Anxiety and Omega-3 Fatty Acids

Anxiety is one of most the common neurological disorders, but it also is one of the most difficult to understand. Simply stated, anxiety is an apprehension of the future, especially about an upcoming challenging task. This is normal. What is not normal is when the reaction is significantly out of proportion to what might be expected. Over the years, a number of specific terms, such as generalized anxiety disorder, panic disorder, phobia, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and separation anxiety disorder have emerged in an attempt to better categorize general anxiety. Any way you describe anxiety, it is a big problem with nearly 20% of Americans suffering from it, thus making anxiety the largest neurological disorder in the United States (1).

If anxiety is worrying about the future, then it has a fellow traveler, depression. Depression can be viewed as an over-reaction about regret associated with past events. Not surprisingly, almost an equal number of Americans suffer from this condition. This leads to the question: Is there a linkage between the two conditions? I believe the answer is yes and it may be caused by radical changes in the American diet in the past 40 years. These changes have resulted in what I term the Perfect Nutritional Storm (2). The result is an increase in the levels of inflammation throughout the body and particularly in the brain.

The brain is incredibly sensitive to inflammation, not the type you can feel but the type of inflammation that is below the perception of pain. I term this cellular inflammation. What makes this type of inflammation so disruptive is that it causes a breakdown in signaling between cells. What causes cellular inflammation is an increase in the omega-6 fatty acid known as arachidonic acid (AA). From this fatty acid comes a wide range of inflammatory hormones known as eicosanoids that are the usual suspects when it comes to inflammation. This is why anti-inflammatory drugs (aspirin, non-steroid anti-inflammatories, COX-2 inhibitions and corticosteroids) all have a single mode of action—to inhibit the formation of these inflammatory eicosanoids. These drugs, however, can’t cross the blood-brain barrier that isolates the brain from a lot of noxious materials in the blood stream. So when the brain becomes inflamed, its only protection is adequate levels of anti-inflammatory omega-3 fatty acids. But what happens when the levels of omega-3 fatty acids are low in the brain? The answer is increased neuro-inflammation and continual disruption of signaling between nerves.

There are two omega-3 fatty acids in the brain. The first is called docosahexaenoic acid or DHA. This is primarily a structural component for the brain. The other is called eicosapentaenoic acid or EPA. This is the primary anti-inflammatory omega-3 fatty acid for the brain. So if the levels of EPA are low in the blood, they are going to be low in the brain. To further complicate the matter, the lifetime of EPA in the brain is very limited (3,4). This means you have to have a constant supply in the blood stream to keep neuro-inflammation under control.

It is known from work with uni-polar and bi-polar depressed patients, that high-dose fish oil rich in EPA has remarkable benefits (5,6). On the other hand, supplementing the diet with oils rich in DHA have virtually no effects (7).

Since anxiety has a significant co-morbidity with depression, the obvious question becomes is it possible that high levels of EPA can reduce anxiety? The answer appears to be yes (8), according to a study conducted in 2008 using substance abusers. It is known that increased anxiety is one of the primary reasons why substance abusers and alcoholics tend to relapse (9,10). When these patients were given a high dose of EPA (greater than 2 grams of EPA per day), there was a statistically significant reduction in anxiety compared to those receiving a placebo. More importantly, the degree of anxiety reduced was highly correlated to the decrease of the ratio of AA to EPA in the blood (8). In other studies with normal individuals without clinical depression or anxiety, increased intake of EPA improved their ability to handle stress and generated significant improvements in mood (11-13). It may be that depression and anxiety are simply two sides of the same coin of increased cellular inflammation in the brain. Even for “normal” individuals, high dose EPA seems to make them happier and better able to handle stress.

So let’s go back to an earlier question and ask about the dietary changes in the American diet that may be factors in the growing prevalence of both depression and anxiety. As I outline in my book Toxic Fat, it is probably due to a growing imbalance of AA and EPA in our diets (2). What causes AA to increase is a combination of increased consumption of vegetable oils rich in omega-6 fatty acids coupled with an increase in the consumption of refined carbohydrates that generate insulin. When excess omega-6 fatty acids interact with increased insulin, you get a surge of AA production. At the same time, our consumption of fish rich in EPA has decreased. The end result is an increasing AA/EPA ratio in the blood, which means a corresponding increase in the same AA/EPA ratio in the brain creating more cellular inflammation.

Cutting back vegetable oil and refined carbohydrate intake is difficult since they are now the most inexpensive source of calories. Not surprisingly, they are key ingredients for virtually every processed food product. So if changing your diet is too hard, then consider eating more fish to get adequate levels of EPA. Of course, the question is how much fish? If we use a daily intake level of 2 grams of EPA per day that was used the successful trials of using omega-3 fatty acids reduce anxiety, then this would translate into consuming 14 pounds of cod per day. If you prefer a more fatty fish like salmon, then you would only need about 2 pounds per day to get 2 grams of EPA. The Japanese are able to reach that level because they are the largest consumers of fish in the world. These are highly unlikely dietary changes for most Americans. However, it has been demonstrated that following a strict anti-inflammatory diet coupled with purified fish oil supplements can generate an AA/EPA ratio similar to that found in the Japanese population (11).

There is simply no easy way out of this problem created by the Perfect Nutritional Storm, which will only intensify with each succeeding generation due to the insidious effect of cellular inflammation on fetal programming in the womb. Unfortunately for most Americans this will require a dietary change of immense proportions. This probably means that Valium and other anti-anxiety medications are here to stay.

References

  1. Kessler RC, Chiu WT, Demler O, Merikangas KR, and Walters EE. “Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication”. Arch Gen Psychiatry 62:617–627 (2005)
  2. Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)
  3. Chen CT, Liu Z, Ouellet M, Calon F, and Bazinet RP. “Rapid beta-oxidation of eicosapentaenoic acid in mouse brain: an in situ study.” Prostaglandins Leukot Essent Fatty Acids 80:157-163 (2009)
  4. Chen CT, Liu Z, and Bazinet RP. “Rapid de-esterification and loss of eicosapentaenoic acid from rat brain phospholipids: an intracerebroventricular study.” J Neurochem 116:363-373 (2011)
  5. Nemets B, Stahl Z, and Belmaker RH. “Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder.” Am J Psychiatry 159:477-479 (2002)
  6. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, and Marangell LB. “Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial.” Arch Gen Psychiatry 56:407-412 (1999)
  7. Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim HF, and Puryear LJ. “A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression.” Am J Psychiatry 160:996-998 (2003)
  8. Buydens-Branchey L, Branchey M, and Hibbeln JR. “Associations between increases in plasma n-3 polyunsaturated fatty acids following supplementation and decreases in anger and anxiety in substance abusers.” Prog Neuropsychopharmacol Biol Psychiatry 32:568-575 (2008)
  9. Willinger U, Lenzinger E, Hornik K, Fischer G, Schonbeck G, Aschauer HN, and Meszaros K. “Anxiety as a predictor of relapse in detoxified alcohol-dependent patients.” Alcohol and Alcoholism 37:609-612 (2002)
  10. Kushner MG, Abrams K, Thuras P, Hanson KL, Brekke M, and Sletten S. “Follow-up study of anxiety disorder and alcohol dependence in comorbid alcoholism treatment patients.” Alcohol Clin Exp Res 29:1432-1443 (2005)
  11. Fontani G, Corradeschi F, Felici A, Alfatti F, Bugarini R, Fiaschi AI, Cerretani D, Montorfano G, Rizzo AM, and Berra B. “Blood profiles, body fat and mood state in healthy subjects on different diets supplemented with Omega-3 polyunsaturated fatty acids.” Eur J Clin Invest 35:499-507 (2005)
  12. Fontani G, Corradeschi F, Felici A, Alfatti F, Migliorini S, and Lodi L. “Cognitive and physiological effects of Omega-3 polyunsaturated fatty acid supplementation in healthy subjects. “Eur J Clin Invest 35:691-699 (2005)
  13. Kiecolt-Glaser JK, Belury MA, Andridge R, Malarkey WB, and Glaser R. “Omega-3 supplementation lowers inflammation and anxiety in medical students: A randomized controlled trial.” Brain Behav Immun 25:1725-1734 (2011)

What is Cellular Inflammation?

People (including virtually all physicians) are constantly confused what cellular inflammation is. So I decided to take the opportunity to explain the concept in more detail.

There are two types of inflammation. The first type is classical inflammation, which generates the inflammatory response we associate with pain such as, heat, redness, swelling, pain, and eventually loss of organ function. The other type is cellular inflammation, which is below the perception of pain. Cellular inflammation is the initiating cause of chronic disease because it disrupts hormonal signaling networks throughout the body.

Definition of Cellular Inflammation

The definition of cellular inflammation is increased activity of the gene transcription factor know as Nuclear Factor-kappaB (NF-κB). This is the gene transcription factor found in every cell, and it activates the inflammatory response of the innate immune system. Although the innate immune system is the most primitive part of our immune response, it has been resistant to study without recent breakthroughs in molecular biology. In fact, the 2011 Nobel Prize in Medicine was awarded for the earliest studies on the innate immune system and its implications in the development of chronic disease.

There are several extracellular events through which NF-κB can be activated by distinct mechanisms. These include microbial invasion recognized by toll-like receptors (TLR), generation of reactive oxygen species (ROS), cellular generation of inflammatory eicosanoids, and interaction with inflammatory cytokines via defined cell surface receptors. We also know that several of these initiating events are modulated by dietary factors. This also means that appropriate use of the diet can either turn on or turn off the activation of NF-κB. This new knowledge is the foundation of anti-inflammatory nutrition (1-3).

Understanding Cellular Inflammation

Although the innate immune system is exceptionally complex, it can be illustrated in a relatively simple diagram as shown below in Figure 1.

Figure 1. Simplified View of the Innate Immune System

Essential fatty acids are the most powerful modulators of NF-κB. In particular, the omega-6 fatty acid arachidonic acid (AA) activates NF-κB, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) does not (4). Recent work suggests that a subgroup of eicosanoids known as leukotrienes that are derived from AA may play a significant factor in NF-κB activation (5,6)

Extracellular inflammatory cytokines can also activate NF-κB by their interaction with specific receptors on the cell surface. The primary cytokine that activates NF-κB is tumor necrosis factor (TNF) (7). Toll-like receptors (TLR) are another starting point for the activation of NF-κB. In particular, TLR-4 is sensitive to dietary saturated fatty acids (8). The binding of saturated fatty acids to TLR-4 can be inhibited by omega-3 fatty acids such as EPA. Finally ROS either induced by ionizing radiation or by excess free radical formation are additional activators of NF-κB (9).

Anti-inflammatory Nutrition To Inhibit Cellular Inflammation

Anti-inflammatory nutrition is based on the ability of certain nutrients to reduce the activation of NF-κB.

The most effective way to lower the activation of NF-κB is to reduce the levels of AA in the target cell membrane thus reducing the formation of leukotrienes that can activate NF-κB. Having the patient follow an anti-inflammatory diet, such as the Zone Diet coupled with the simultaneous lowering omega-6 fatty acid intake are the primary dietary strategies to accomplish this goal (1-3).

Another effective dietary approach (and often easier for the patient to comply with) is the dietary supplementation with adequate levels of high-dose fish oil rich in omega-3 fatty acids, such as EPA and DHA. These omega-3 fatty acids taken at high enough levels will lower AA levels and increase EPA levels. This change of the AA/EPA ratio in the cell membrane will reduce the likelihood of the formation of inflammatory leukotrienes that can activate NF-κB. This is because leukotrienes derived from AA are pro-inflammatory, whereas those from EPA are non-inflammatory. The increased intake of omega-3 fatty acids is also a dietary approach that can activate the anti-inflammatory gene transcription factor PPAR-γ (10-12), decrease the formation of ROS (13) and decrease the binding of saturated fatty acids to TLR-4 (14). This illustrates the multi-functional roles that omega-3 fatty acids have in controlling cellular inflammation.

A third dietary approach is the adequate intake of dietary polyphenols. These are compounds that give fruits and vegetables their color. At high levels they are powerful anti-oxidants to reduce the generation of ROS (15). They can also inhibit the activation of NF-κB (16).

Finally, the least effective dietary strategy (but still useful) is the reduction of dietary saturated fat intake. This is because saturated fatty acids will cause the activation of the TLR-4 receptor in the cell membrane (8,14).

Obviously, the greater the number of these dietary strategies implemented by the patient, the greater the overall effect on reducing cellular inflammation.

Clinical Measurement of Cellular Inflammation

Since cellular inflammation is confined to the cell itself, there are few blood markers that can be used to directly measure the levels of systemic cellular inflammation in a cell. However, the AA/EPA ratio in the blood appears to be a precise and reproducible marker of the levels of the same ratio of these essential fatty acids in the cell membrane.

As described above, the leukotrienes derived from AA are powerful modulators of NF-κB. Thus a reduction in the AA/EPA ratio in the target cell membrane will lead to a reduced activation of NF-κB by decreased formation of inflammatory leukotrienes. The cell membrane is constantly being supplied by AA and EPA from the blood. Therefore the AA/EPA ratio in the blood becomes an excellent marker of the same ratio in the cell membrane (17). Currently the best and most reproducible marker of cellular inflammation is the AA/EPA ratio in the blood as it represents an upstream control point for the control of NF-κB activation.

The most commonly used diagnostic marker of inflammation is C-reactive protein (CRP). Unlike the AA/EPA ratio, CRP is a very distant downstream marker of past NF-κB activation. This is because one of inflammatory mediators expressed in the target cell is IL-6. It must eventually reach a high enough level in the blood to eventually interact with the liver or the fat cells to produce CRP. This makes CRP a more long-lived marker in the blood stream compared to the primary inflammatory gene products (IL-1, IL-6, TNF, and COX-2) released after the activation of NF-κB. As a consequence, CRP is easier to measure than the most immediate inflammatory products generated by NF-κB activation. However, easier doesn’t necessarily translate into better. In fact, an increase AA/EPA ratio in the target cell membrane often precedes any increase of C-reactive protein by several years. An elevated AA/EPA ratio indicates that NF-κB is at the tipping point and the cell is primed for increased genetic expression of a wide variety of inflammatory mediators. The measurement of CRP indicates that NF-κB has been activated for a considerable period of time and that cellular inflammation is now causing systemic damage.

Summary

I believe the future of medicine lies in the control of cellular inflammation. This is most effectively accomplished by the constant application of anti-inflammatory nutrition. The success of such dietary interventions can be measured clinically by the reduction of the AA/EPA ratio in the blood.

References

  1. Sears B. The Anti-Inflammation Zone. Regan Books. New York, NY (2005)
  2. Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)
  3. Sears B and Riccordi C. “Anti-inflammatory nutrition as a pharmacological approach to treat obesity.” J Obesity doi:10.1155/2011/431985 (2011)
  4. Camandola S, Leonarduzzi G,Musso T, Varesio L, Carini R, Scavazza A, Chiarpotto E, Baeuerle PA, and Poli G. “Nuclear factor kB is activated by arachidonic acid but not by eicosapentaenoic acid.” Biochem Biophys Res Commun 229:643-647 (1996)
  5. Sears DD, Miles PD, Chapman J, Ofrecio JM, Almazan F, Thapar D, and Miller YI. “12/15-lipoxygenase is required for the early onset of high fat diet-induced adipose tissue inflammation and insulin resistance in mice.” PLoS One 4:e7250 (2009)
  6. Chakrabarti SK, Cole BK, Wen Y, Keller SR, and Nadler JL. “12/15-lipoxygenase products induce inflammation and impair insulin signaling in 3T3-L1 adipocytes.” Obesity 17:1657-1663 (2009)
  7. Min JK, Kim YM, Kim SW, Kwon MC, Kong YY, Hwang IK, Won MH, Rho J, and Kwon YG. “TNF-related activation-induced cytokine enhances leukocyte adhesiveness: induction of ICAM-1 and VCAM-1 via TNF receptor-associated factor and protein kinase C-dependent NF-kappaB activation in endothelial cells.” J Immunol 175: 531-540 (2005)
  8. Kim JJ and Sears DD. “TLR4 and Insulin Resistance.” Gastroenterol Res Pract doi:10./2010/212563 (2010)
  9. Bubici C, Papa S, Dean K, and Franzoso G. “Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance.” Oncogene 25: 6731-6748 (2006)
  10. Li H, Ruan XZ, Powis SH, Fernando R, Mon WY, Wheeler DC, Moorhead JF, and Varghese Z. “EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: Evidence for a PPAR-gamma-dependent mechanism.” Kidney Int 67: 867-874 (2005)
  11. Kawashima A, Harada T, Imada K, Yano T, and Mizuguchi K. “Eicosapentaenoic acid inhibits interleukin-6 production in interleukin-1beta-stimulated C6 glioma cells through peroxisome proliferator-activated receptor-gamma.” Prostaglandins LeukotEssent Fatty Acids 79: 59-65 (2008)
  12. Chambrier C, Bastard JP, Rieusset J, Chevillotte E, Bonnefont-Rousselot D, Therond P, Hainque B, Riou JP, Laville M, and Vidal H. “Eicosapentaenoic acid induces mRNA expression of peroxisome proliferator-activated receptor gamma.” Obes Res 10: 518-525 (2002)
  13. Mas E, Woodman RJ, Burke V, Puddey IB, Beilin LJ, Durand T, and Mori TA. “The omega-3 fatty acids EPA and DHA decrease plasma F(2)-isoprostanes.” Free Radic Res 44: 983-990 (2010)
  14. Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugam P, Bray G, and Hwang DH. “Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids.” J Lipid Res 44: 479-486 (2003)
  15. Crispo JA, Ansell DR, Piche M, Eibl JK, Khaper N, Ross GM, and Tai TC. “Protective effects of polyphenolic compounds on oxidative stress-induced cytotoxicity in PC12 cells.” Can J Physiol Pharmacol 88: 429-438 (2010)
  16. Romier B, Van De Walle J, During A, Larondelle Y, and Schneider YJ. “Modulation of signaling nuclear factor-kappaB activation pathway by polyphenols in human intestinal Caco-2 cells.” Br J Nutr 100: 542-551 (2008)
  17. Yee LD, Lester JL, Cole RM, Richardson JR, Hsu JC, Li Y, Lehman A, Belury MA, and Clinton SK. “Omega-3 fatty acid supplements in women at high risk of breast cancer have dose-dependent effects on breast adipose tissue fatty acid composition.” Am J Clin Nutr 91: 1185-1194 (2010)

Hard times are ahead

Last month was a red-letter month for the future of mankind as the world population passed 7 billion. Unfortunately, this fact dovetails with recent research that indicates it is likely that one-half of all Americans will be diabetic by 2050 (1).

The combination of these two trends does not bode well for the future. To begin with, how are we going to feed all these people? Most of the arable land on the planet is already under cultivation. Furthermore, urbanization is destroying prime cropland at a rapid pace.

Added to these facts is that the diversity of most of the world’s calories is rapidly decreasing. Currently the five top sources of calories in the world are corn, soybeans, wheat, rice and potatoes (as well as its kissin’ cousin cassava, which is incredibly poor in protein and nutrients). The first two crops (corn and soy) are rich sources of omega-6 fatty acids. In addition, corn, wheat, and rice provide extremely high-glycemic carbohydrates that can be easily refined to last forever and make thus a wide variety of processed foods. (Potatoes and cassava tend to decompose rapidly and can’t be easily refined, except perhaps as potato chips). As a consequence, omega-6 fatty acids and refined carbohydrates are now the cheapest form of calories in the world. In fact, it is estimated that they are 400 times less expensive per calorie than fresh fruits and vegetables.

So how can you feed this growing population of more than 7 billion people? The answer is easy—produce even more refined carbohydrates and omega-6 fatty acids.

Unfortunately, feeding the growing population of the world with cheap omega-6 fatty acids and refined carbohydrates is exactly the best way to increase cellular inflammation and drive the development of diabetes (2). It is estimated that by 2050 diabetes will be the primary non-infectious disease on the planet. This is equally bad news as it is also the most expensive chronic disease to treat on a long-term basis.

Today, more than 26 percent of all Americans older than 65 has diabetes. If the estimates of increased diabetes are correct (1), then it is likely that the number of Americans older than 65 in 2050 with diabetes may be greater than 50 percent. The current level of diabetes is the primary reason why our health-care expenses are spiraling out of control. If you double number of older Americans with diabetes by 2050, there is no way the current health-care system, as we know it can possibly survive. Add to the fact that once you have diabetes, you are 2-4 times more likely to develop heart disease and Alzheimer’s. It is not a very pleasant picture of the future of health care in America.

What can you do about it? On a global basis, not much unless you would like to see an apocalyptic event that reduces the population from 7 billion to a more manageable 1-2 billion individuals. Of course, this is highly unlikely. However, on the individual basis there is a lot you can do to protect yourself in the future. Simply take control of your future by focusing on managing cellular inflammation for a lifetime by following an anti-inflammatory diet. This may be your only real health security in times of increasing demands on the planet’s resources to produce food. There is no question that we have other troubles brewing like climate change, decreasing water supplies, and decreasing cheap energy, all of which will also impact the cost of food, driving more individuals toward inexpensive sources of calories no matter what the health consequences. But the rise of diabetes will occur first.

Old folks like myself will probably be OK, but the future generations will take the brunt of trouble brewing ahead.

References

  1. Boyle JP , Thompson TJ, Gregg EW, Barker LE, and Williamson DF. “Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence.” Population Health Metrics 8:29 (2010)
  2. Sears B. “Toxic Fat.” Thomas Nelson. Nashville, TN (2008)

Eat Less, Get Hungry

Telling an obese person simply to eat less rarely succeeds. Is it because they are weak-willed individuals or is there something more complex going on? New research indicates the latter. A new article in Cell Metabolism showed that during extreme calorie restriction, the levels of fatty acids begin to rapidly rise in the blood as the body begins breaking down stored fat for energy. These newly released fatty acids from the fat cells can then enter into the brain (the hypothalamus to be exact) and cause the self-digestion of cells in the hunger neurons (1). This self-digestion of the cells in the hunger neurons produces a rise in the very powerful hunger hormone (AgRP) from the same bundle of neurons. Not surprisingly, the urge to eat becomes almost overpowering. This begins to explain why very low calorie diets can cause rapid weight loss, but are rarely successful in keeping the weight off.

This is why very low calorie diets that promise quick weight loss invariably cause the rapid release of stored fatty acids that promotes constant hunger. This is clearly not a sustainable way to maintain long-term weight management.

Of course the question might be whether it is all fatty acids or just one that causes the problem of cellular death in the hunger neurons? I believe the answer comes back to the usual suspect, arachidonic acid (2). It has been known for 20 years that when you put obese individuals on a very low calorie diet there is a rapid increase in the levels of arachidonic acid levels in the blood (3). Arachidonic acid can easily cross the blood brain barrier and enter into the hypothalamus. Since arachidonic acid is a powerful promoter of cell death (4), increased concentrations inside the hypothalamus may be the primary accelerator of the death of the hunger neurons. Increased levels of arachidionic acid in the blood are also the underlying cause of insulin resistance because of its effect on the generation of cellular inflammation (2). So as you build up the levels of stored arachidonic acid in the fat cells, caused by the Perfect Nutritional Storm (2), you are almost ensuring constant hunger when you try to lose weight quickly by following very low calorie diets. To make matters even worse, as arachidonic acid levels also build up in the brain increasing the production of endocannabinoids (5). These are the hormones that give you the continual munchies (they are related to the active ingredient in marijuana).

So is there any good news in all of this research? Yes as long as you develop a lifetime dietary strategy for reducing arachidonic acid and the cellular inflammation it causes as well as following a reasonable low calorie diet that supplies adequate levels of fat to moderate the release of stored fatty acids from the fat cells. It means following an anti-inflammatory diet with adequate protein using low-glycemic load carbohydrates and fats very low in omega-6 fatty acids, but adequate in monounsaturated and omega-3 fats.

That’s why you never want to start any type of weight loss program without adding omega-3 fatty acids to counteract the released of stored arachidonic acid from the fat cells. Not only will these omega-3 fatty acids reduce the degradation of the hunger neurons thereby reducing the release of powerful hunger hormones during calorie restriction, but they will also inhibit the release of endocannabinoids in the brain (6). The combination of the two events will ensure weight loss without hunger and that’s sustainable.

References

  1. Kaushik S,Rodriguez-Navarro JA, Arias E, Kiffin R, Sahu S, Schwartz GJ, Cuervo AM, and Singh R. “Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance.” Cell Metabolism 14: 173-183 (2011)
  2. Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)
  3. Phinney SD, Davis PG, Johnson SB, and Holman RT. “Obesity and weight loss alter serum polyunsaturated lipids in humans.” Amer J Clin Nutr 53: 831-838 (1991)
  4. Pompeia C, Lima T, and Curi R. “Arachidonic acid cytotoxicity: can arachidonic acid be a physiological mediator of cell death?” Cell Biochemistry and Function 21:97-104 (2003)
  5. Kim J, Li Y, and Watkins BA. “Endocannabinoid signaling and energy metabolism: A target for dietary intervention.” Nutrition 27: 624-632 (2011)
  6. Oda E. “n-3 Fatty acids and the endocannabinoid system.” Am J Clin Nutr 85: 919 (2007)

Nothing contained in this blog is intended to be instructional for medial diagnosis or treatment. If you have a medical concern or issue, please consult your personal physician immediately.

How to eliminate 50 percent of all coronary events

The European Society of Cardiology estimates a 50 percent reduction of coronary events if you can stabilize soft, vulnerable plaques (1). We are often led to believe that plaques you can see on an angiogram are “killer” plaques. It’s true that if they are large enough to obstruct blood flow, they will decrease oxygen transfer to the heart muscle cells making them more tired with less effort.

This is the definition of stable angina. It simply means it takes less effort to over-exert the heart muscles before they fatigue. However, you need approximately a 90 percent total obstruction of the blood vessel to develop stable angina. These plaques account for most of the plaques you might find in an angiogram. This is why if you take an angiogram, you are often immediately wheeled into the operating room to have a stent put into the artery with the belief you are only seconds away from an immediate heart attack and death.

However, the same angiogram can’t see a few plaques (because they are so small), known as the soft, vulnerable ones. When soft, vulnerable plaques rupture (like a pimple), then you have the death and disability (i.e., damaged heart tissue) that truly characterize heart disease. Technically, this is called an acute coronary event, and it has very little to do with the stable plaques that can cause angina. It is this small number of “rogue” soft, vulnerable plaques that are the true killers in heart disease (2,3).

The ultimate cause of plaque rupture is cellular inflammation inside the plaque. Cellular inflammation degrades the fibrous external coating of the plaque. Usually inside these soft, vulnerable plaques are also a lot of macrophages engorged with lipids. This is called the “necrotic core”. When the plaque bursts, these lipid pools are released into the bloodstream causing platelet aggregation and the rapid blockage of the artery resulting in a complete restriction of blood flow (as opposed to a limited restriction of blood flow with a typical stable plaque that will never rupture). It is estimated that about 75 percent of all coronary events are caused by ruptures of the soft, vulnerable plaques (2).

As I mentioned above, the really scary part of this story is that there is no type of imaging technology that can detect dangerous soft, vulnerable plaques. In essence, you don’t know if you have them or not. This is why the prediction of impeding cardiovascular events remains a guessing game. Even more interesting is that these soft, vulnerable plaques seem to form rather quickly (in about 10 years) as opposed to growing slowly over a lifetime (4). Moreover, the rate of growth of these soft, vulnerable plaques is strongly correlated with increasing insulin levels in the blood (4).

So what does this mean for people who don’t want to die from a sudden rupture of soft, vulnerable plaques that can’t be detected? The first thing is to reduce the inflammation within the plaque. Surprisingly, there is only one clinical study that has ever been published that addressed this question, and it used fish oil (5). This study indicated that if you give patients relatively high doses of fish oil, you could see a definite remodeling of the soft, vulnerable plaques in about 40 days compared to subjects taking a placebo composed of safflower oil. The plaques in the subjects taking the fish oil became less inflamed, had higher levels of omega-3 fatty acids, fewer macrophages and more well-formed fibrous caps compared to those taking the placebo. So taking a therapeutic level of fish oil for a lifetime seems to be a good way to reduce the rupture of these plaques.

Another way to potentially reduce their formation in the first place is lower insulin levels. The reason insulin levels are elevated is because organs, such as the adipose tissue, the liver and the muscles, are also inflamed (6). The best way to reduce that systemic inflammation is to follow the anti-inflammatory diet and take therapeutic levels of fish oil for a lifetime. Your success is best measured by the AA/EPA ratio in the blood. Call me crazy, but I think that’s what I have been recommending for the past 16 years (7).

References

  1. Yia-Herttulala S, Bentzon JF, Daemen M, Falk E, Garcia-Garcia HM, Merrmann J, Hoefer IM, Juekma JW, Krams R, Kwak BR, Marx N, Maruszeqica M, Newby A, Pasterkamp G, Serruys PWJC, Waltenberger J, Weber C, and Tokgozoglu L. “Stabilization of atherosclerotic plaques.” Thomobosis and Haemostasis 106: 1-19 (2011)
  2. Schaar JA, Muller JE, Falk E, Virmani R, Fuster V, Serruys PW, Colombo A, Stefanadis C, Ward Casscells S, Moreno PR, Maseri A, and van der Steen AF. “Terminology for high-risk and vulnerable coronary artery plaques. Report of a meeting on the vulnerable plaque.” Eur Heart J 25: 1077-1082 (2004)
  3. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, Ford E, Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott M, Meigs J, Mozaffarian D, Nichol G, O’Donnell C, Roger V, Rosamond W, Sacco R, Sorlie P, Stafford R, Steinberger J, Thom T, Wasserthiel-Smoller S, Wong N, Wylie-Rosett J, and Hong Y. “Heart disease and stroke statistics–2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.” Circulation 119:480-486 (2009)
  4. Hagg S, Salehpour M, Noori P, Lundstrom J, Possnert G, Takolander R, Konrad P, Rosfors S, Ruusalepp A, Skogsberg J, Tegner J, and Bjorkegren J. “Carotid plaque age is a feature of plaque stability inversely related to levels of plasma insulin.” PLoS One 6: e1824 (2011)
  5. Thies F, Garry JM, Yaqoob P, Rerkasem K, Williams J, Shearman CP, Gallagher PJ, Calder PC, and Grimble RF. “Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomized controlled trial.” Lancet 2003 361: 477-485 (2003)
  6. Sears, B. “Toxic Fat.” Thomas Nelson. Nashville, TN (2008)
  7. Sears B. “The Zone.” Regan Books. New York, NY (1995)

Nothing contained in this blog is intended to be instructional for medial diagnosis or treatment. If you have a medical concern or issue, please consult your personal physician immediately.

If you’re fat, you may be OK

It is well known from epidemiological studies that about 30 percent of obese individuals and 50 percent of overweight individuals are relatively healthy in terms of cardiometabolic risk factors (1). The same study also indicated that about 25 percent of normal-weight individuals have significant cardiometabolic risk. A follow-up study indicated individuals defined as “metabolically healthy obese” are not at any long-term risk of heart disease (2).

Is the world turning upside down?

I explained the reasons behind these paradoxical observations in my most recent book, “Toxic Fat,” published three years ago (3). It simply depends on what type of fat cells you have. If you have healthy fat cells (“good” fat), they will pull excess arachidionic acid out of the bloodstream and store it in the fat cells. This buried arachidonic acid can spread inflammation to other organs that ultimately results in the appearance of cardiometabolic risk factors. On the other hand, if you have “bad” fat (unhealthy or sick fat cells), they are not very effective in removing arachidonic acid from the bloodstream. Once this happens, circulating arachidonic acid can metastasize like a cancer to other organs. This begins a very slippery slope toward the early development of cardiometabolic diseases, such as diabetes and heart disease. Finally, you get to the stage of dying fat cells that are surrounded by inflammatory macrophages. Now you are in true trouble as the previously stored arachidonic acid is more rapidly released back into the bloodstream.

Now let's fast forward to a new article in the Journal of the American College of Cardiology (4) that simply confirms what I wrote about fat cell inflammation three years ago. As with the earlier epidemiological study, researchers found that about 30 percent of the obese subjects had little inflammation in their fat cells as indicated by the absence of inflammatory macrophages. This percentage of obese patients was essentially identical to that found in the earlier epidemiological study (1). When the arterial blood flow of the metabolically healthy obese was compared to lean subjects, the rates were virtually identical, whereas the arterial blood flow rates were much lower (that's bad) in the obese subjects who had significant fat cell inflammation.

Unfortunately, their characterization of inflamed fat cells was incorrect. What they were really looking at was dying fat cells. The fat cells of these so-called metabolically healthy obese subjects were already sick (i.e., bad fat) since there were metabolic markers (hyperinsulinemia, increased TG/HDL ratios, elevated blood glucose and increased CRP levels) that indicated that inflammation was already spreading to other organs (such as the liver, muscles and pancreas).

The best way to know if you have truly healthy fat cells (no matter how many you have) is to have a low AA/EPA ratio in the blood. This remains the best clinical marker of the true health of the adipose tissue. If you have healthy fat cells (good fat), then you can expect cellular inflammation in other organs will be reduced leading to a longer and better life no matter what your weight.

References

  1. Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, Wylie-Rosett J, and Sowers MR. “The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population.” (NHANES 1999-2004) Arch Intern Med 168: 1617-1624 (2008)
  2. Wildman RP. “Healthy obesity.” Curr Opin Clin Nutr Metab Care 12: 438-443 (2009)
  3. Sears B. “Toxic Fat.” Thomas Nelson. Nashville, TN (2008)
  4. Farb MG, Bigornia S, Mott M, Tanriverdi K, Morin KM, Freedman JE, Joseph L, Hess DT, Apovian CM, Vita JA, and Gokce N. “Reduced adipose tissue inflammation represents an intermediate cardiometabolic phenotype in obesity.” J Am Coll Cardiol 58: 232-237 (2011)

Nothing contained in this blog is intended to be instructional for medial diagnosis or treatment. If you have a medical concern or issue, please consult your personal physician immediately.

Pass the salt please?

One of the great “truths” in cardiovascular medicine is that to prevent stroke and cardiovascular death you reduce your salt intake. But is it true? A new analysis of the existing literature from the Cochrane Library indicates this may not be the case (1). Analyzing a great number of published studies, researchers came to the conclusion that there is no strong evidence to support the idea that salt restriction reduces cardiovascular disease or all-cause mortality in people with either normal or increased blood pressure. Furthermore, they found that while reducing salt intake did decrease blood pressure, it also increased the risk of all-cause death in people with existing congestive heart failure.

If that wasn’t enough, an article in the May 4 issue of the Journal of the American Heart Association found that low salt increased the risk of death from heart attacks and stokes, while not reducing blood pressure (2). This study was done with middle-aged Europeans and followed them for nearly eight years. During this time, the less salt they consumed, the greater the number who died of heart disease.

Needless to say, the American Heart Association (the same people who recommend eating lots of omega-6 fats) was enraged, similar to the Wizard of Oz telling Dorothy to ignore the man behind the curtain.

So why might restriction of salt consumption cause increased heart attacks? The reason may be due to increased insulin resistance induced by salt restriction (3). Insulin resistance increases insulin levels, and if that is combined with increased consumption of omega-6 fatty acids (remember the American Heart Association), you now have a sure-fire prescription to produce more arachidonic acid. It’s the inflammatory eicosanoids derived from arachidionic acid that would cause inflammation in the arterial wall leading to a heart attack.

This is not to say that some people are not salt-sensitive (African-Americans are particularly so), but I believe the problem is more a matter of balance. You need some sodium, but you also need potassium to balance it. This is confirmed by a recent study from Harvard Medical School that demonstrates that the higher the sodium-to-potassium ratio in the blood, the greater the likelihood of cardiovascular mortality (4). The relationship for increased death was significantly greater for a high sodium-to-potassium level than simply the sodium level itself.

Getting sodium in your diet is easy (sprinkle salt on your food), but getting adequate levels of potassium means eating a lot of fruits and vegetables. So rather than restricting salt intake or taking drugs (i.e. diuretics) to reduce the levels of sodium in the body, think about eating more fruits and vegetables if your goal is to reduce the likelihood of a heart attack. Oh, yes, also ignore the advice of American Heart Association and take more omega-3 and less omega-6 fatty acids.

References

  1. Taylor, RS, Ashton KE, Moxham T, Hooper L and Ebrahim S. “Reduced dietary salt for the prevention of cardiovascular disease.” Cochrane Database of Systematic Reviews DOI: 10.1002/14651858.CD009217 (2011)
  2. Stolarz-Skrzypek K, Kuznetsova T, Thijs L, Tikhonoff V, Seidlerova J, Richart T, Jin Y, Olszanecka A, Malyutina S, Casiglia E, Filipovsky J, Kawecka-Jaszcz K, Nikitin Y, and Staessen JA. “Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion.” JAMA 305: 1777-1785 (2011)
  3. Alderman MH. “Evidence relating dietary sodium to cardiovascular disease.” J Am Coll Nutr 25: 256S-261S (2006)
  4. Yang Q, Liu T, Kuklina EV, Flanders WD, Hong Y, Gillespie C, Chang M-H, Gwinn M, Dowling N, Khoury MJ, and Hu FB. “Sodium and potassium intake and morality among US adults.” Arch Intern Med 171: 1183-1191 (2011)

Nothing contained in this blog is intended to be instructional for medial diagnosis or treatment. If you have a medical concern or issue, please consult your personal physician immediately.

Obesity continues to climb

Last week the Robert Wood Johnson Foundation reported that more than 12 states now have adult obesity rates greater than 30 percent, and that one in three children are either overweight or obese. However, 16 years ago, no state in the United States had an adult obesity rate greater than 20 percent. So in less than a generation, adult obesity has skyrocketed. Yet at the same time, according to the Centers for Disease Control, the percentage of overweight people has remained fairly constant since 1960, while the percentage of obese individuals has increased significantly since 1980. What this suggests is that there is a genetic component that can be activated in those individuals predisposed to gain weight. Once activated, accumulation of excess fat accelerates.

I feel the driving force between this activation of genetic factors is the increasing inflammatory nature of the American diet. We know that it is elevated insulin levels that make us fat and keep us fat. But what really causes insulin to become elevated in the first place? The simple explanation is that it comes from eating excess carbohydrates. However, that is too simplistic an explanation since one-third of adult Americans who are thin are also eating excess carbohydrates.

A more comprehensive answer is it’s insulin resistance that causes elevated insulin levels. Insulin resistance is a consequence of disturbances in the body’s insulin-signaling pathways in the cell caused by cellular inflammation. My most recent book, “Toxic Fat,” goes into great detail on this subject (1). But simply stated, the more cellular inflammation you have in your cells, the greater the likelihood of insulin resistance. And if you are genetically prone to gain weight, increasing insulin resistance will really pack on the extra fat. More insidious is that insulin resistance also creates a “fat trap” through which incoming dietary calories are trapped in your fat cells and can’t be released to provide the necessary energy the body needs. This means you are constantly hungry.

If you are surrounded by cheap processed foods (rich in omega-6 fatty acids and refined carbohydrates), then you are going to quench that hunger with those foods that increase cellular inflammation to even greater levels. The end result is an increasing rise of obesity.

But the fastest growing segment of the overweight and obese population is not adults, but children under the age of 5, with 20 percent now either overweight or obese before entering kindergarten (2). You can’t blame school lunches for this because they are not in school yet. What you can blame is epigenetics (3). This is how the metabolic future of the child can be greatly determined in the womb by the inflammatory nature of the mother’s diet. When these children are born, their altered genetics make them sitting targets for a world full of inflammatory food. Unless you change the foundation of the food supply to become more anti-inflammatory (less omega-6 fatty acids and a lower glycemic load), then the future for these children is incredibly bleak.

References

  1. Sears B. “Toxic Fat.” Thomas Nelson. Nashville, TN (2008)
  2. Kim J, Peterson KE, Scanlon KS, Fitzmaurice GM, Must A, Oken E, Rifas-Shiman SL, Rich-Edwards JW, and Gillman MW. “Trends in overweight from 1980 through 2001 among preschool-aged children enrolled in a health maintenance organization. Obesity 14: 1107-1112 (2006)
  3. Lustig RH editor. “Obesity Before Birth.” Springer. New York (2011)


Nothing contained in this blog is intended to be instructional for medial diagnosis or treatment. If you have a medical concern or issue, please consult your personal physician immediately.

The key to a healthy gut

Most people think all you need for a healthy gut is to consume bacterial-fortified yogurt products. In reality, the balance of bacteria in your gut may hold a key toward managing systemic inflammation in our bodies.

First of all, there are a lot of bacteria in our guts. The human body contains about 100 trillion cells, but the number of bacteria in the gut is 10 times greater in number. Furthermore, these bacteria are not just taking up space; they are actually providing numerous useful functions that make them a symbiotic “organ” to our own body. In particular, they can ferment carbohydrates to provide additional energy, make various vitamins, break down toxins we might ingest, and help prevent the growth of pathogenic bacteria.

Although there are literally millions of different bacteria in the world, only about 500 species actually reside in our guts. We also know that these gut bacteria can be further divided into three distinct bacterial ecosystems (1). Just like there are four unique blood groups that can classify every human, we also have three distinct bacterial systems. Once one of these systems becomes established in the gut, it begins to alter the gut environment that only certain species of other bacteria can follow and safely begin their symbiotic relationship with us.

So how does each ecosystem of bacteria keep out the bad apples (like Salmonella)? First of all, the bacteria in each distinct ecosystem have to alert our own immune cells in the intestine that they are friends, not foes. Apparently they have learned how to suppress the immune system in our own cells so they can co-exist in our gut (2). However, I believe even though these ecosystems of bacteria can be recognized as friends and not foes, they still need unique nutrients to help them act as the first line of defense against millions of other harmful bacteria.

Those nutrients are polyphenols. In the plant world, these polyphenols act as antibiotics against microbial attack. There is evidence that the “good” bacteria in our gut can use them as a means to help ward off invading bacteria that threaten our own unique bacterial fingerprint. Of course, the only way we can continue to help our unique bacterial partners in our gut is to continue to eat lots of fruits and vegetables that are rich in polyphenols. That’s why your grandmother told you to eat an apple a day to keep the doctor away.

References

  1. Arumugam M, Raes J, Pelletier E, et al. “Enterotypes of the human gut microbiome.” Nature DOI: 10.1038/nature09944 (2011)
  2. Round JL, Lee SM, Li Jennifer, Tran G, Bana J, Chatila TA and Mazmanian SK. “The toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota.” Science DOI:10.1126/scienc.1206095 (2011)
  3. Moreno S, Scheyer T, Romano CS, and Vojnov AA. “Antioxidant and antimicrobial activities of rosemary extracts linked to their polyphenol composition.” Free Radic Res 40: 223-231 (2006)

Nothing contained in this blog is intended to be instructional for medial diagnosis or treatment. If you have a medical concern or issue, please consult your personal physician immediately.

Zone diet validation studies

Weight Loss

Any diet that restricts calories will result in equivalent weight loss. However, the same doesn’t hold true as to what the source of that weight loss is. Weight loss from either dehydration (such as ketogenic diets) or cannibalization of muscle and organ mass (such as low-protein diets) has no health benefits. Only when the weight loss source is from stored fat do you gain any health benefits. Here the Zone diet has been shown to be superior to all other diets in burning fat faster (1-4). It has been demonstrated that if a person has a high initial insulin response to a glucose challenge, then the Zone diet is also superior in weight loss (5,6). A recent study from the New England Journal of Medicine indicates that a diet composition similar to the Zone diet is superior to other compositions in preventing the regain of lost weight (7). This is probably caused by the increased satiety induced by the Zone diet compared to other diets (1,8,9).

Reduction of cellular inflammation

There is total agreement in the research literature that the Zone diet is superior in reducing cellular inflammation (10-12). Since cellular inflammation is the driving force for chronic disease, then this should be the ultimate goal of any diet. Call me crazy for thinking otherwise.

Heart disease

It is ironic that the Ornish diet is still considered one of the best diets for heart disease, since the published data indicates that twice as many people had fatal heart attacks on the Ornish diet compared to a control diet (13). This is definitely the case of don’t confuse me with the facts. On the other hand, diets with the same balance of protein, carbohydrate and fat as the Zone diet has have been shown to be superior in reducing cardiovascular risk factors, such as cholesterol and fasting insulin (14,15).

Diabetes

The first publication validating the benefits of the Zone diet in treating diabetes appeared in 1998 (16). Since that time there have been several other studies indicating the superiority of the Zone diet composition for reducing blood glucose levels (17-20). In 2005, the Joslin Diabetes Research Center at Harvard Medical School announced its new dietary guidelines for treating obesity and diabetes. These dietary guidelines were essentially identical to the Zone diet. Studies done at the Joslin Diabetes Research Center following those dietary guidelines confirm the efficacy of the Zone diet to reduce diabetic risk factors (21). If the Zone diet isn’t recommended for individuals with diabetes, then someone should tell Harvard.

Ease of use

The Zone diet simply requires balancing one-third of your plate with low-fat protein with the other two-thirds coming from fruits and vegetables (i.e. colorful carbohydrates). Then you add a dash (that’s a small amount) of heart-healthy monounsaturated fats. The Zone diet is based on a bell-shaped curve balancing low-fat protein and low-glycemic-index carbohydrates, not a particular magic number. If you balance the plate as described above using your hand and your eye, it will approximate 40 percent of the calories as carbohydrates, 30 percent of calories as protein, and 30 percent of the calories as fat. Furthermore, it was found in a recent Stanford University study that the Zone diet provided greater amounts of micronutrients on a calorie-restricted program than any other diet (22).

Eventually all dietary theories have to be analyzed in the crucible of experimentation to determine their validity. So far in the past 13 years since I wrote my first book, my concepts of anti-inflammatory nutrition still seem to be at the cutting edge.

References

  1. Skov AR, Toubro S, Ronn B, Holm L, and Astrup A. “Randomized trial on protein vs carbohydrate in ad libitum fat reduced diet for the treatment of obesity.” Int J Obes Relat Metab Disord 23: 528-536 (1999)
  2. Layman DK, Boileau RA, Erickson DJ, Painter JE, Shiue H, Sather C, and Christou DD. “A reduced ratio of dietary carbohydrate to protein improves body composition and blood lipid profiles during weight loss in adult women.” J Nutr 133: 411-417 (2003)
  3. Fontani G, Corradeschi F, Felici A, Alfatti F, Bugarini R, Fiaschi AI, Cerretani D, Montorfano G, Rizzo AM, and Berra B. “Blood profiles, body fat and mood state in healthy subjects on different diets supplemented with omega-3 polyunsaturated fatty acids.” Eur J Clin Invest 35: 499-507 (2005)
  4. Layman DK, Evans EM, Erickson D, Seyler J, Weber J, Bagshaw D, Griel A, Psota T, and Kris-Etherton P. “A moderate-protein diet produces sustained weight loss and long-term changes in body composition and blood lipids in obese adults.” J Nutr 139: 514-521 (2009)
  5. Ebbeling CB, Leidig MM, Feldman HA, Lovesky MM, and Ludwig DS. “Effects of a low-glycemic-load vs low-fat diet in obese young adults: a randomized trial.” JAMA 297: 2092-2102 (2007)
  6. Pittas AG, Das SK, Hajduk CL, Golden J, Saltzman E, Stark PC, Greenberg AS, and Roberts SB. “A low-glycemic-load diet facilitates greater weight loss in overweight adults with high insulin secretion but not in overweight adults with low insulin secretion in the CALERIE Trial.” Diabetes Care 28: 2939-2941 (2005)
  7. Larsen TM, Dalskov SM, van Baak M, Jebb SA, Papadaki A, Pfeiffer AF, Martinez JA, Handjieva-Darlenska T, Kunesova M, Pihlsgard M, Stender S, Holst C, Saris WH, and Astrup A. “Diets with high or low protein content and glycemic index for weight-loss maintenance.” N Engl J Med 363: 2102-2113 (2010)
  8. Ludwig DS, Majzoub JA, Al-Zahrani A, Dallal GE, Blanco I, Roberts SB, Agus MS, Swain JF, Larson CL, and Eckert EA. “Dietary high-glycemic-index foods, overeating, and obesity.” Pediatrics 103: E26 (1999)
  9. Agus MS, Swain JF, Larson CL, Eckert EA, and Ludwig DS. “Dietary composition and physiologic adaptations to energy restriction.” Am J Clin Nutr 71: 901-907 (2000)
  10. Pereira MA, Swain J, Goldfine AB, Rifai N, and Ludwig DS. “Effects of a low-glycemic-load diet on resting energy expenditure and heart disease risk factors during weight loss.” JAMA 292: 2482-2490 (2004)
  11. Pittas AG, Roberts SB, Das SK, Gilhooly CH, Saltzman E, Golden J, Stark PC, and Greenberg AS. “The effects of the dietary glycemic load on type 2 diabetes risk factors during weight loss.” Obesity 14: 2200-2209 (2006)
  12. Johnston CS, Tjonn SL, Swan PD, White A, Hutchins H, and Sears B. “Ketogenic low-carbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets.” Am J Clin Nutr 83: 1055-1061 (2006)
  13. Ornish D, Scherwitz LW, Billings JH, Brown SE, Gould KL, Merritt TA, Sparler S, Armstrong WT, Ports TA, Kirkeeide RL, Hogeboom C, and Brand RJ, “Intensive lifestyle changes for reversal of coronary heart disease.” JAMA 280: 2001-2007 (1998)
  14. Wolfe BM and Piche LA. “Replacement of carbohydrate by protein in a conventional-fat diet reduces cholesterol and triglyceride concentrations in healthy normolipidemic subjects.” Clin Invest Med 22: 140-1488 (1999)
  15. Dumesnil JG, Turgeon J, Tremblay A, Poirier P, Gilbert M, Gagnon L, St-Pierre S, Garneau C, Lemieux I, Pascot A, Bergeron J, and Despres JP. “Effect of a low-glycaemic index, low-fat, high-protein diet on the atherogenic metabolic risk profile of abdominally obese men.” Br J Nutr 86:557-568 (2001)
  16. Markovic TP, Campbell LV, Balasubramanian S, Jenkins AB, Fleury AC, Simons LA, and Chisholm DJ. “Beneficial effect on average lipid levels from energy restriction and fat loss in obese individuals with or without type 2 diabetes.” Diabetes Care 21: 695-700 (1998)
  17. Layman DK, Shiue H, Sather C, Erickson DJ, and Baum J. “Increased dietary protein modifies glucose and insulin homeostasis in adult women during weight loss.” J Nutr 133: 405-410 (2003)
  18. Gannon MC, Nuttall FQ, Saeed A, Jordan K, and Hoover H. “An increase in dietary protein improves the blood glucose response in persons with type 2 diabetes.” Am J Clin Nutr 78: 734-741 (2003)
  19. Nuttall FQ, Gannon MC, Saeed A, Jordan K, and Hoover H. “The metabolic response of subjects with type 2 diabetes to a high-protein, weight-maintenance diet.” J Clin Endocrinol Metab 2003 88: 3577-3583 (2003)
  20. Gannon MC and Nuttall FQ. “Control of blood glucose in type 2 diabetes without weight loss by modification of diet composition.” Nutr Metab (Lond) 3: 16 (2006)
  21. 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 (2008)
  22. Gardner CD, Kim S, Bersamin A, Dopler-Nelson M, Otten J, Oelrich B, and Cherin R. “Micronutrient quality of weight-loss diets that focus on macronutrients: results from the A TO Z study.” Am J Clin Nutr 92: 304-312 (2010)

Nothing contained in this blog is intended to be instructional for medial diagnosis or treatment. If you have a medical concern or issue, please consult your personal physician immediately.