Supporting Immune Function by Metabolic Engineering™

The immune system is a minor part of the far more complex systems comprising metabolism.  Metabolism is how we stay alive.  Besides converting food into energy, metabolism also controls inflammation, our immune response to injury and infection, the repair of damaged tissue, the expression of our genes, and our rate of aging. Thus, an efficient immune system requires an efficient metabolism.  What ultimately controls metabolism in each of your 37 trillion cells is a master regulatory switch known as AMPK (1,2).   AMPK is under robust dietary control (3).  Therefore, your diet will ultimately determine how strong your immune system is.

            AMPK activity is challenging to measure, but a surrogate marker of its efficiency is the level of insulin resistance (4).    As insulin resistance increases, metabolic efficacy decreases, and the ability of the immune system to not only fight off infectious disease but also prevent the development of chronic diseases associated with chronic low-level inflammation is also reduced (4).

            There is no single magic dietary bullet for the reduction of insulin resistance, but there is a defined dietary program that can.  That dietary system falls under the general term of Metabolic Engineering™.   This is an integrated dietary system composed of the calorie-restricted Zone diet, adequate levels of omega-3 fatty acids such as EPA and DHA, and increased intake of polyphenols, primarily a subclass known as delphinidins, that are found in high concentrations in berries and red wine.  Working together, they can maximally activate AMPK in every cell and thus improve immune system performance.

            Calorie restriction is the most potent dietary way to activate AMPK, thus lowering insulin resistance directly.  The Zone diet is patented to reduce insulin resistance (5). Furthermore, it has been the most clinically validated program to lower insulin resistance (6-9).  The Zone diet is a calorie-restricted, protein-adequate, carbohydrate-moderate (but rich in non-starchy vegetables), and low-fat diet.  Because of this unique dietary composition, the Zone diet suppresses appetite using molecular mechanisms similar to howinjectable weight-loss drugs work.  In addition, the Zone diet has also been demonstrated to be clinically superior to the Mediterranean diet in reducing insulin resistance (10).

            Omega-3 fatty acids lower insulin resistance by their conversion into pro-resolution hormones that directly reduce inflammation (11) and indirectly activate AMPK rough (12).  Finally, delphinidins reduce oxidative stress, a cause of insulin resistance (13,14).

            The dietary components of Metabolic Engineering™ are the foundation of the nutritional pathway to increase metabolism by increasing AMPK activity.  Each element alone is clinically validated, but working together as a metabolic team, they are far more potent because of their synergistic relationships (3).

            Can other lifestyle interventions improve metabolic efficiency by activating AMPK activity?  Exercise is one such lifestyle intervention (15).  The best is exercise, especially high-intensity interval training (16,17).  Another lifestyle intervention to activate AMPK is using stress reduction activities such as meditation.  One of the benefits of stress reduction is the reduction of cortisol levels.  The reduction of cortisol-induced insulin resistance improves AMPK activity (18).

            Unfortunately, lifestyle interventions are far less potent than Metabolic Engineering™ to activate AMPK.  I use the 80-15-5 rule to rank the efficacy of potential interventions to reduce insulin resistance by activating AMPK.  Eighty percent of your final success will come from consistent use of Metabolic Engineering™, 15 percent from exercise (especially high-intensity interval training), and five percent from stress reduction. All the described interventions are good but not equal.

            In conclusion, if you want to maximize your immune defenses, Metabolic Engineering™ will be your best approach, but you must use it consistently as if it were a drug.




  1. Garcia D and Shaw J.AMPK:  Mechanisms of cellular energy sensing and restoration of metabolic balance.  Mol Cell. 2017 66:789-800 (2017)
  2. Townend LK and Steinberg GR.AMPK and the endocrine control of metabolism.  Endocrine Reviews.  2023 44:910-933. doi: 10.1210/endrev/bnad012.
  3. Sears B and Saha AK.Dietary control of inflammation and resolution.  Front Nutr. 2021 8:709435. doi: 10.3389/fnut.2021.709435.
  4. Ruderman NB et al. AMPK, insulin resistance, and the metabolic syndrome.J Clin Invest. 2013 123:2764-2772. doi: 10.1172/JCI67227.
  5. Sears, B. “Method of and nutritional and pharmaceutical compositions for reduction of hyperinsulinemia.” U.S. Patent No. 6,140,304 (2000)
  6. Markovic TP et al. The determinants of glycemic responses to diet restriction and weight loss in obesity and NIDDM. Diabetes Care. 1998 21:687-694. doi: 10.2337/diacare.21.5.687.
  7. Ludwig DS et al. High glycemic index foods, overeating, and obesity. Pediatrics. 1999 103:E26. doi: 10.1542/peds.103.3.e26.
  1. Hamdy O and Carver C. The Why WAIT program: Improving clinical outcomes through weight management in type 2 diabetes. Curr Diab Rep. 2008 8:413-420. doi: 10.1007/s11892-008-0071-5.
  2. Stulnig TM.“The Zone diet and metabolic control in type 2 diabetes.”  J Am Coll Nutr 34 Suppl 1:39-41 (2015) doi: 10.1080/07315724.2015.1080110.
  3. Tettamanzi F et al. A high protein diet Is more effective in improving insulin resistance and glycemic variability compared to a Mediterranean diet: A cross-over controlled inpatient dietary study.  Nutrients. 2021 13:4380. doi: 10.3390/nu13124380.
  4. Borja-Magno A et al.Differential effects of high dose omega-3 fatty acids on metabolism and inflammation in patients with obesity: eicosapentaenoic and docosahexaenoic acid supplementation.  Front. Nutr.  2021 10:1156995.
  5. Hosseini Z et al. Resolvin D1 enhances necroptotic cell clearance through promoting macrophage fatty acid oxidation and oxidative phosphorylation. Arterioscler Thromb Vasc Biol. 2021 41:1062-1075. doi: 10.1161/ATVBAHA.120.315758. Epub 2021 Jan 21.
  1. Davinelli S et al. A randomized clinical trial evaluating the efficacy of an anthocyanin-maqui berry extract (Delphinol®) on oxidative stress biomarkers. J Am Coll Nutr. 2015 34 Suppl 1:28-33. doi: 10.1080/07315724.2015.1080108.
  1. Onyango AN.Cellular stresses and stress responses in the pathogenesis of insulin resistance.  Oxid Med Cell Longev. 2018  2018:4321714. doi: 10.1155/2018/4321714.
  2. Richter EA and Ruderman NB. AMPK and the biochemistry of exercise: Implications for human health and disease. Biochem J. 2009 418:261-275. doi: 10.1042/BJ20082055.
  3. Marcinko K et al.High intensity interval training improves liver and adipose tissue insulin sensitivity.  Mol Metab. 2015 Oct 9;4(12):903-15. doi: 10.1016/j.molmet.2015.09.006.
  4. Casuso RA et al.High-intensity high-volume swimming induces more robust signaling through PGC-1α and AMPK activation than sprint interval swimming.  PLoS One. 2017 12(10):e0185494. doi: 10.1371/journal.pone.0185494.
  5. Bhasin MK et al. Specific transcriptome changes associated with blood pressure reduction in hypertensive patients after relaxation response training. J Altern Complement Med. 2018 24:486-504. doi: 10.1089/acm.2017.0053.
2 replies
  1. Zack Gillman says:

    Do you think the inclusion of anti-inflammatory nutrients to Zone meals like allulose and fermentable fiber is more important than getting the exact correct balance of protein to glycemic load? So if one was to theoretically consume slightly more or less protein or carbohydrate at a meal than what would be considered a perfect Zone balance, would high levels of allulose and fermentable fiber make up for that because of their unique benefits in Metabolic Engineering?

  2. Barry Sears says:

    They are both important. However, you first need to stop hunger, and that is why the 30 grams of protein at meal is the critical first step. Your success in getting the correct level of carbohydrate to balance the protein will come from the length of appetite suppression.


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