fat (a process called beta oxidation). This happens without the muscle loss associated with GLP-1 drugs. Muscle is protected because glucose and fatty acid delivery to muscles are enhanced while keeping cellular ATP stable, completely bypassing the starvation pathways that cause muscle wasting when people lose weight by fasting or taking GLP-1 agonist drugs.

While I do not advocate taking pills instead of exercise I view ATX-304 as a better alternative weight loss medication compared to GLP-1 drugs for several reasons. First and foremost one can avoid the 20-40% loss of muscle associated with GLP-1 drugs. Secondly, ATX-304 increases metabolic rate, causing greater energy expenditure.

While ATX-304 represents an exciting potential approach to weight loss while improving insulin sensitivity without loss of muscle, you cannot build muscle strength, muscle mass, improve balance and coordination, or challenge your brain (with the resulting cognitive protection) by taking a pill. You must exercise including resistance training to accomplish those specific beneficial outcomes.

For a deeper dive into ATX-304 and a more detailed understanding how our bodies use glucose and fat to produce energy, as well as understanding how exercise works to improve metabolic health, what follows is a conversation I had with Google Gemini.

Conversation with Gemini

how does atx304 improve glucose control, enhance exercise performance and reduce body fat while maintaining muscle, use only peer reviewed scientific papers and cite references

ATX-304 (formerly known as O304) is a first-in-class, small-molecule, non-allosteric PAN-AMPK activator (AMP-activated protein kinase) currently in clinical development for metabolic and cardiovascular diseases (Ericsson et al., 2021; Steneberg et al., 2018). It functions primarily by protecting phosphorylated AMPK (p-AMPK) from dephosphorylation by protein phosphatases like PP2C, effectively acting as an “exercise mimetic” that triggers catabolic, energy-generating pathways (Steneberg et al., 2018).

Peer-reviewed academic research details the distinct physiological mechanisms through which ATX-304 improves glucose control, enhances exercise performance, and selectively targets body fat while preserving lean muscle mass:

1. Improvement of Glucose Control

ATX-304 manages blood sugar levels through a dual mechanism targeting both skeletal muscle and pancreatic tissues:

  • Insulin-Independent Glucose Uptake: In skeletal muscle, ATX-304 activates AMPK signaling, which drives the translocation of glucose transporter 4 (GLUT4) vesicles to the cell membrane. This allows muscle tissue to pull glucose from the bloodstream independently of insulin action (Steneberg et al., 2018).
  • Beta-Cell Preservation and Rest: By reducing systemic glucose demand and chronic hyperglycemia, the compound mitigates pancreatic β-cell stress. Clinical evidence from Phase IIa trials in patients with Type 2 Diabetes (T2D) demonstrated substantial reductions in fasting plasma glucose (FPG) and overall insulin resistance, quantified by HOMA-IR (Steneberg et al., 2018).
  • Reversal of Age-Related Insulin Resistance: In longitudinal animal models, prolonged administration of the compound prevented the progressive, age-associated hyperinsulinemia that typically induces metabolic syndrome (Ericsson et al., 2021).

2. Enhancement of Exercise Performance

As an exercise mimetic, ATX-304 induces cellular adaptations similar to endurance training:

  • Cardiovascular & Microvascular Remodeling: ATX-304 mimics the cardiac stressors of exercise by enhancing left ventricular stroke volume, increasing end-diastolic volume, and lowering resting heart rate without inducing pathological cardiac hypertrophy (Ericsson et al., 2021; Steneberg et al., 2018). Furthermore, it improves peripheral microvascular perfusion and blood pressure regulations.
  • Mitochondrial Homeostasis: The compound enhances mitochondrial respiration, upregulates fatty acid oxidation, and increases baseline oxygen consumption rates (OCR) in metabolic tissues (Katerelos et al., 2024). These changes directly translate to significantly improved exercise capacity and total work endurance, especially in aged or metabolically compromised subjects (Ericsson et al., 2021).

3. Reduction of Body Fat While Maintaining Muscle

One of the key advantages of direct pan-AMPK activation via ATX-304 is its ability to execute a systemic “metabolic switch” that differentiates between fat tissue and lean body mass:

  • Upregulation of Lipid Oxidation: ATX-304 stimulates cellular catabolism by phosphorylating Acetyl-CoA Carboxylase (ACC). Phosphorylation inhibits ACC, which decreases malonyl-CoA levels, disinhibits carnitine palmitoyltransferase-1 (CPT1), and permits rapid fatty acid oxidation in both the liver and adipose tissue (Holm et al., 2024).
  • Selective Adiposity Loss: Body composition analysis via EchoMRI reveals that the rapid weight reduction induced by ATX-304 corresponds almost entirely to a loss in adipose (fat) mass (Holm et al., 2024). It also limits hepatic de novo lipogenesis and drives down blood cholesterol levels.
  • Muscle Preservation (Lean Weight Maintenance): Unlike severe caloric restriction or certain anti-obesity medications that trigger concurrent muscle loss, animals treated with ATX-304 maintain their absolute lean weight (muscle mass) (Holm et al., 2024). The compound drives a significant long-term increase in energy expenditure, meaning that even when food intake naturally rebounds or increases by 20% to 30%, fat mass continues to decrease while skeletal muscle architecture is protected (Holm et al., 2024).

References

Ericsson, M., Steneberg, P., Nyrén, R., & Edlund, H. (2021). AMPK activator O304 improves metabolic and cardiac function, and exercise capacity in aged mice. Communications Biology, 4(1), 1–12. https://doi.org/10.1038/s42003-021-02837-0 Cited by: 30

Holm, E., Vermeulen, I., Parween, S., López-Pérez, A., Cillero-Pastor, B., Vandenbosch, M., Remeseiro, S., & Hörnblad, A. (2024). AMPK-activator ATX-304 reduces oxidative stress and improves MASLD via metabolic switching. JCI Insight, 9(7). https://doi.org/10.1101/2024.02.13.578901 Cited by: 10

Katerelos, M., Gleich, K., Harley, G., Loh, K., Oakhill, J. S., Kemp, B. E., de Souza, D. P., Narayana, V. K., Coughlan, M. T., Laskowski, A., Ling, N. X. Y., Murray-Segal, L., Brink, R., Lee, M., Power, D. A., & Mount, P. F. (2024). The AMPK activator ATX-304 alters cellular metabolism to protect against cisplatin-induced acute kidney injury. Biomedicine & Pharmacotherapy, 175, 116730. https://doi.org/10.1016/j.biopha.2024.116730 Cited by: 9

Steneberg, P., Lindahl, E., Dahl, U., Lidh, E., Straseviciene, J., Backlund, F., Kjellkvist, E., Berggren, E., Lundberg, I., Bergqvist, I., Ericsson, M., Eriksson, B., Linde, K., Westman, J., Edlund, T., & Edlund, H. (2018). PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients. JCI Insight, 3(12). https://doi.org/10.1172/jci.insight.99114 Cited by: 132

how do the effects on ACC and CPT1 lead to increased fat oxidation

The biochemical mechanism linking Acetyl-CoA Carboxylase (ACC) and Carnitine Palmitoyltransferase-1 (CPT1) is the primary pathway through which AMPK activators like ATX-304 accelerate fat oxidation.

In cellular metabolism, CPT1 is the “gatekeeper” for fat burning, but its activity is strictly regulated by a molecular brake called malonyl-CoA. Direct activation of AMPK breaks this cycle, shifting the cell into a dedicated fat-burning state.

The Molecular Chain Reaction

When ATX-304 activates AMPK, it initiates a sequential cascade that directly impacts the mitochondria:

        ATX-304 / AMPK Activated

                   │

                   ▼

         ACC is Phosphorylated

             (Inactivated)

                   │

                   ▼

       Malonyl-CoA Levels Drop

         (The “Brake” is Removed)

                   │

                   ▼

        CPT1 is Disinhibited

             (Gate Opens)

                   │

                   ▼

 Fatty Acids Enter Mitochondria ──► Beta-Oxidation (Fat Burning)

1. The Inactivation of ACC

Under normal conditions, the enzyme ACC converts acetyl-CoA into malonyl-CoA. Malonyl-CoA is the fundamental building block for synthesizing new fatty acids (de novo lipogenesis).

When ATX-304 activates AMPK, AMPK attaches a phosphate group to ACC (specifically the ACC1 and ACC2 isoforms). This phosphorylation inactivates ACC, halting the production of malonyl-CoA.

2. The Disinhibition of CPT1

Malonyl-CoA acts as a powerful allosteric inhibitor (a biological “off switch”) for CPT1. CPT1 is an enzyme anchored to the outer mitochondrial membrane. Long-chain fatty acids cannot cross into the mitochondria on their own; they must be attached to carnitine by CPT1 to gain entry.

Because ATX-304 shuts down ACC, cellular levels of malonyl-CoA rapidly drop. Without malonyl-CoA around to inhibit it, CPT1 transitions into its fully active state.

3. Increased Mitochondrial Beta-Oxidation

With the CPT1 gateway open, long-chain fatty acids are rapidly converted into acyl-carnitines, allowing them to pass through the mitochondrial membranes via the carnitine shuttle. Once inside the mitochondrial matrix, these fatty acids undergo β-oxidation (beta-oxidation).

During β-oxidation, the fatty acids are chopped down into acetyl-CoA molecules, which directly feed into the Tricarboxylic Acid (TCA) cycle to generate ATP (cellular energy).

Summary: By turning off ACC, ATX-304 depletes the molecule (malonyl-CoA) that normally blocks CPT1. This unlocks the mitochondrial gateway, forcing the cell to pull circulating fatty acids out of storage and burn them for fuel, ultimately driving down systemic body fat (Holm et al., 2024; Steneberg et al., 2018).

Want to know how this specific fat-burning pathway preserves muscle mass?

Yes

How does ATX-304 increase fat oxidation via ACC and CPT1 without triggering skeletal muscle breakdown or protein degradation?

The preservation of skeletal muscle mass during accelerated fat oxidation is a defining feature of ATX-304. Typically, extreme caloric restriction or non-selective metabolic stressors that force fat burning also trigger a counter-regulatory catabolic state, where muscle tissue is broken down for amino acids.

ATX-304 avoids skeletal muscle breakdown through several distinct molecular and metabolic safeguards:

1. Preservation of Cellular ATP Levels

diabetesjournals.org

Traditional methods of AMPK activation (like mitochondrial poisons or extreme energy deprivation) severely deplete cellular ATP. When ATP drops drastically, hyper-activated AMPK signals the cell that it is starving, which triggers the ubiquitin-proteasome system (via MuRF1 and MAFbx/Atrogin-1) and FoxO3-mediated autophagy to degrade muscle protein for emergency energy.

  • The ATX-304 Difference: ATX-304 activates AMPK by preventing the dephosphorylation of p-AMPK by protein phosphatases, rather than by draining the cell of energy (Steneberg et al., 2018).

http://www.researchgate.net

  • Peer-reviewed data confirms that cellular ATP levels and mitochondrial membrane potential (MMP) are fully preserved under ATX-304 exposure (Diabetes, 2026). Because the muscle cell is never in a true energetic crisis or ATP deficit, the signals that initiate muscle proteolysis (protein degradation) are never switched on.

diabetesjournals.org

2. Enhanced Glucose and Nutrient Delivery to Muscle

insight.jci.org

Muscle wasting often occurs when a lack of localized energy forces muscle fibers to degrade. ATX-304 directly protects muscle tissue by optimizing its nutrient environment:

  • GLUT4 Translocation: In skeletal muscle, ATX-304-driven AMPK activation stimulates the moving of GLUT4 transporters to the cell membrane, enhancing insulin-independent glucose uptake (Steneberg et al., 2018).

http://www.baybridgebio.com

  • Microvascular Perfusion: The compound improves capillary blood flow and microvascular perfusion directly to skeletal muscle tissue. This ensures a continuous supply of blood sugar, oxygen, and systemic nutrients to the muscle, keeping the tissue fueled and preventing the need for autophagic self-cannibalization.

3. Metabolic Substrate Switching Away from Proteolysis

By targeting the ACC-CPT1 axis, ATX-304 forces a highly selective “metabolic switch.”

  • The inhibition of ACC stops fatty acid synthesis and drops malonyl-CoA levels, allowing CPT1 to constantly shuttle long-chain fatty acids into the mitochondria (Holm et al., 2024).
  • This floods the mitochondrial matrix with lipids for β-oxidation. Because the cell is over-supplied with lipid-derived acetyl-CoA to feed the TCA cycle, it heavily relies on fat as its primary fuel source. Consequently, there is no biochemical demand to oxidize branched-chain amino acids (BCAAs) from structural muscle proteins.

4. Absence of the “Starvation Deficit” Loop

In long-term animal studies, subjects treated with ATX-304 experienced a substantial reduction in fat mass while maintaining absolute lean body weight (Holm et al., 2024). Because ATX-304 increases baseline energy expenditure through increased mitochondrial respiration, treated subjects naturally maintain a normal or slightly increased dietary intake to compensate. This stands in sharp contrast to crash dieting or GLP-1 receptor agonists, where profound appetite suppression and extreme caloric deficits frequently result in up to 20–40% of the lost weight coming from lean muscle mass.

http://www.researchgate.net

In short: ATX-304 accelerates fat burning through the ACC-CPT1 pathway without sacrificing muscle because it increases lipid availability and muscle glucose uptake while keeping cellular ATP stable—completely bypassing the starvation pathways that cause muscle wasting.

References

  • Holm, E., et al. (2024). AMPK-activator ATX-304 reduces oxidative stress and improves MASLD via metabolic switching. JCI Insight, 9(7).

http://www.biorxiv.org

  • Steneberg, P., et al. (2018). PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients. JCI Insight, 3(12).

pmc.ncbi.nlm.nih.gov

  • American Diabetes Association (ADA) Scientific Sessions. (2026). Abstract 1788-P: AMPK Activation by ATX-304 Is Not Secondary to Changes in ATP Levels. Diabetes, 75(Supplement 1).

diabetesjournals.org+ 1

THIS WEBSITE PROVIDES INFORMATION FOR EDUCATIONAL PURPOSES ONLY. CONSULT YOUR HEALTH CARE PROVIDER FOR MEDICAL ADVICE.

Eat clean, drink filtered water, love, laugh, exercise outdoors in a greenspace, get some morning sunlight, block the blue light before bed, engage in meaningful work, find a sense of purpose, spend time with those you love, AND sleep well tonight.

Doctor Bob

What can I do to improve insulin sensitivity?

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  1. Exercise (aerobic and resistance training, in the gym, on the dance floor, outside in a greenspace, with friends and family)
  2. Get adequate restorative sleep (follow regular sleep habits, see also #s1, 3, 4 to 12)
  3. Enhance circadian rhythm (outdoor light exposure early in the day, avoid screen time prior to bed and/or use blue light blocking glasses and screen software, see also #1, #2, # 4 to 12)
  4. Reduce stress (meditation, yoga, tai chi, family time, #s1-3, 5-12)
  5. Engage in meaningful work
  6. Spend time with those you love
  7. Eat an anti-inflammatory (paleo) diet
  8. If overweight, employ therapeutic carbohydrate restriction (if on medications for diabetes this must be done under medical supervision following established published guidelines for medication adjustments)
  9. Spend time outdoors in a greenspace, especially early in the day. (Forest bathing)
  10. When working (on the computer) or reading indoors, do it in front of a large window to increase outdoor light exposure.
  11. Regularly use a sauna
  12. Consider brief cold immersion sessions (2-4 minutes of cold shower or cold-water immersion, approach this gradually)

Exercise: per minute spent, resistance training offers the most benefit. Second to resistance training is HIIT (High Intensity Interval Training) per unit of time spent. Finally moderate aerobic exercise (heart rate 60 to 80% of maximum predicted heart rate for age) places third for benefit per unit time spent. Most importantly, find some exercise that you enjoy and will sustain. Dancing, especially for seniors, combines the benefits of socialization, exercise, and simultaneous use of multiple brain areas, preserving and enhancing cognitive function in addition to mitigation of insulin resistance, chronic inflammation and cardiovascular risk. Engaging in sports that require coordination, balance, strength and complex movements also utilizes multiple areas of the brain simultaneously, providing for cognitive, metabolic and cardiovascular benefit.  A single bout of exercise can increase insulin sensitivity for at least 16 h post exercise in healthy as well as diabetic subjects.

Sleep and Circadian Rhythm

Just one night of short-sleep causes acute insulin resistance. Chronic sleep deprivation contributes to chronic inflammation and insulin resistance. Go the bed and wake up on a consistent schedule. Avoid food and screen time for 3 hours before bed. Allow yourself at least 8 hours per night of sleep opportunity. Find relaxing routines to follow for an hour or two before bedtime. Avoid strenuous exercise in the evening. No caffeine after 12 noon. Getting outdoor light exposure early in the day facilitates restorative sleep. During sleep our brains flush out metabolic debris that accumulates during the day through the glymphatic system.  Melatonin production during sleep provides multiple benefits including anti-inflammatory effects. Sleep in a cool very dark bedroom.

Optimizing sleep and circadian rhythm involves a combination of timing, environmental control, and biological signaling. These habits aim to align your internal master clock (the suprachiasmatic nucleus) with the external 24-hour light-dark cycle.

Summary Table: Daily Habits

HabitTimingPrimary Benefit
View SunlightFirst 60 mins of daySets the circadian “timer”
ExerciseMorning or AfternoonIncreases sleep pressure/adenosine
Last Meal3 hours before bedPrevents metabolic circadian shift
Cool RoomAll nightFacilitates core temp drop
Darkness1–2 hours before bedAllows natural melatonin rise

In my next posts I will explore items 5 through 12 above.

Yan R, Chen L, Lin G, Shi Y, Huang W, Mai Y, Sun J, Li D. Comparative effectiveness of different exercise modality on glycaemic control and lipid profile for prediabetes: systematic review and network meta-analysis. Front Endocrinol (Lausanne). 2025 Jul 24;16:1518871. doi: 10.3389/fendo.2025.1518871. PMID: 40778279; PMCID: PMC12328182. https://pubmed.ncbi.nlm.nih.gov/40778279/

Zhang L, Cheng X, Yang Y, Li X, Yuan Y. Optimal dosage and modality of exercise on glycemic control in people with prediabetes: a systematic review and network meta-analysis. Front Endocrinol (Lausanne). 2025 Apr 28;16:1560676. doi: 10.3389/fendo.2025.1560676. PMID: 40357204; PMCID: PMC12066256. https://pubmed.ncbi.nlm.nih.gov/40357204/

Huang L, Fang Y, Tang L. Comparisons of different exercise interventions on glycemic control and insulin resistance in prediabetes: a network meta-analysis. BMC Endocr Disord. 2021 Sep 6;21(1):181. doi: 10.1186/s12902-021-00846-y. PMID: 34488728; PMCID: PMC8422751. https://pubmed.ncbi.nlm.nih.gov/34488728/

Amaravadi SK, Maiya GA, K V, Shastry BA. Effectiveness of structured exercise program on insulin resistance and quality of life in type 2 diabetes mellitus-A randomized controlled trial. PLoS One. 2024 May 21;19(5):e0302831. doi: 10.1371/journal.pone.0302831. PMID: 38771888; PMCID: PMC11108169. https://pubmed.ncbi.nlm.nih.gov/38771888/

Alghadir AH, Gabr SA, Iqbal A. The effects of supervised aerobic training on dyslipidaemia among diabetic older patients. BMC Endocr Disord. 2024 Oct 9;24(1):212. doi: 10.1186/s12902-024-01745-8. PMID: 39385223; PMCID: PMC11462724. https://pubmed.ncbi.nlm.nih.gov/39385223/

Abdelbasset WK. Resistance Exercise Versus Aerobic Exercise Combined with Metformin Therapy in the Treatment of type 2 Diabetes: A 12-Week Comparative Clinical Study. Endocr Metab Immune Disord Drug Targets. 2021;21(8):1531-1536. doi: 10.2174/1871530320999200918143227. PMID: 32957900. https://pubmed.ncbi.nlm.nih.gov/32957900/

Li J, Cheng W, Ma H. A Comparative Study of Health Efficacy Indicators in Subjects with T2DM Applying Power Cycling to 12 Weeks of Low-Volume High-Intensity Interval Training and Moderate-Intensity Continuous Training. J Diabetes Res. 2022 Jan 13;2022:9273830. doi: 10.1155/2022/9273830. PMID: 35071605; PMCID: PMC8776485. https://pubmed.ncbi.nlm.nih.gov/35071605/

Findikoglu G, Altinkapak A, Yaylali GF. Is isoenergetic high-intensity interval exercise superior to moderate-intensity continuous exercise for cardiometabolic risk factors in individuals with type 2 diabetes mellitus? A single-blinded randomized controlled study. Eur J Sport Sci. 2023 Oct;23(10):2086-2097. doi: https://pubmed.ncbi.nlm.nih.gov/36622777/

Cox ER, Gajanand T, Keating SE, Hordern MD, Burton NW, Green DJ, Ramos JS, Ramos MV, Fassett RG, Cox SV, Coombes JS, Bailey TG. Effect of low-volume combined aerobic and resistance high-intensity interval training on vascular health in people with type 2 diabetes: a randomised controlled trial. Eur J Appl Physiol. 2024 Sep;124(9):2819-2833. doi: 10.1007/s00421-024-05473-8. Epub 2024 May 2. PMID: 38695912; PMCID: PMC11365856. https://pubmed.ncbi.nlm.nih.gov/38695912/

Li Z, Luo S, Bai X, Huang L, Guo H, Chen S, Wang D. Effects of different exercise types on vascular endothelial function in individuals with abnormal glycaemic control: a systematic review and network meta-analysis. PeerJ. 2025 Aug 8;13:e19839. doi: 10.7717/peerj.19839. PMID: 40792010; PMCID: PMC12338059. https://pubmed.ncbi.nlm.nih.gov/40792010/

Borghouts LB, Keizer HA. Exercise and insulin sensitivity: a review. Int J Sports Med. 2000 Jan;21(1):1-12. doi: 10.1055/s-2000-8847. PMID: 10683091. https://pubmed.ncbi.nlm.nih.gov/10683091/

Wojtaszewski JF, Richter EA. Effects of acute exercise and training on insulin action and sensitivity: focus on molecular mechanisms in muscle. Essays Biochem. 2006;42:31-46. doi: 10.1042/bse0420031. PMID: 17144878. https://pubmed.ncbi.nlm.nih.gov/17144878/

Böhm A, Weigert C, Staiger H, Häring HU. Exercise and diabetes: relevance and causes for response variability. Endocrine. 2016 Mar;51(3):390-401. doi: 10.1007/s12020-015-0792-6. Epub 2015 Dec 7. PMID: 26643313; PMCID: PMC4762932. https://pubmed.ncbi.nlm.nih.gov/26643313/

Reutrakul S, Van Cauter E. Sleep influences on obesity, insulin resistance, and risk of type 2 diabetes. Metabolism. 2018 Jul;84:56-66. doi: 10.1016/j.metabol.2018.02.010. Epub 2018 Mar 3. PMID: 29510179. https://pubmed.ncbi.nlm.nih.gov/29510179/

Antza C, Kostopoulos G, Mostafa S, Nirantharakumar K, Tahrani A. The links between sleep duration, obesity and type 2 diabetes mellitus. J Endocrinol. 2021 Dec 13;252(2):125-141. doi: 10.1530/JOE-21-0155. PMID: 34779405; PMCID: PMC8679843. https://pubmed.ncbi.nlm.nih.gov/34779405/

Koren D, Taveras EM. Association of sleep disturbances with obesity, insulin resistance and the metabolic syndrome. Metabolism. 2018 Jul;84:67-75. doi: 10.1016/j.metabol.2018.04.001. Epub 2018 Apr 6. PMID: 29630921. https://pubmed.ncbi.nlm.nih.gov/29630921/

Duffy, J. F., & Czeisler, C. A. (2009). Effect of Light on Human Circadian Physiology. Sleep Medicine Clinics. https://pubmed.ncbi.nlm.nih.gov/20161220/

Okamoto-Mizuno, K., & Mizuno, K. (2012). Effects of thermal environment on sleep and circadian rhythm. Journal of Physiological Anthropology. https://pubmed.ncbi.nlm.nih.gov/22738673/

Roenneberg, T., et al. (2012). Social Jetlag and Obesity. Current Biology. https://pubmed.ncbi.nlm.nih.gov/22578422/

Drake, C., et al. (2013). Caffeine effects on sleep taken 0, 3, or 6 hours before going to bed. Journal of Clinical Sleep Medicine. https://pubmed.ncbi.nlm.nih.gov/24235903/

Gooley, J. J., et al. (2011). Exposure to Room Light before Bedtime Suppresses Melatonin Onset and Shortens Melatonin Duration in Humans. The Journal of Clinical Endocrinology & Metabolism. https://pubmed.ncbi.nlm.nih.gov/21193540/

Speksnijder EM, Bisschop PH, Siegelaar SE, Stenvers DJ, Kalsbeek A. Circadian desynchrony and glucose metabolism. J Pineal Res. 2024 May;76(4):e12956. doi: 10.1111/jpi.12956. PMID: 38695262. https://pubmed.ncbi.nlm.nih.gov/38695262/

Engin A. Misalignment of Circadian Rhythms in Diet-Induced Obesity. Adv Exp Med Biol. 2024;1460:27-71. doi: 10.1007/978-3-031-63657-8_2. PMID: 39287848. https://pubmed.ncbi.nlm.nih.gov/39287848/

Koh JYJ, Tan CYH, Li M, Liu MH, Chew HSJ. The Effectiveness of Time-Restricted Eating as an Intermittent Fasting Approach on Shift Workers’ Glucose Metabolism: A Systematic Review and Meta-Analysis. Nutrients. 2025 May 15;17(10):1689. doi: 10.3390/nu17101689. PMID: 40431429; PMCID: PMC12114545. https://pubmed.ncbi.nlm.nih.gov/40431429/

Wang A, Vreijling J, Jongejan A, Rumanova VS, Versteeg RI, Kalsbeek A, Serlie MJ, la Fleur SE, Bisschop PH, Baas F, Stenvers DJ. The Acute Effects of Morning Bright Light on the Human White Adipose Tissue Transcriptome: Exploratory Post Hoc Analysis. Clocks Sleep. 2025 Aug 27;7(3):45. doi: 10.3390/clockssleep7030045. PMID: 40981208; PMCID: PMC12452623. https://pubmed.ncbi.nlm.nih.gov/40981208/

THIS WEBSITE PROVIDES INFORMATION FOR EDUCATIONAL PURPOSES ONLY. CONSULT YOUR HEALTH CARE PROVIDER FOR MEDICAL ADVICE.

Eat clean, drink filtered water, love, laugh, exercise outdoors in a greenspace, get some morning sunlight, block the blue light before bed, engage in meaningful work, find a sense of purpose, spend time with those you love, AND sleep well tonight.

Doctor Bob

Insulin Resistance, the silent killer and root cause of modern chronic disease.

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Insulin is much more than a blood sugar hormone. Produced by the pancreas primarily in response to carbohydrate and sugar consumption, insulin is a master anabolic signal that dictates how every cell in your body grows, uses energy, and repairs itself. When insulin levels are healthy, it keeps the body in a state of “build and store.” When insulin resistance (IR) develops, the body loses its ability to hear this signal, leading to systemic breakdown. Instead of “build and store” the body deteriorates, causing loss of muscle mass, strength, energy production, memory and cognitive function, bone strength, brain cells and connections, ability of blood vessels to relax, ability for the heart to pump blood, ability to achieve restorative sleep, ability of the liver and kidneys to clear toxins from the body, even the ability to reproduce resulting in infertility and erectile dysfunction. Visceral fat stores increase to destructive levels resulting in obesity and obesity-related complications including chronic inflammation which further drives IR to higher levels.

IR is a root cause of cardiovascular disease (heart attack, stroke, hypertension, heart failure), many kinds of cancer (directly linked to breast, prostate and colon cancer), kidney failure, heart failure, dementia, osteoporosis, osteoarthritis, and much more.  IR is causally linked or a contributor to, every chronic non-communicable disease of modern civilization.

WHAT IS INSULIN RESISTANCE?

Insulin resistance is the inability of cells and organs to respond normally to insulin signaling. Every cell of every organ has insulin receptors that initiate action by the cell and organ.

WHAT CAUSES INSULIN RESISTANCE?

There are many causes of IR. Stress hormones (cortisol, adrenaline), inflammation, and high insulin levels themselves (response to dietary sugar and refined carbohydrates), each alone and in combination, cause immediate (within minutes to hours) insulin resistance. When these conditions persist over time insulin resistance becomes a chronic state. As fat cells grow in size, they reach a point where there is inadequate blood flow to the cells themselves and macrophages (immune cells that reside between the fat cells, most prominently in visceral fat) produce inflammatory chemicals called cytokines. Cytokines flow through the blood stream and effect every organ and every cell in the body creating a state of chronic inflammation which further worsens IR, creating a vicious cycle. As IR continues the pancreas produces increasingly higher amounts of insulin to maintain normal blood sugar levels but eventually IR becomes so great that blood sugar levels move into the “pre-diabetes” and eventually the diabetes range. IR builds for years to decades before blood sugar regulation fails. By the time blood sugar levels are “abnormal” insulin resistance has done great damage throughout the body.

Most doctors tragically do not order fasting insulin levels as routine blood tests. Fasting insulin levels rise long before fasting blood sugars and hemoglobin A1c start to rise. Meanwhile the damage progresses under the radar of routine testing.

1. Metabolic Engines: Muscle and Liver

Muscle

  • Normal Action: Insulin acts as a key that opens “doors” (GLUT4 receptors) to let glucose in for fuel. it also stimulates protein synthesis. Protein synthesis is essential to maintaining and increasing muscle mass and strength.
  • Insulin Resistance Effect: The “doors” stay locked. Glucose stays in the blood, and the muscle becomes “starched,” leading to sarcopenia (muscle wasting) and fatigue. The muscle can no longer utilize dietary protein to maintain or increase muscle mass.

Liver

  • Normal Action: Tells the liver to stop producing glucose and start storing it as glycogen or converting excess into fat.
  • Insulin Resistance Effect: The liver ignores the “stop” signal and keeps pumping out glucose while simultaneously ramping up fat production. This results in Non-Alcoholic Fatty Liver Disease (NAFLD).

2. Fat Cells (Adipose Tissue)

Visceral (Deep Fat) vs. Subcutaneous (Under Skin)

  • Normal Action: Insulin promotes fat storage and inhibits the breakdown of stored fat (lipolysis).
  • Insulin Resistance Effect: Fat cells—especially visceral ones—become “leaky.” They spill free fatty acids into the bloodstream and release inflammatory cytokines. This causes weight gain that is biologically difficult to lose because high insulin levels keep the “fat-burning” switch permanently off.

3. The Vital Organs: Heart, Kidneys, and Arteries

Heart and Arteries

  • Normal Action: Insulin stimulates the release of nitric oxide, which helps arteries relax and dilate.
  • Insulin Resistance Effect: Nitric oxide production drops, causing arteries to stiffen (hypertension). High insulin also damages the endothelial lining, leading to atherosclerosis (plaque buildup). This is the primary driver of heart failure, heart attacks and strokes.

Kidneys

  • Normal Action: Helps regulate sodium reabsorption.
  • Insulin Resistance Effect: The kidneys hold onto too much salt, increasing blood pressure. Over time, high blood sugar and inflammation damage the filtering units, leading to chronic kidney disease (CKD).

4. The Brain, Memory, and Sleep

Brain and Memory

  • Normal Action: Insulin crosses the blood-brain barrier to regulate appetite and support synaptic plasticity (the basis of learning).
  • Insulin Resistance Effect: Often called “Type 3 Diabetes,” brain IR starves neurons of energy and allows amyloid plaques and neurofibrillary tangles to build up. Worse, the brain is unable to utilize glucose to meet energy demands it starts to malfunction. This is a direct pathway to Alzheimer’s disease and dementia. As the small arteries in the brain become atherosclerotic and unable to deliver adequate oxygen and nourishment to brain cells small areas of the brain become permanently damaged eventually leading to vascular dementia.

Sleep

  • Insulin Resistance Effect: IR is heavily linked to Obstructive Sleep Apnea. (OSA) High insulin affects the central respiratory drive and increases fat deposits around the neck (a major contributor to obstructive sleep apnea), disrupting sleep cycles and creating periods of inadequate oxygen flow to the brain resulting in the acute stress response and awakening with each apneic event. Even without OSA, high insulin levels impair the production of melatonin which is essential to normal-restorative sleep. Throughout the day the brain accumulates metabolic toxins that must be cleared through the glymphatic system at night during sleep. As sleep is impaired this clearance system is disrupted, contributing to structural damage and functional loss. Sleep disruption and apneic episodes are stressful events, increasing stress hormones which then worsen IR, creating another vicious cycle. One night of sleep disruption causes acute IR. Chronic sleep disruption contributes to chronic IR.

5. Immunity and Structural Health

Immune System

  • Action: High insulin/glucose impairs white blood cell function.
  • Effect: Chronic inflammation (high CRP levels) and a weakened defense against infections. This is why diabetics often have poor wound healing. As normal immune regulation is impaired the immune system both over-reacts and under-reacts. Under-reaction increases risk of infection. Over-reaction produces cytokine storms seen with Covid-19 and other infections. Chronic inflammation worsens IR creating another vicious cycle. Chronic inflammation contributes to most chronic diseases.

Bone and Joints

  • Action: Insulin is bone-building.
  • Effect: IR leads to poor bone quality (despite high density) and osteoarthritis due to systemic inflammation and the “glycosylation” (sugar-coating) of joint cartilage, making it brittle.

6. The Pancreas: Beta and Alpha Cells

  • Normal Action: Beta cells produce insulin; Alpha cells produce glucagon (which raises sugar). They balance each other.
  • Insulin Resistance Effect:
    • Beta Cells: Work overtime to produce massive amounts of insulin to compensate, eventually “burning out” and dying. This can produce per4manent irreversible damage to the pancreas.
    • Alpha Cells: Become resistant to insulin’s “stop” signal and keep secreting glucagon, further raising blood sugar levels which in turn cause higher insulin secretion, both of which worsen IR, creating another vicious cycle.

7. Reproductive Effects: Infertility

  • In Women: High insulin stimulates the ovaries to produce excess testosterone, which is the primary driver of Polycystic Ovary Syndrome (PCOS) and infertility.
  • In Men: IR is a leading cause of low testosterone and erectile dysfunction (due to the arterial damage mentioned above).

Summary of Systemic Effects

ConditionPrimary Mechanism of Insulin Resistance
AtherosclerosisEndothelial dysfunction, high triglycerides, low HDL, increased TG/HDL ratio, increased small dense LDL and remnant particles, increased endothelial permeability.
DementiaNeuronal glucose starvation and plaque buildup, brain small vessel disease, disruption of blood brain barrier.
Chronic InflammationRelease of cytokines from visceral fat.
Heart FailureStiffening of the heart muscle and high blood pressure.
DiabetesPancreatic beta cell and alpha cell damage

Insulin’s Role vs. Insulin Resistance (IR)

Organ/SystemNormal Insulin ActionEffects of Insulin Resistance
LiverStops glucose production; stores glucose as glycogen.The liver ignores the “stop” signal, pumping out sugar even when you haven’t eaten (fatty liver).Fatty liver disease is the greatest cause of liver failure in the US.
MusclePrimary site for glucose uptake; promotes protein synthesis.Muscles can’t take in fuel efficiently, leading to fatigue and muscle wasting (sarcopenia). Muscle cells cannot use amino acids from dietary protein to maintain or build muscle. Elderly lose muscle and strength, resulting in falls, fractures and head trauma. Loss of muscle (the major sink for blood sugar after a meal) further increases duration and degree of blood sugar and insulin rise after a meal, which in turn increases IR. (vicious cycle)
Fat (Adipose)Stores fat; inhibits the breakdown of stored fat.Fat cells leak fatty acids into the blood, leading to high triglycerides and visceral fat gain. Macrophages (immune cells) produce inflammatory cytokines which circulate through the body contributing to chronic inflammation which worsens IR, another vicious cycle.
BrainRegulates appetite, memory, and cognitive function.Linked to “Type 3 Diabetes”; impaired memory and increased risk of neurodegeneration. Brain loses ability to meet energy demands and clear toxins. Insulin resistance in the brain explains memory loss, cognitive impairment, loss of neurons and synapses, loss of neuroplasticity. BDNF (brain derived neurotrophic factor) production is decreased by IR.
ArteriesStimulates nitric oxide for vasodilation (keeps vessels flexible).Reduced nitric oxide causes vessels to stiffen, raising blood pressure and plaque buildup. This is called endothelial dysfunction, the precursor to heart attack, stroke, peripheral vascular disease and a root cause for neuropathy and amputations.
HeartRegulates fuel use (switching between glucose and fats).The heart becomes “metabolically inflexible,” increasing the risk of heart failure.
KidneyManages sodium reabsorption and filtration.High insulin causes the kidneys to hold onto salt, driving up blood pressure and damaging filters. Oxidative stress leads to kidney failure.
Immune SystemModulates inflammation and helps T-cell function.Creates a state of “chronic low-grade inflammation” and weakens the response to infections.
BoneStimulates bone-forming cells (osteoblasts).Bone quality decreases; despite higher bone density in some cases, the bones are more brittle.
JointsMaintains cartilage and reduces systemic inflammation.High insulin promotes pro-inflammatory cytokines, accelerating osteoarthritis and gout.

 A meal with sugar and refined carbohydrates causes excessive swings in blood sugar and insulin levels, creating insulin resistance and downstream damage. Alcohol consumption contributes to this process. Fat consumption does not cause a rise in blood sugar or insulin levels. Protein consumption produces a minimal rise in insulin levels in the absence of IR.

Fat storage can occur through hyperplasia (increase in number of fat cells) or hypertrophy (increase in size). Some ethnic groups are more prone to hypertrophy (south and east Asian). Hypertrophy in visceral fat (fat around the internal organs as opposed to fat under the skin) results in macrophage production of inflammatory cytokines. Eventually, the fat cells themselves can literally burst from too much volume.

 In my next post, I will discuss what we can do to prevent and reverse IR.

REFERENCES

Chadt A, Al-Hasani H. Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflugers Arch. 2020 Sep;472(9):1273-1298. doi: 10.1007/s00424-020-02417-x. Epub 2020 Jun 26. PMID: 32591906; PMCID: PMC7462924.

https://pmc.ncbi.nlm.nih.gov/articles/PMC7462924/

Fujita S, Rasmussen BB, Cadenas JG, Grady JJ, Volpi E. Effect of insulin on human skeletal muscle protein synthesis is modulated by insulin-induced changes in muscle blood flow and amino acid availability. Am J Physiol Endocrinol Metab. 2006 Oct;291(4):E745-54. doi: 10.1152/ajpendo.00271.2005. Epub 2006 May 16. PMID: 16705054; PMCID: PMC2804964.

https://pmc.ncbi.nlm.nih.gov/articles/PMC2804964

Vargas E, Joy NV, Carrillo Sepulveda MA. Biochemistry, Insulin Metabolic Effects. [Updated 2022 Sep 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK525983/

https://www.ncbi.nlm.nih.gov/books/NBK525983/

Bugianesi E, Moscatiello S, Ciaravella MF, Marchesini G. Insulin resistance in nonalcoholic fatty liver disease. Curr Pharm Des. 2010 Jun;16(17):1941-51. doi: 10.2174/138161210791208875. PMID: 20370677.

https://pubmed.ncbi.nlm.nih.gov/20370677/

Cardillo C, Nambi SS, Kilcoyne CM, Choucair WK, Katz A, Quon MJ, Panza JA. Insulin stimulates both endothelin and nitric oxide activity in the human forearm. Circulation. 1999 Aug 24;100(8):820-5. doi: 10.1161/01.cir.100.8.820. PMID: 10458717.

https://pubmed.ncbi.nlm.nih.gov/10458717/

Ke JF, Wang JW, Zhang ZH, Chen MY, Lu JX, Li LX. Insulin Therapy Is Associated With an Increased Risk of Carotid Plaque in Type 2 Diabetes: A Real-World Study. Front Cardiovasc Med. 2021 Feb 1;8:599545. doi: 10.3389/fcvm.2021.599545. PMID: 33598483; PMCID: PMC7882504.

https://pubmed.ncbi.nlm.nih.gov/33598483/

Brosolo G, Da Porto A, Bulfone L, Vacca A, Bertin N, Scandolin L, Catena C, Sechi LA. Insulin Resistance and High Blood Pressure: Mechanistic Insight on the Role of the Kidney. Biomedicines. 2022 Sep 23;10(10):2374. doi: 10.3390/biomedicines10102374. PMID: 36289636; PMCID: PMC9598512.

https://pubmed.ncbi.nlm.nih.gov/36289636/

Kumar M, Dev S, Khalid MU, Siddenthi SM, Noman M, John C, Akubuiro C, Haider A, Rani R, Kashif M, Varrassi G, Khatri M, Kumar S, Mohamad T. The Bidirectional Link Between Diabetes and Kidney Disease: Mechanisms and Management. Cureus. 2023 Sep 20;15(9):e45615. doi: 10.7759/cureus.45615. PMID: 37868469; PMCID: PMC10588295.

https://pmc.ncbi.nlm.nih.gov/articles/PMC10588295/

Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther. 2012 Oct;136(1):82-93. doi: 10.1016/j.pharmthera.2012.07.006. Epub 2012 Jul 17. PMID: 22820012; PMCID: PMC4134675.

https://pubmed.ncbi.nlm.nih.gov/22820012/

Rahman MS, Hossain KS, Das S, Kundu S, Adegoke EO, Rahman MA, Hannan MA, Uddin MJ, Pang MG. Role of Insulin in Health and Disease: An Update. Int J Mol Sci. 2021 Jun 15;22(12):6403. doi: 10.3390/ijms22126403. PMID: 34203830; PMCID: PMC8232639.

https://pmc.ncbi.nlm.nih.gov/articles/PMC8232639/

Scherrer U, Sartori C. Insulin as a vascular and sympathoexcitatory hormone: implications for blood pressure regulation, insulin sensitivity, and cardiovascular morbidity. Circulation. 1997 Dec 2;96(11):4104-13. doi: 10.1161/01.cir.96.11.4104. PMID: 9403636.

https://pubmed.ncbi.nlm.nih.gov/9403636/

Affuso F, Micillo F, Fazio S. Insulin Resistance, a Risk Factor for Alzheimer’s Disease: Pathological Mechanisms and a New Proposal for a Preventive Therapeutic Approach. Biomedicines. 2024 Aug 19;12(8):1888. doi: 10.3390/biomedicines12081888. PMID: 39200352; PMCID: PMC11351221.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11351221/

Park MH, Kim DH, Lee EK, Kim ND, Im DS, Lee J, Yu BP, Chung HY. Age-related inflammation and insulin resistance: a review of their intricate interdependency. Arch Pharm Res. 2014 Dec;37(12):1507-14. doi: 10.1007/s12272-014-0474-6. Epub 2014 Sep 20. PMID: 25239110; PMCID: PMC4246128.

https://pubmed.ncbi.nlm.nih.gov/25239110/

Hardy OT, Czech MP, Corvera S. What causes the insulin resistance underlying obesity? Curr Opin Endocrinol Diabetes Obes. 2012 Apr;19(2):81-7. doi: 10.1097/MED.0b013e3283514e13. PMID: 22327367; PMCID: PMC4038351.

https://pmc.ncbi.nlm.nih.gov/articles/PMC4038351/

THIS WEBSITE PROVIDES INFORMATION FOR EDUCATIONAL PURPOSES ONLY. CONSULT YOUR HEALTH CARE PROVIDER FOR MEDICAL ADVICE.

Eat clean, drink filtered water, love, laugh, exercise outdoors in a greenspace, get some morning sunlight, block the blue light before bed, engage in meaningful work, find a sense of purpose, spend time with those you love, AND sleep well tonight.

Doctor Bob

The new dietary guidelines, a major improvement

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The new Dietary Guidelines for Americans (DGA) represent a major improvement over previous guidelines. The storm of criticism registered by some “experts” and quoted by the media is NOT based on valid evidence. There has been excessive and irrational criticism over inverting the food pyramid, with animal sources of protein on the top. Until now recommendations for daily protein intake have been based upon estimates to avoid protein deficiency rather than optimization. The recommendations for 1.2-1.6 grams per kilogram bodyweight per day (up from 0.8 g/kg/day) is supported by data on muscle building, muscle maintenance and bone health (when combined with resistance exercise), especially for elderly individuals.

 Unfortunately, the 10% restriction on saturated fat remains, but the guidelines appropriately state that there is a lack of evidence to keep that restriction at 10% of caloric intake. The controversy over saturated fat remains despite meta-analyses of randomized controlled clinical trials that conclude that restriction of saturated fat has not been found to improve cardiovascular, metabolic, or cancer outcomes.

I doubt that those critical of the new DGA have read the 416-page appendices that document scientific references and explanations for each of the dietary recommendations. That’s right, 416 pages of narrative and scientific references are in the appendices of the DGA.

If you go here, you can download 4 documents including the Scientific Foundation Appendices (416 pages), the Scientific Foundation for DGA (90 pages), The Daily Servings Guide (3 pages) and the DGA (10 pages)

Here is an excerpt that is very useful.

How can you identify highly processed foods? Highly processed foods tend to have: 1. Refined grains and/or added sugars 2. Refined fats and oils 3. Long, complicated ingredient lists including chemical additives (e.g., artificial sweeteners, flavor enhancers, artificial colors, and emulsifiers). Examples are provided in Figures 4.3 and 5.8.

And a good explanation for why refined grains (any food made with flour) causes rapid and high blood sugar responses.

Refined Grains and Starches are Sugar • Refined grains are highly purified sources of starch. • Starches are long chains of glucose—a form of sugar. • During chewing and digestion, enzymes rapidly break down starch into glucose, raising blood sugar much like table sugar does. • Refined grain foods—white bread, crackers, breakfast cereals, chips, pastries, and pasta—can therefore act metabolically like sugar, delivering fast-absorbing carbohydrates with few nutrients or fiber to slow absorption. Take-home message: Refined grains are sugar in disguise. Choose whole grains, beans, or vegetables instead.

The following two graphics demonstrate the results of previous dietary guidelines that demonized healthy fats and animal sources of protein. The first shows the rise in obesity and diabetes but does not address the insulin resistance that evolves over decades before crossing the arbitrary threshold of diabetes, wreaking metabolic havoc long before diabetes occurs. The second graphic reveals how Americans consume 60% or more caloric intake in the form of refined carbohydrates (equivalent to sugar)

The following graphic displays the difference between minimally processed, moderately processed and highly processed foods according to the NOVA classification system (a system I will discuss and criticize in future posts). For now, suffice it to say that a simpler and more practical definition of “processed food” would include any food with one or more of the following: added sugar, artificial sweeteners, refined starch especially flour made from grains, refined “vegetable” oils, emulsifiers, artificial coloring, preservatives, and other additives found to disrupt the microbiome, intestinal barrier function or cause cancer. This graphic importantly covers the issue of food packaging which can contribute to the consumption of micro plastics, phthalates and PFAs

I have consistently advocated for a diet that consists of free-range meat, poultry, eggs, seafood (low mercury varieties), organic vegetables, fruits, nuts, seeds, an ancestral or paleo diet. The new DGA go a long way to produce evidence-based recommendations to help Americans eat healthy food. I continue to advocate for getting fiber from vegetables and fruits, eliminating grains, for reasons previously discussed but if you want to eat grains and are not gluten sensitive or suffer from celiac disease, consume the grains as a whole food, not in a food made from flour. “Whole grain bread” is not a whole grain food, nor is “whole grain” pasta. Once flour is made from grains the cellular components are destroyed producing a product with a glycemic index akin to sugar with the resultant metabolic disturbance which over the long run leads to insulin resistance, obesity and chronic disease.

If you want to consume dairy it makes much more sense to consume full fat fermented dairy foods instead of the low-fat dairy products advocated by prior DGA. The new DGA go into great detail to describe the nutrient deficiencies associated with vegan and vegetarian diets unless specific supplements are consumed. Specific recommendations for pregnant and breast-feeding mothers cover most important points as do age specific recommendations for infants and children. The importance of choline could have received a little more attention (best sources include eggs and liver). The importance of marine omega-3 fats (EPA, DHA, DPA) received adequate attention.

Overall, I consider the 2026 DGA a major improvement compared to previous iterations which ignored a large body of nutritional science.

The following references support my position on SFA and properly raised and prepared animal protein.

https://pubmed.ncbi.nlm.nih.gov/32562735/

Astrup A, Magkos F, Bier DM, Brenna JT, de Oliveira Otto MC, Hill JO, King JC, Mente A, Ordovas JM, Volek JS, Yusuf S, Krauss RM. Saturated Fats and Health: A Reassessment and Proposal for Food-Based Recommendations: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Aug 18;76(7):844-857. doi: 10.1016/j.jacc.2020.05.077. Epub 2020 Jun 17. PMID: 32562735.

Reimara Valk, James Hammill, Jonas Grip, Saturated fat: villain and bogeyman in the development of cardiovascular disease?, European Journal of Preventive Cardiology, Volume 29, Issue 18, December 2022, Pages 2312–2321, https://doi.org/10.1093/eurjpc/zwac194

Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study Dehghan, MahshidDiaz, R et al. The Lancet, Volume 390, Issue 10107, 2050 – 2062

https://pubmed.ncbi.nlm.nih.gov/36216940/

Lescinsky H, Afshin A, Ashbaugh C, Bisignano C, Brauer M, Ferrara G, Hay SI, He J, Iannucci V, Marczak LB, McLaughlin SA, Mullany EC, Parent MC, Serfes AL, Sorensen RJD, Aravkin AY, Zheng P, Murray CJL. Health effects associated with consumption of unprocessed red meat: a Burden of Proof study. Nat Med. 2022 Oct;28(10):2075-2082. doi: 10.1038/s41591-022-01968-z. Epub 2022 Oct 10. PMID: 36216940; PMCID: PMC9556326.

Red and processed meat consumption and risk of incident coronary heart disease, stroke, and diabetes mellitus: a systematic review and meta-analysis Renata Micha1, Sarah K Wallace, Dariush Mozaffarian, Circulation CIRCULATIONAHA.109.924977. Epub 2010 May 17. https://pubmed.ncbi.nlm.nih.gov/20479151/

Unprocessed Red Meat and Processed Meat Consumption: Dietary Guideline Recommendations from the Nutritional Recommendations (NutriRECS) Consortium Bradley C. Johnston, PhD, Dena Zeraatkar, Msc, et. al. Ann Intern Med 2019: 1:756-764 doi: 10.7326/M19-1621

Reduction of Red and Processed Meat Intake and Cancer Mortality and Incidence A Systematic Review and Meta-analysis of Cohort Studies Mi Ah Han, MD, PhD; Dena Zeraatkar, MSc; et. al., Ann Intern Med. 2019;171:711-720. doi:10.7326/M19-0699

Patterns of Red and Processed Meat Consumption and Risk for Cardiometabolic and Cancer Outcomes A Systematic Review and Meta-analysis of Cohort Studies Robin W.M. Vernooij, PhD*; Dena Zeraatkar, MSc Ann Intern Med.2019;171:732-741. doi:10.7326/M19-1583

Red and Processed Meat Consumption and Risk for All-Cause Mortality and Cardiometabolic OutcomesA Systematic Review and Meta-analysis of Cohort Studies Dena Zeraatkar, MSc, Mi Ah Han MD, PhD, et. al, Annals of Internal Medicine 1 October 2019: 171-710 doi: 10.7326/M19-0655

Effect of Lower Versus Higher Red Meat Intake on Cardiometabolic and Cancer Outcomes

A Systematic Review of Randomized Trials Dena Zeraatkar, MSc, Bradley C Johnston, PhD, et. al. Ann Intern Med. 2019;171:721-731. doi:10.7326/M19-https://doi.org/10.7326/M19-0622

E, Lavie CJ, Hill JO. The Failure to Measure Dietary Intake Engendered a Fictional Discourse on Diet-Disease Relations. Front Nutr. 2018 Nov 13;5:105. doi: 10.3389/fnut.2018.00105. PMID: 30483510 Archer; PMCID: PMC6243202.

Archer E, Hand GA, Blair SN (2013) Validity of U.S. Nutritional Surveillance: National Health and Nutrition Examination Survey Caloric Energy Intake Data, 1971–2010. PLoS ONE 8(10): e76632. https://doi.org/10.1371/journal.pone.0076632

O’Connor, Lauren E., et al. “Effects of total red meat intake on glycemic control and inflammatory biomarkers: a meta-analysis of randomized controlled trials.” Advances in Nutrition 12.1 (2021): 115-127.

Kiani AK, Dhuli K, Donato K, Aquilanti B, Velluti V, Matera G, Iaconelli A, Connelly ST, Bellinato F, Gisondi P, Bertelli M. Main nutritional deficiencies. J Prev Med Hyg 2022;63(suppl.3):E93-E101.https://doi.org/10.15167/2421-4248/jpmh2022.63.2S3.2752

Bailey RL, West KP Jr, Black RE. The epidemiology of global micronutrient deficiencies. Ann Nutr Metab. 2015;66 Suppl 2:22-33. doi: 10.1159/000371618. Epub 2015 Jun 2. PMID: 26045325.

Global, regional and national burdens of common micronutrient deficiencies from 1990 to 2019: A secondary trend analysis based on the Global Burden of Disease 2019 study. Zu Han et. al., eClinicalMedicine, February 11, 2022 https://doi.org/10.1016/j.eclinm.2022.101299

Sean R. Lynch, Why Nutritional Iron Deficiency Persists as a Worldwide Problem, The Journal of Nutrition, Volume 141, Issue 4, April 2011, Pages 763S–768S, https://doi.org/10.3945/jn.110.130609

Meat supplementation improves growth, cognitive, and behavioral outcomes in Kenyan children , J Nutr. 2007 Apr;137(4):1119-23.

Animal source foods have a positive impact on the primary school test scores of Kenyan schoolchildren in a cluster-randomised, controlled feeding intervention trial – PubMed (nih.gov), Hulett JL, Weiss RE, Bwibo NO, Galal OM, Drorbaugh N, Neumann CG.Br J Nutr. 2014 Mar 14;111(5):875-86. doi: 10.1017/S0007114513003310. Epub 2013 Oct 30.PMID: 24168874 Clinical Trial.

Meat supplementation increases arm muscle area in Kenyan schoolchildren – PubMed (nih.gov), Br J Nutr. 2013 Apr 14;109(7):1230-40. doi: 10.1017/S0007114512003121. Epub 2012 Aug 2.PMID: 22856533 Clinical Trial.

School snacks decrease morbidity in Kenyan schoolchildren: a cluster randomized, controlled feeding intervention trial.

Neumann CG, Bwibo NO, Jiang L, Weiss RE.Public Health Nutr. 2013 Sep;16(9):1593-604. doi: 10.1017/S1368980013000876. Epub 2013 Mar 28.PMID: 23537728

Effects of animal source foods, with emphasis on milk, in the diet of children in low-income countries.

Allen LH, Dror DK.Nestle Nutr Workshop Ser Pediatr Program. 2011;67:113-30. doi: 10.1159/000325579. Epub 2011 Feb 16.PMID: 21335994

https://www.bmj.com/content/351/bmj.h4962

The scientific report guiding the US dietary guidelines: is it scientific?

BMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h4962 (Published 23 September 2015)

https://pmc.ncbi.nlm.nih.gov/articles/PMC9794145/

Teicholz N. A short history of saturated fat: the making and unmaking of a scientific consensus. Curr Opin Endocrinol Diabetes Obes. 2023 Feb 1;30(1):65-71. doi: 10.1097/MED.0000000000000791. Epub 2022 Dec 8. Erratum in: Curr Opin Endocrinol Diabetes Obes. 2025 Aug 1;32(4):166. doi: 10.1097/01.med.0001118356.22843.75. PMID: 36477384; PMCID: PMC9794145.

THIS WEBSITE PROVIDES INFORMATION FOR EDUCATIONAL PURPOSES ONLY. CONSULT YOUR HEALTH CARE PROVIDER FOR MEDICAL ADVICE.

Eat clean, drink filtered water, love, laugh, exercise outdoors in a greenspace, get some morning sunlight, block the blue light before bed, engage in meaningful work, find a sense of purpose, spend time with those you love, AND sleep well tonight.

Doctor Bob

Normal Thyroid function tests (T4 and TSH) do not guarantee you have normal thyroid function.

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In his book Blindspots, Marty Makary MD (slated to be the next FDA commissioner) discusses why routine medical practices are often slow to change, despite mounting evidenced that those practices are not supported by best evidence. Although not discussed in his book, the evaluation and treatment of hypothyroidism presents a prime example of this problem. Before diving into the issues, lets review some basic physiology.

The hypothalamus in the brain produces TRH (thyrotropin releasing hormone) in response to circulating levels of T3 and T4 (two forms of thyroid hormone). TRH then stimulates production and release of TSH (thyroid stimulating hormone) in the pituitary gland. In turn, TSH stimulates the thyroid gland to produce thyroid hormone. The two forms of thyroid hormone produced by the thyroid gland are called T4 and T3 (T3 has 3 iodine molecules, T4 has 4) T4 is the predominant hormone produced by the thyroid gland. In the liver and the kidney T4 is converted to T3 through a process called deiodination, supplying 80% of circulating T3. Importantly, T3 is 7 to 10 times more potent than T4.

Both T3 and T4 directly inhibit TSH synthesis. This feedback system helps maintain homeostasis under conditions of optimal health. (https://www.ncbi.nlm.nih.gov/books/NBK278958/)

Taken from: https://rootfunctionalmedicine.com/conversion-of-t4-to-t3-thyroid-hormone/

When testing thyroid function, most physicians order only TSH (thyroid stimulating hormone) and T4. But to have normal thyroid function several conditions must be met. Of those many conditions, three are often not considered by most physicians and not evaluated with TSH and T4. First, there must be adequate conversion of T4 into T3, because T3 is the form of thyroid hormone that provides most physiologic effect. Second, there must be adequate transport of T4 and T3 into your cells. Third, levels of reverse T3 should not be high enough to block adequate amounts of Thyroid Hormone binding to receptors on your cells.

The “normal” range of TSH in most labs is 0.4 to 5.0 mU/L. Recently a narrower range of 0.5-2.5 mU/L has been proposed to exclude individuals with “minimal” thyroid dysfunction, but this is controversial. This controversy is the crux of one of the many problems in interpreting “normal” thyroid function tests. Proponents of the narrower range maintain that patients with symptoms of hypothyroidism and a TSH above 2.5 might benefit from treatment. In addition, proponents of the narrower range suggest that some patients with TSH levels above 2.5 may not report symptoms of hypothyroidism but their physiology may be suboptimal for health. (https://www.ncbi.nlm.nih.gov/books/NBK278958/) Physiology of the Hypothalamic-Pituitary-Thyroid Axis.

Treatment with T4 alone, may not provide adequate thyroid replacement.

If a physician orders only T4 and TSH to evaluate thyroid function, but conversion of T4 to T3 is impaired, a normal T4 and normal TSH will be interpreted as normal thyroid function. But with low T3 levels, a patient can experience symptoms of hypothyroidism. Likewise, if a patient is only treated with T4 (levothyroxine) but has issues converting T4 to T3, they may need to receive a prescription for T3 and T4. Using the ratio of Free T3 to Free T4 one can identify patients with problems caused by inadequate deiodination (conversion of T4 to T3). Monotherapy with levothyroxine (T4) has been standard of care for decades. But studies have demonstrated that patients treated with T4 only have relatively low serum levels of T3 (tri-iodothyronine) compared to the general population and symptoms of hypothyroidism persist for some patients despite normal TSH levels.

Issues of active versus passive transport.

T3 and T4 enter the hypothalamus and pituitary glands “passively”, meaning an active transport mechanism is not necessary. But in the rest of the body active transport of T3 and T4 into cells is necessary. If there is a problem with the active transport system, the hypothalamus and pituitary may “see” normal levels of T3 and T4 but the rest of the body may not be getting the full benefit of thyroid hormone. Thus, TSH levels will be normal, T4 levels will be normal, but cellular T3 and T4 levels will not be adequate. Yet physicians will interpret a normal TSH and T4 to mean normal thyroid function. Conditions that impair thyroid hormone transport into cells include: insulin resistance, diabetes, obesity, chronic and acute dieting, diabetes, depression, anxiety, bipolar disorder, neurodegenerative diseases, chronic fatigue syndrome, fibromyalgia, cardiovascular disease, inflammation and chronic illness, and disorders of lipid metabolism.

Reverse T3 can cause problems.

High levels of reverse T3 can occur under many conditions including chronic stress, chronic inflammation and many chronic diseases. As previously discussed, Reverse T3 binds to Thyroid hormone receptors but does not have the beneficial effect of normal T3, thus blocking T3 from doing its job. Most physicians do not measure reverse T3 or calculate the T3/reverse T3 ratio.

Therefore, in addition to problems with deiodinase (conversion of T4 to T3), high levels of reverse t3 can render monotherapy with levothyroxine inadequate, while leaving TSH and T4 levels “normal”.

How to calculate t3/reverse t3 ratio – National Academy of Hypothyroidism

This has been a quick discussion of a complex system. Not all aspects of thyroid testing and treatment have been addressed. Hopefully this discussion will help you understand why simply measuring TSH and T4 (a common practice) will not tell you whether you have normal thyroid function. Ideally, all patients being tested would have free T3 and reverse T3 measured in addition to T4 and TSH. In addition, the free T3/reverse T3 ratio and the free T3/freeT4 ratio would be considered when deciding whether treatment with T4 alone (levothyroxine monotherapy) is adequate. Many patients would benefit from adding T3 (triiodothyronine) to T4 (levothyroxine) therapy. In addition, a TSH level above 2.5 should be carefully evaluated for hypothyroid symptoms as levels above 2.5 are arguably “abnormal” (or at least should raise a red flag as to the possibility). Finally, recognize that this discussion presents controversies in medicine. Most practitioners apply the concept of “sick euthyroid” to patients with acute illness and low T3 levels, considering it a “normal” protective mechanism that does not require thyroid hormone therapy. But under chronic conditions, many practitioners who think “outside the box” would consider poor conversion of T4 to T3 and/or high levels of reverse T3, as possible indications for thyroid hormone therapy when symptoms of hypothyroidism are present. Under these circumstances directly addressing underlying causes such as chronic inflammation may provide the best initial approach. (anti-inflammatory diet, regular exercise, good sleep habits, stress reduction, strengthen social support)

But when a patient is already on monotherapy with T4, consideration of adding T3 to improve quality of life and physiologic function is worthy of consideration when comprehensive laboratory evaluation suggests problems as described above (cellular transport, T4 to T3 conversion, high reverse T3).

For a greater dive into this subject follow these links.

Physiology of the Hypothalamic-Pituitary-Thyroid Axis.

The relevance of T3 in the management of hypothyroidism – The Lancet Diabetes & Endocrinology

Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients

Is a Normal TSH Synonymous With “Euthyroidism” in Levothyroxine Monotherapy?

Thyroid Hormone Transport into cellular tissue.

HPA axis dysfunction in Chronic Fatigue Syndrome and Fibromyalgia

Hormone replacement therapy in the geriatric patient, part 1.

Hormone replacement therapy in the geriatric patient, part 2.

Peripheral thyroid hormone conversion.

What is reverse T3 syndrome?

A complete pathway map of T4 and T3 metabolism and clearance

The Low T3 syndrome

THIS WEBSITE PROVIDES INFORMATION FOR EDUCATIONAL PURPOSES ONLY. CONSULT YOUR HEALTH CARE PROVIDER FOR MEDICAL ADVICE.

Eat clean, drink filtered water, love, laugh, exercise outdoors in a greenspace, get some morning sunlight, block the blue light before bed, engage in meaningful work, find a sense of purpose, spend time with those you love, AND sleep well tonight.

Doctor Bob

Omega-3 fatty acids, Pain and Arthritis

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Before modern pharmacy an early treatment for Rheumatoid Arthritis (RA) was cod liver oil, rich in omega-3 fats and vitamin D. A 2013 study demonstrated that consumption of cod liver oil resulted in a reduction of daily diclofenac in Rheumatoid Arthritis. As early as 1959 cod liver oil was recommended for arthritis in the medical literature. A 2017 review of marine omega-3 fats for arthritis pain found moderate quality evidence in rheumatoid arthritis patients. A 2024 review of prevention and treatment for RA suggested that a diet rich in fiber, vitamins, omega 3 and low glycemic index foods contributes to protection from RA. A comprehensive review of omega-3 fatty acids for RA included analysis of several studies and concluded that omega-3 was a valuable therapeutic option to improve pain symptoms, tender joint count, duration of morning stiffness and the frequency of NSAID consumption. A 2019 review of cumulative data on omega-3 fats to combat autoimmune diseases concluded:

“The promising findings coming from the cumulative research work over the last decade solidified the role of ω-3 PUFAs as a potential candidate to prevent or even treat such autoimmune diseases as type 1 diabetes, RA, SLE, MS”

A 2024 review of marine omega-3 PUFA (polyunsaturated fatty acids) for RA reported:

“Altogether the data reported in this review show that anti-inflammatory interventions, i.e., high fish consumption or supplements containing n-3 PUFAs, should be the standard of care, along with pharmacotherapy, in treating patients with RA.”

And here is a graphic from that article showing the effect of SPMs (specialized pro-resolving mediators, derived from omega-3s):

What about osteoarthritis?

A multicenter randomized double blind placebo controlled trial of krill oil containing 0.60 g EPA/d, 0.28 g DHA/d, 0.45 g astaxanthin/d demonstrated improvements in pain, stiffness and physical function.

Some omega-3 supplement studies have demonstrated no significant pain relief in osteoarthritis. Those studies did not reduce the consumption of pro-inflammatory n-6 fatty acids which compete with omega-3 fats for the enzymes which can lead to pro or anti-inflammatory mediators. They also did not measure the omega 6/omega 3 ratio in blood or tissues. Nor did they measure the omega-3 index (% of omega-3 achieved in red blood cell membranes, the gold standard for evaluating tissue levels achieved) This 2018 analysis stated:

“High Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are associated with lower levels of inflammatory mediators, anti-nociception, and adaptive cognitive/emotional functioning. High Omega-6 (n-6) PUFAs are associated with inflammation, nociception, and psychological distress. While findings related to n-3 supplementation in knee OA are mixed, consideration of the n-6:n-3 ratio and additional outcome measures may provide improved understanding of the potential relevance of these fatty acids in OA”

The authors went on to access blood n-6/n-3 ratios in patients with OA and found the following:

“The high ratio group reported greater pain and functional limitations, (all p’s<0.04), mechanical temporal summation (hand and knee, p<0.05), and perceived stress (p=0.008) but not depressive symptoms.”

“In adults with knee pain, a high n-6:n-3 ratio is associated with greater clinical pain/functional limitations, experimental pain sensitivity, and psychosocial distress compared to a low ratio group.”

The anti-inflammatory diet that I follow and recommend eliminates the major sources of excess omega-6 in the diet, specifically the “vegetable oils” which are actually seed, grain, and legume oils predominated by soy oil, corn oil, peanut and cottonseed oil present in cooking “vegetable oils” and processed foods. A table that displays the ratio of omega 3 to omega 6 in various oils can be found here. Note that this table does not reveal the amounts of MUFA (mono unsaturated fatty acids) which are arguably “heart healthy”. Nor does it address the important issue of protective polyphenols and anti-oxidants (such as in Extra Virgin Olive oil aka EVOO). So do not make choices of oil based only on the omega-3/6 ratio.

Another consideration in choosing oils for cooking (as opposed to salad dressing) is the smoke point. Under high heat, oils are subject to oxidation which creates a proinflammatory effect when consumed. Refined Avocado oil has the highest smoke point (520 degrees F). But we digress. Back to pain and arthritis.

An article just published in Nutrients reviewed Omega-3 Supplementation and Its Effects on Osteoarthritis.

“omega-3 polyunsaturated fatty acids (PUFA) have demonstrated an influential role in the progression of OA, resulting in the reduction of cartilage destruction, inhibition of pro-inflammatory cytokine cascades, and production of oxylipins that promote anti-inflammatory pathways.” 

“Research has demonstrated a positive effect on the modulation of OA symptoms through diet and exercise to promote an anti-inflammatory environment. More specifically, omega-3 PUFAs have demonstrated a reduction in inflammatory biomarkers and cartilage degradation, counteracting the natural disease state of OA. In addition to their chondroprotective role, omega-3 supplementation has been shown to have indirect positive effects on muscle tissue recovery following exercise, which is necessary to prevent the progression of OA and maintain an independent, healthy lifestyle. The effects of omega-3 supplementation on the disease state of OA and its symptoms remain inconclusive. Further clinical trials utilizing human participants are warranted to provide a conclusive recommendation on standardized supplementation of omega-3 for the modulation of osteoarthritis.”

Given the cardioprotective effects, discussed in my last post (including an 80% reduction in sudden death at the highest quintile of omega-3 index) and other benefits (reduction in all cause mortality with high tissue levels), there are many reasons to include large amounts of low mercury fatty fish (wild Alaskan salmon, sardines, herring, trout) in the diet and to consider supplementation when your omega 3 index is < 8%. Likewise, in the presence of arthritis and pain, getting tissue levels of omega 3 up and reducing excessive pro-inflammatory omega 6 will likely provide significant benefit.

Here is a graphic with the omega 3 content of some foods.

And another:

As mentioned in my previous post about omega-3 and cardiovascular health, 1800 mg of omega-3 FA daily is adequate in most people to achieve and omega-3 index of 8%, the level at which cardiovascular protection is greatest.

THIS WEBSITE PROVIDES INFORMATION FOR EDUCATIONAL PURPOSES ONLY. CONSULT YOUR HEALTH CARE PROVIDER FOR MEDICAL ADVICE.

Eat clean, drink filtered water, love, laugh, exercise outdoors in a greenspace, get some morning sunlight, block the blue light before bed, engage in meaningful work, find a sense of purpose, spend time with those you love, AND sleep well tonight.

Doctor Bob

Omega-3 in your diet and supplements

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The benefit of omega-3 supplementation has been debated in the cardiology and nutritional literature for many years. Most studies of supplementation have failed to measure tissue levels achieved and often used very low doses. But when tissue levels were measured, either in the serum or red blood cell membrane, the studies consistently demonstrated significant reductions in all-cause mortality and cardiovascular mortality associated with high levels of omega-3 fatty acids.

In addition, higher levels of omega 3 are associated with >=80% reduction in sudden death associated with acute myocardial infarction (acute MI) and > 80% reduction in sudden death in cohorts without known coronary artery disease followed long term.

Two Coronary CT Angiogram (CCTA) studies demonstrated that patients with stable coronary artery disease on statin therapy randomized to high dose EPA and DHA had “prevention of coronary plaque progression when an omega-3 fatty acid index >= 4% was achieved.”

 Another CCTA study demonstrated that patients receiving omega 3 supplementation had significantly less coronary atherosclerotic “high risk” lipid rich plaque prevalence (3.8% versus 32%) and lower total non-calcified plaque burden independent of cardiovascular risk factors compared to matched controls not receiving omega 3 supplements.

Omega 3 supplementation after an acute myocardial infarction has been found to reduce infarct size, reduce scaring (fibrosis), and enhance heart tissue healing. (Randomized controlled clinical trial) However a post MI study in 1027 elderly patients randomized to receive 1.8 grams per day of EPA+DHA versus a control group receiving corn oil showed no reduction in the primary composite cardiovascular endpoint between the two groups at 2 years but a higher incidence of AF in the omega 3 group that did not reach statistical significance.

Recently a study, widely reported by the lay press, suggested that high dose omega-3 supplementation was associated with increased risk of atrial fibrillation (AF). These results conflicted with previous studies which demonstrated just the opposite, specifically prior studies demonstrated reduced risk of AF. The more recent study suffered a significant design flaw. The study in question failed to make statistical adjustment for the increased life span associated with higher levels of omega-3. Since age is a primary risk factor for AF, any intervention which increases life span would be expected to result in more AF over the lifetime of the patients as they aged (i.e., more elder years results in increased risk of AF). Therefore, statistical adjustment for that effect should be employed, but was not done in the study.

Unfortunately, science journalism has deteriorated to a state where the conclusions of study authors are most often quoted without interpretation or context, and without critical analysis or comparisons with previous studies that may have demonstrated opposing results.

In addition to large well-designed studies that have suggested a reduced risk of AF associated with omega-3 fatty acids, there have been natural experiments that provide reassuring information. The indigenous Inuit people of Greenland, for example, historically consumed large amounts of omega-3 in their diet with no evidence of increased risk of AF. In fact, before the introduction of western processed foods, estimates of AF among the Inuit were 0.6% (1963) compared to a “worldwide prevalence of AF in adults between 2 and 4%, between one and two percent in Canadian and the general US population and between 0.5% and 3% in most low- and middle-income countries.” A more recent study of Greenland yielded a prevalence of 1.4% likely reflecting a change in habits consisting of less exercise, more tobacco use and a shift to a more Western diet.

Still, multiple studies that used high dose omega 3 supplements in patients with known cardiac disease suggest an increased risk of AF. A good review of omega-3 fatty acids and atrial fibrillation was published in the Korean Journal of Internal Medicine, referenced below.

My interpretation of the complex data in this area is as follows.

At supplemental doses of EPA+DHA above 1.8 grams per day (and perhaps above 1 gram per day) in patients with known coronary artery disease (CAD), at high risk of CAD, or following a myocardial infarction, the risk of AF is increased by about 25% (relative risk). But the risk of lethal ventricular arrythmias (sudden death) associated with myocardial infarction (heart attack) is 80% lower in patients with a red blood cell omega 3 index of >=8. In people without known CAD, an omega-3 index >=8% is associated with an 80% reduction in sudden cardiac death. CCTA studies show significantly lower unstable “vulnerable” plaque in patients on omega-3 supplements. Similarly, omega 3 supplementation in patients on statins associates with halted plaque progression determined by serial CCTA in non-diabetics.

In addition, higher tissue levels of omega 3 are associated with significantly reduced all-cause, cardiovascular, and cancer mortality.

Omega-3 fatty acids are the chemical precursors of SPMs, specialized pro-resolving lipid mediators which help resolve inflammation. We know that cardiovascular events are driven by chronic inflammation in the walls of arteries, often mediated by insulin resistance. Chronic inflammation contributes to atherosclerosis (production of plaque in the artery wall) as well as cardiovascular events that result when unstable plaque ruptures.  Studies suggest that n-3 fatty acids may have antiarrhythmic properties with membrane-stabilizing effects in addition to antithrombotic and anti-inflammatory properties on the endothelial level. Basic science, observational studies and clinical trials have demonstrated that higher tissue levels of omega 3 fatty acids are associated with longer health span and lifespan. This understanding must be balanced with a probable increased risk of AF in certain clinical situations associated with high dose omega-3 supplements as described above (people with known CAD, high risk for CAD, or following and MI). Note that current AHA and ACC dietary guidelines include at least 2 servings of fatty fish per week, one serving provides approximately 1800 mg of omega-3.

Getting omega-3 fatty acids from cold water fatty fish would be ideal. Unfortunately, many individuals do not like salmon, sardines, mackerel or herring and simply will not consume enough of this fish to achieve protective tissue levels. Other species of fish and seafood provide much less amounts of omega 3. Another consideration is that individuals process omega 3 fats differently so different amounts of omega 3 will be necessary to reach the same protective levels in tissue. You can obtain a red blood cell omega-3 index using a home kit and a finger prick without a prescription (https://omegaquant.com/). The sample is mailed in to the lab and results reported directly to you. I have no financial relationship with these folks.

Bill Harris, PhD, is widely published in the area of omega-3 science. He developed the first clinically useful tissue assay which measures the % of omega 3 fat in red blood cell membranes, the “omega-3 index” which is the gold standard for omega 3 research and clinical testing. Although serum levels correlate with the red blood cell index, the later reveals dietary consequences of a 2-3 month period while serum levels reflect just a few days of most recent dietary habits. The red blood cell omega 3 index is analogous to the hemoglobin A1c which reveals average blood sugars over a 2–3-month period. Bill Harris suggests that 1800 mg per day of omega 3 fat consumption (food plus supplements) will achieve an index of >= 8% in most individuals.

Here are some references.

Harris WS, Tintle NL et.al., Fatty Acids and Outcomes Research Consortium (FORCE). Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies. Nat Communications. 2021 Apr 22;12(1):2329. doi: 10.1038/s41467-021-22370-2. PMID: 33888689; PMCID: PMC8062567. https://pubmed.ncbi.nlm.nih.gov/33888689/

“Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes”

Blood Levels of Long-Chain n–3 Fatty Acids and the Risk of Sudden Death Authors: Christine M. Albert, M.D., M.P.H., Hannia Campos, Ph.D., Meir J. Stampfer, M.D., Dr.P.H., Paul M. Ridker, M.D., M.P.H., JoAnn E. Manson, M.D., Dr.P.H., Walter C. Willett, M.D., Dr.P.H., and Jing Ma, M.D., Ph.D.

Published April 11, 2002 N Engl J Med 2002;346:1113-1118DOI:10.1056/NEJMoa012918 VOL. 346 NO. 15 https://www.nejm.org/doi/full/10.1056/NEJMoa012918

We conducted a prospective, nested case–control analysis among apparently healthy men who were followed for up to 17 years in the Physicians’ Health Study. The fatty-acid composition of previously collected blood was analyzed by gas–liquid chromatography for 94 men in whom sudden death occurred as the first manifestation of cardiovascular disease and for 184 controls matched with them for age and smoking status.

RESULTS

Base-line blood levels of long-chain n–3 fatty acids were inversely related to the risk of sudden death both before adjustment for potential confounders (P for trend = 0.004) and after such adjustment (P for trend = 0.007). As compared with men whose blood levels of long-chain n–3 fatty acids were in the lowest quartile, the relative risk of sudden death was significantly lower among men with levels in the third quartile (adjusted relative risk, 0.28; 95 percent confidence interval, 0.09 to 0.87) and the fourth quartile (adjusted relative risk, 0.19; 95 percent confidence interval, 0.05 to 0.71).

CONCLUSIONS

The n–3 fatty acids found in fish are strongly associated with a reduced risk of sudden death among men without evidence of prior cardiovascular disease.

Heydari B, Abdullah S, Pottala JV, Shah R, Abbasi S, Mandry D, Francis SA, Lumish H, Ghoshhajra BB, Hoffmann U, Appelbaum E, Feng JH, Blankstein R, Steigner M, McConnell JP, Harris W, Antman EM, Jerosch-Herold M, Kwong RY. Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL Randomized Clinical Trial. Circulation. 2016 Aug 2;134(5):378-91. doi: 10.1161/CIRCULATIONAHA.115.019949. PMID: 27482002; PMCID: PMC4973577. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.115.019949

Conclusions: Treatment of patients with acute myocardial infarction with high-dose omega-3 fatty acids was associated with reduction of adverse left ventricular remodeling, noninfarct myocardial fibrosis, and serum biomarkers of systemic inflammation beyond current guideline-based standard of care.

Effect of Different Antilipidemic Agents and Diets on Mortality A Systematic Review

Studer M, Briel M, Leimenstoll B, Glass TR, Bucher HC. Effect of Different Antilipidemic Agents and Diets on Mortality: A Systematic Review. Arch Intern Med. 2005;165(7):725–730. doi:10.1001/archinte.165.7.725

Compared with control groups, risk ratios for cardiac mortality indicated benefit from statins (0.78; 95% CI, 0.72-0.84), resins (0.70; 95% CI, 0.50-0.99) and n-3 fatty acids (0.68; 95% CI, 0.52-0.90).

Feuchtner G, Langer C, Barbieri F, Beyer C, Dichtl W, Friedrich G, Schgoer W, Widmann G, Plank F. The effect of omega-3 fatty acids on coronary atherosclerosis quantified by coronary computed tomography angiography. Clin Nutr. 2021 Mar;40(3):1123-1129. doi: 10.1016/j.clnu.2020.07.016. Epub 2020 Jul 22. PMID: 32778459. https://pubmed.ncbi.nlm.nih.gov/32778459/

Conclusions: Omega-3-PUFA supplementation is associated with less coronary atherosclerotic “high-risk” plaque (lipid-rich) and lower total non-calcified plaque burden independent on cardiovascular risk factors. Our study supports direct anti-atherogenic effects of Omega-3-PUFA.

Alfaddagh A, Elajami TK, Saleh M, Mohebali D, Bistrian BR, Welty FK. An omega-3 fatty acid plasma index ≥4% prevents progression of coronary artery plaque in patients with coronary artery disease on statin treatment. Atherosclerosis. 2019 Jun;285:153-162. doi: 10.1016/j.atherosclerosis.2019.04.213. Epub 2019 Apr 13. PMID: 31055222; PMCID: PMC7963401.An omega-3 fatty acid plasma index ≥4% prevents progression of coronary artery plaque in patients with coronary artery disease on statin treatment – PMC (nih.gov)

Conclusions: EPA and DHA added to statins prevented coronary plaque progression in nondiabetic subjects with mean LDL-C <80 mg/dL, when an omega-3 index ≥4% was achieved. Low omega-3 index <3.43% identified nondiabetic subjects at risk of coronary plaque progression despite statin therapy

Association of Plasma Phospholipid Long-Chain Omega-3 FattyAcids with Incident Atrial Fibrillation in Older Adults: The Cardiovascular Health Study, Circulation Volume 125, Number 9 https://doi.org/10.1161/CIRCULATIONAHA.111.062653

Among 3326 US men and women ≥65 years of age and free of AF or heart failure at baseline, plasma phospholipid levels of eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid were measured at baseline by use of standardized methods. Incident AF (789 cases) was identified prospectively from hospital discharge records and study visit ECGs during 31 169 person-years of follow-up (1992-2006).

Conclusions: In older adults, higher circulating total long-chain n-3 PUFA and docosahexaenoic acid levels were associated with lower risk of incident AF (atrial fibrillation). These results highlight the need to evaluate whether increased dietary intake of these fatty acids could be effective for the primary prevention of AF.

Omega-3 Fatty Acid Therapy: The Tide Turns for a Fish Story https://www.mayoclinicproceedings.org/article/S0025-6196(16)30764-9/fulltext

An omega-3 index of less than 4% is associated with increased CHD risk, particularly for sudden cardiac death. In contrast, an omega-3 index of more than 8% is associated with low CHD risk, whereas the range between 4% and 8% is considered intermediate risk

Risk of sudden death

Alfaddagh A, Elajami TK, Ashfaque H, Saleh M, Bistrian BR, Welty FK. Effect of Eicosapentaenoic and Docosahexaenoic Acids Added to Statin Therapy on Coronary Artery Plaque in Patients with Coronary Artery Disease: A Randomized Clinical Trial. J Am Heart Assoc. 2017; 6: e006981. 10.1161/JAHA.117.006981. https://pubmed.ncbi.nlm.nih.gov/29246960/

“High-dose eicosapentaenoic acid and docosahexaenoic acid provided additional benefit to statins in preventing progression of fibrous coronary plaque in subjects adherent to therapy with well-controlled low-density lipoprotein cholesterol levels.”

Huh JH, Jo SH. Omega-3 fatty acids and atrial fibrillation. Korean J Intern Med. 2023 May;38(3):282-289. doi: 10.3904/kjim.2022.266. Epub 2022 Dec 14. PMID: 36514212; PMCID: PMC10175873 https://pubmed.ncbi.nlm.nih.gov/36514212/

.

Effects of omega-3 fatty acid supplementation on the risk of atrial fibrillation. HR, hazard ratio; CI, confidence interval; VITAL, Vitamin D and Omega-3 Trial; ASCEND, A Study of Cardiovascular Events in Diabetes; STRENGTH, Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia; RP, Risk and Prevention Study; REDUCE-IT, Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial; GISSI-HF, Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca-Heart Failure; OMEMI, Omega-3 Fatty Acids in Elderly With Myocardial Infarction. Effects of omega-3 fatty acid supplementation on the risk of atrial fibrillation. HR, hazard ratio; CI, confidence interval; VITAL, Vitamin D and Omega-3 Trial; ASCEND, A Study of Cardiovascular Events in Diabetes; STRENGTH, Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia; RP, Risk and Prevention Study; REDUCE-IT, Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial; GISSI-HF, Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca-Heart Failure; OMEMI, Omega-3 Fatty Acids in Elderly With Myocardial Infarction. Effects of omega-3 fatty acid supplementation on the risk of atrial fibrillation. HR, hazard ratio; CI, confidence interval; VITAL, Vitamin D and Omega-3 Trial; ASCEND, A Study of Cardiovascular Events in Diabetes; STRENGTH, Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia; RP, Risk and Prevention Study; REDUCE-IT, Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial; GISSI-HF, Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca-Heart Failure; OMEMI, Omega-3 Fatty Acids in Elderly With Myocardial Infarction

THIS WEBSITE PROVIDES INFORMATION FOR EDUCATIONAL PURPOSES ONLY. CONSULT YOUR HEALTH CARE PROVIDER FOR MEDICAL ADVICE.

Eat clean, drink filtered water, love, laugh, exercise outdoors in a greenspace, get some morning sunlight, block the blue light before bed, engage in meaningful work, find a sense of purpose, spend time with those you love, AND sleep well tonight.

Doctor Bob

4th International Evolutionary Health Conference

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Sorry for the confusion. The website for the International Evolutionary Health Conference changed when the venue changed from Boston to Virtual. Here is the correct website link which gives a list of speakers/topics and sign up information. 

https://2023.evolutionaryhealthconference.com/

The previously published link will lead you to a site that says “canceled”. The conference is not cancelled, the venue has changed to virtual. 

Dr. Bob

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Fourth International Evolutionary Health Conference

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I’ve been asked to talk at the fourth International Evolutionary Health Conference on the topic of Cardiovascular Risk Assessment. This year the conference is virtual. Presenters include clinicians and researchers discussing many topics related to health. The underlying principle of this approach attributes modern degenerative and chronic diseases to mismatch between our evolutionary biology and present day life. You can sign up for this virtual event here.

https://2023.evolutionaryhealthconference.com/

Agenda

9:45 AM – 10:00 AM

Opening remarks

Prof. Lynda Frassetto

10:00 AM – 10:30 AM

Maladaptive cognitive/emotional processing as the cause of the stress response

Prof. Igor Mitrovic

Physiologic reserve is spare capacity activated when demand exceeds baseline, causing stress. If demand surpasses reserve, it damages the system and leads to death. The brain predicts the future to a…
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10:30 AM – 11:00 AM

How breathing patterns affect health

Dr. Michael Mew

11:00 AM – 11:15 AM

Round table with Q & A (Moderator: Darryl Edwards)

Dr. Michael Mew

Prof. Igor Mitrovic

11:15 AM – 11:45 AM

Break and Poster session

If you would like to submit a poster, please contact us at evolution.conference@nutriscience.pt

11:45 AM – 12:15 PM

Decoding The Truth: Cancer, Carbs and Cure

Darryl Edwards, MSc

1. We will delve into the extensive evidence showcasing how higher levels of physical activity can reduce the risk of various cancers. 2. While awareness of the importance of exercise exists, we will…
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12:15 PM – 12:45 PM

Influential factors on sun-induced vitamin D synthesis

Pedro Bastos, PhD candidate

Ultraviolet B radiation is absorbed in the epidermis by 7-dehydrocholesterol, giving rise to previtamin D3 and subsequently to vitamin D3. In the liver, vitamin D is converted to one of the various c…
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12:45 PM – 1:00 PM

Round table with Q & A (Moderator: Prof. Lynda Frassetto)

Darryl Edwards, MSc

Pedro Bastos, PhD candidate

1:00 PM – 2:15 PM

Lunch Break

2:15 PM – 2:45 PM

How nutrition can impact microbiome composition/permeability/immune response

Prof. Alessio Fasano

Improved hygiene and reduced microorganism exposure are linked to the ‘epidemic’ of chronic inflammatory diseases (CID) in developed nations. This hygiene hypothesis suggests that lifestyle and envir…
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2:45 PM – 3:15 PM

Comprehensive cardiovascular risk assessment

Dr. Robert Hansen

Assessing insulin resistance is central to predicting CV risk. LDL-C and standard lipid profile is extremely limited in predictive value. A systems engineering understanding of atherosclerosis and ev…
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3:15 PM – 3:30 PM

Round table with Q & A (Moderator: Pedro Bastos)

Prof. Alessio Fasano

Dr. Robert Hansen

3:30 PM – 3:45 PM

Short Break

3:45 PM – 4:15 PM

Environmental influences on cellular senescence and aging

Prof. Peter Stenvinkel

Planetary health recognizes that human well-being depends on the health of ecosystems. Neglecting this concept has led to an anthropocentric world, causing increased greenhouse gas emissions, heat st…
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4:15 PM – 4:45 PM

Fueling a Bright Future: The Role of Diet in Preventing Childhood Obesity

Dr. Polina Sayess

Childhood obesity is a global health issue. In my presentation, I’ll explore its origins, classifications, and mitigation strategies. I’ll discuss the definitions and distinctions between “overweight…
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4:45 PM – 5:00 PM

Round table with Q & A (Moderator: Prof. Lynda Frassetto)

Prof. Peter Stenvinkel

Dr. Polina Sayess

5:00 PM – 5:30 PM

Final discussion with all speakers and moderators

Establishing future research and intervention directions.

5:30 PM – 5:45 PM

Closing remarks

Prof. Lynda Frassetto

Please join us if you can.

Dr. Bob