The Insulin Resistance Challenge: The Zone Diet versus the Mediterranean Diet

Insulin resistance is the driving factor for many chronic disease states, including obesity, diabetes, heart disease, and Alzheimer’s.  Yet the level of insulin resistance in each of your organs is under robust dietary control. Therefore, the correct diet should reduce, if not eliminate, insulin resistance.  So, what is the best diet for reducing insulin resistance? The Zone diet was patented in 2000 for reducing insulin resistance (1), however popular polls rank the Mediterranean diet as the best and therefore the ideal diet for general health and reducing insulin resistance (2). To answer the question of whether the Zone or Mediterranean diet is the best for reducing insulin resistance can only be done by doing carefully controlled clinical research.

One of the significant problems in doing good dietary research is its complexity.  Drug studies which are relatively straight forward to undertake since you are comparing a single drug to a placebo.  On the other hand, studies of diets are challenging because of the number of variables that must be controlled to give meaningful results.  You have four variables that must be addressed in any research study in comparing different diets: (a) total calorie intake, (b) total protein intake,  (c) total carbohydrate intake, and (d) total fat intake. Then, because of their dynamic interrelationships between each of those variables, you must fix two of those four variables to study the effects of the two remaining dietary components.   The result is that very few useful dietary studies exist in the literature.

An example of this is the Mediterranean diet.  For years the Mediterranean diet has been touted as the best based on relatively poor data published in 2013 and then had to be retracted and republished because of methodological problems (3).  Furthermore, as I pointed out in my book, The Mediterranean Zone, there are no specific caloric or macronutrient composition to define the Mediterranean diet (4).  The Mediterranean diet not a bad diet because many of the recommended food ingredients are common to the Zone diet, but it not defined nor has never tested under clinically controlled conditions.  Despite these shortfalls, the Mediterranean diet is consistently voted the top diet for general health and management of insulin resistance although lacking the support of rigorous clinical data (2).

A recent study presents a direct head-on comparison of the Mediterranean diet to the Zone diet, so it was a winner-take-all case (5).  The study was conducted in a metabolic ward in a hospital where all the food was provided to the subjects.  The subjects also were severely obese (BMI > 40), and all had significant insulin resistance (HOMA-IR > 4).  Since the subjects were confined to the hospital, their dietary intake was supervised and monitored.  The control group received a calorie-restricted Mediterranean diet (500 calories less than needed to maintain their current weight) consisting of 55 percent carbohydrates, 20 percent protein, and 25 percent fat.  The active group also had the same level of calorie restriction but now composed of 40 percent carbohydrates, 30 percent protein, and 30 percent fat.  Although the authors cite this higher protein diet as a “high-protein Mediterranean diet,” it was identical to the Zone diet I described in 1995 (6).  Furthermore, it was a crossover study since halfway through the study; the diets were switched after ten days to reduce the impact of individual metabolic characteristics of the subjects on the results.  What were those results?  The Zone diet demonstrated superior insulin resistance and hyperinsulinemia improvements compared to the Mediterranean diet. The Zone diet also reduced the variability of blood glucose levels, indicating better hormonal stability between meals.   This is hardly new information since Harvard investigators reported similar results after a single Zone meal compared to an isocaloric meals containing a higher level of carbohydrates and a lower level of protein in 1999 (7).  In addition, the Zone diet is the primary dietary program used by the Joslin Diabetes Research Center at Harvard Medical School for treating type 2 diabetes (811).

So why don’t you hear more about the Zone diet in the medical research literature?  I believe a primary reason appears to be the researchers wish to believe they came up with the idea that all on their own, even though more than six million books on the Zone diet have been sold in the United States since the publication of The Zone in 1995 (4).  Nonetheless, it is personally rewarding to see the Zone diet (or whatever term is used to describe it) being consistently confirmed as a powerful treatment for insulin resistance.

Another problem in the dietary treatment of insulin resistance is addressing the actual underlying molecular problem that causes what is termed insulin resistance.  Insulin resistance can be best understood as a blanket term describing a systemic disruption of your metabolism.  Furthermore, insulin resistance is associated with many other chronic disease conditions other than obesity and type 2 diabetes.  From a molecular biology perspective, the most likely suspect causing insulin resistance is the inhibition of the master regulator of metabolism known as AMPK (12).

To promote AMPK activation, you need a dietary triad consisting of the calorie-restricted Zone diet coupled with adequate intakes of omega-3 fatty acids and polyphenols.  Each of these nutritional interventions works synergistically with each other to increase AMPK activity.  However, when you combine all three dietary interventions together, they become a powerful biotechnology to address the underlying cause of insulin resistance (inhibition of AMPK) and all the conditions (obesity, diabetes, heart disease, Alzheimer’s, etc.) that arise from it.  The molecular mechanisms of their interactions are complicated, but nutrition is always more complex than simple pharmacology, and a lot safer.



1. Sears, B. “Method of and nutritional and pharmaceutical compositions for reduction of hyperinsulinemia.”  S. Patent No. 6,140,304 (2000)

2. U.S. News and World Reports. “Best overall diets 2023.

3. Estruch R et al. “Retraction and Republication: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. N Engl J Med 2013;368:1279-90 Retraction of Publication.”  N Engl J Med. 378:2441-2442. doi: 10.1056/NEJMc1806491. (2018)

4. Sears B.The Mediterranean Zone.  Ballantine Books.  New York, NY (2014)

5. 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 13:4380. doi: 10.3390/nu13124380. (2021)

6. Sears B. The Zone.  Regan Books.  New York, NY (1995)

7. Ludwig DS et al. “High glycemic index foods, overeating, and obesity.”  Pediatrics 103:E26. doi: 10.1097/00008480-199908000-00005. (1999)

8. Giusti J and Rizzott J. “Interpreting the Joslin Diabetes Center and Joslin Clinic clinical guideline for overweight and obese adults with type 2 diabetes.”  Curr Diab Report 6:405-408. doi: 10.1007/s11892-006-0014-y. (2006)

9. Hamdy O. “Diabetes weight management in clinical practice—the Why Wait model,” US Endocrinology 4:49–54. org/10.17925/USE.2008.04.2.49. (2008)

10. Hamdy O. and Carver C. “The Why WAIT program: improving clinical outcomes through weight management in type 2 diabetes.”  Curr Diab Rep 8:413-420. doi: doi: 10.1007/s11892-008-0071-5. (2008)

11. Hamdy O. et al. “Long-term effect of intensive lifestyle intervention on cardiovascular risk factors in patients with diabetes in real-world clinical practice: a 5-year longitudinal study.” BMJ Open Diabetes Res Care 5:e000259. doi: 10.1136/bmjdrc-2016-000259. (2017)

12. Sears B and Saha A. “Dietary activation of AMP-activated protein kinase (AMPK) to treat insulin resistance.” Evolving Concepts in Insulin Resistance doi: (2022)

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