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Phenotypic Nutrition

December 2005

By Steven V. Joyal, MD

Glucose and Dietary Carbohydrates

The Mediterranean diet is rich in whole grains, fruits, vegetables, and fat from fish, nuts, and olives. Low in rapidly digested simple carbohydrates, this diet is helpful in decreasing genetic expression of fat-storage enzymes activated by high amounts of dietary carbohydrates.

Scientists have realized that in addition to the key regulatory hormone insulin, glucose itself plays a critical role in helping to regulate glucose metabolism and fat storage (lipogenesis). Decreased ChREBP gene expression results in decreased fat-storage gene expression, thereby demonstrating the direct implication of ChREBP in glucose action and fat storage.29

Randomized clinical trials have shown that high-carbohydrate/low-fat diets accentuate the metabolic abnormalities of patients with glucose dysregulation such as diabetes. For example, a trial evaluated patients with type II diabetes mellitus after they were randomly placed on diets comprising either 55% carbohydrates, 30% fat, and 15% protein, or 40% carbohydrates, 45% fat, and 15% protein for six weeks, followed by crossover to the other diet. The high-carbohydrate/low-fat diet in patients with type II diabetes led to:

  • higher day-long plasma glucose, insulin, and triglyceride concentrations
  • postprandial accumulation of triglyceride-rich lipoproteins from the intestine
  • increased production of very low-density lipoprotein-triglyceride (VLDL-TG).30

Simply stated, in people with impaired blood glucose control, a diet high in carbohydrates will cause gene expression to activate enzymes involved in fat storage. Furthermore, a diet moderate in carbohydrates and relatively high in monounsaturated fat from olive oil and polyunsaturated fatty acids from fish, such as the Mediterranean diet, has been shown in prospective, randomized clinical trials to decrease insulin resistance, improve endothelial function, and decrease markers of inflammation.31 Also, this dietary approach may be better than the National Cholesterol Education Program’s Step 1 prudent diet in preventing cardiac events.32

Other prospective clinical trials have shown that replacing carbohydrate calories with calories from nuts such as almonds, which are rich in monounsaturated and polyunsaturated fats, reduces many of the metabolic abnormalities associated with metabolic syndrome.33

Clearly, a Mediterranean-type diet low in simple sugars and rich in vegetables, fruits, fish, nuts, olive oil, and whole grains is an ideal dietary strategy for helping to prevent metabolic syndrome.


Inflammation and associated insulin resistance play a critical role in the development of metabolic syndrome and type II diabetes.34,35 Nutrients that act to down-regulate genes involved in inflammation are critical to preventing metabolic syndrome.

Quercetin, a potent bioflavonoid found in vegetables, has been shown to inhibit the genetic expression of pro-inflammatory cytokines through inhibition of the NfkB pathway both in cell studies and animal trials.36

Along with quercetin, the bioflavonoid resveratrol, found in the skin of red fruits like grapes, has been shown in molecular pre-clinical studies to inhibit NfkB and cAMP response element binding protein-dependent, pro-inflammatory gene transcription to a greater extent than the potent cortico-steroid dexamethasone.37

The benefits of olive polyphenols are striking. Olive polyphenols have direct effects on the expression of genes involved in the vascular endothelium (the lining of blood vessel walls). At nutritionally relevant concentrations, hydroxytyrosol, a principal polyphenol in olives, reduced cell “stickiness” to the vascular endothelium by decreasing genetic expression for NfkB of vascular cell adhesion molecule-1 (VCAM-1) messenger RNA (mRNA).38

Furthermore, pre-clinical studies have shown that olive oil with a higher content of polyphenolic compounds shows protective effects in models of inflammation.39 Other pre-clinical studies have shown that olive polyphenols dramatically increase the resistance of LDL to oxidation.40 Oxidized LDL is a potent trigger for atherosclerosis.41


Vitamin E is an important nutrient in preventing metabolic syndrome, as it helps regulate several genes affecting cardiovascular disease risk:42

  • Genes that are associated with lipid uptake and atherosclerosis (CD36, SR-BI, and SR-AI)
  • Genes that are related to inflammation, cell adhesion, and platelet aggregation (E-selectin, ICAM-1, integrins, glycoprotein IIb, IL-2, IL-4, and IL-beta).

Furthermore, the appropriate genetic regulation of glucose transport protein (GLUT-3) is critical to optimal blood glucose control. Studies have shown that both aging and vitamin E deficiency are associated with decreased expression of GLUT-3.43

Carotenoids and Retinoids

Using data from the Third National Health and Nutrition Examination Survey (1988-1994), researchers evaluated the intake of vitamins A and C, retinyl esters, five carotenoids, and other trace nutrients in 8,808 US adults aged 20 and older with and without metabolic syndrome. After adjusting for factors like age, sex, ethnicity, education, smoking status, and physical activity, they found that individuals with metabolic syndrome had significantly lower concentrations of retinyl esters, vitamin C, and carotenoids, except lycopene.44

Vitamin A is particularly important in preventing metabolic syndrome, given research showing that vitamin A plays a role in the regulation of genes involved in systemic insulin resistance. Specifically, researchers have shown that retinoic acid, the acid form of vitamin A, is a signal that inhibits the expression of resistin, an adipocyte-secreted protein previously proposed to act as an inhibitor of adipocyte differentiation and as a systemic insulin resistance factor.45

Pre-clinical models of early development have also shown that suboptimal intake of vitamin A decreases insulin-producing cells, and that this reduction can be attributed to a reduced rate of fetal beta-cell replication. This could potentially contribute to impaired glucose tolerance later in adult life.46


High-risk blood parameters
• Triglycerides > 130 mg/dL
• Triglycerides/HDL ratio > 3.0
• Insulin > 15 µU/mL
• C-reactive protein > 3.00 mg/L
• DHEA < 400 mcg/dL (men);< 350 mcg/dL (women)

Dietary strategy
• Avoid refined carbohydrates (for example, white flour, soda, potato chips, bagels) and saturated fats (such as bacon, beef, and tropical oils)
• Emphasize fish, nuts, olive oil, vegetables, and whole fruits

Nutraceutical strategy
• DHEA: 10-50 mg per day to start (men), 10-30 mg per day to start (women); assess effect via repeat blood test
• EPA/DHA: 2 capsules twice daily
• Lipoic acid: 150 mg once or twice daily
• Mixed bioflavonoids: 1400 mg twice daily
• Mixed tocopherols: 400 IU twice daily with mixed tocotrienols (75 mg twice daily)
• Vitamin A: 5000 IU per day, with mixed carotenoids (for example, lutein 5000 mcg, lycopene 3000 mcg, and zeaxanthin 360 mcg) daily
• Water-soluble cinnamon extract: 85 mg three times daily, 30 minutes before meals
• Barley extract: 2.5 grams three times daily with meals
• Pycnogenol: 200 mg daily
• Coffee extract standardized for 50% phenolic acids: 100 mg three times daily, 30 minutes before meals

Exercise strategy
• Moderate aerobic activity: 3-5 days per week for 20-40 minutes per session

Cinnamon Extracts

Figure 4: Effects of Malted Barley Extract on Fasting Blood Glucose Levels in Genetically Diabetic Mice

In clinical trials, cinnamon has demonstrated remarkable effects on glucose control.

In 2003, a placebo-controlled study of type II diabetes patients who were given one, three, or six grams a day of cinnamon or placebo showed that after 40 days, all three levels of cinnamon reduced mean fasting serum glucose by 18-29%, triglycerides by 23-30%, LDL by 7-27%, and total cholesterol by 12-26%. No significant changes were noted in the placebo groups.47

Cinnamon also has been shown to have excellent antioxidant properties. Natural water-soluble cinnamon extract has been shown to inhibit oxidation by 88%, while a synthetic antioxidant control, butylated hydroxytoluene, inhibited oxidation by only 80%.48

Water-soluble polyphenol polymers (polyphenol type-A polymers) from cinnamon increase insulin-dependent glucose metabolism in vitro. These polymers have recently been characterized by nuclear magnetic resonance and mass spectroscopy.49

The polyphenol type-A polymers from cinnamon up-regulate expression of genes involved in activation (phosphorylation) of the insulin receptor and increase glucose uptake in cell studies.50 In other cell studies, other cinnamon polyphenol polymers such as methylhydroxychalcone have been shown to be potent insulin mimics.51

Barley Extracts

Purine adenine derivatives called cytokinins (not to be confused with the pro-inflammatory glycoproteins called cytokines) have been shown to control ribosomal RNA (rRNA) in barley.52 Furthermore, cytokinin genes in barley have recently been cloned.53

In pre-clinical studies, cytokinin-rich barley extract has been shown to alleviate many diabetes symptoms, including fasting serum glucose, in genetically obese mice, without affecting insulin levels.54

Most compelling is that the barley extract appears to function similarly to the drug metformin, known to dramatically improve plasma glucose in patients with type II diabetes. Cell study data show that barley extract inhibits gluconeogenesis (creation of new glucose molecules) in liver cells.55

Human pilot studies have also been impressive. The preliminary data show that barley extract reduced fasting and postprandial glucose levels in type II diabetes, reduced the LDL/HDL ratio, improved postprandial (after-meal) glucose, and improved glucose transport into muscle cells.55

Coffee Polyphenols

Several published studies associate coffee consumption with a dramatically reduced risk of type II diabetes.

For example, a large study (involving 16,670 men and women) published in JAMA in 2004 showed a very strong relationship between increased coffee consumption and decreased risk of developing type II diabetes mellitus.56 Another very large study that followed 41,934 men from 1986 to 1998, and 84,276 women from 1980 to 1998, showed a similar, powerful association between greater coffee intake and reduced risk for type II diabetes after adjusting for age, body mass index, and other risk factors.57

Water extracts of roasted coffee residues, including the primary coffee polyphenols caffeic acid and chlorogenic acid, have also been found to scavenge free radicals and offer protection against lipid peroxidation and the oxidative damage of protein.58

Found in relatively abundant amounts in coffee beans, chlorogenic acid is also found in blueberries, apples, and eggplant. Animal studies have shown that chlorogenic acid improves glucose tolerance, decreases fasting plasma cholesterol and triglycerides, and improves mineral pool distribution.59

Clinical studies have shown that chlorogenic acid delays glucose absorption and improves gastrointestinal hormone secretion. For example, a randomized crossover study in healthy volunteers showed that consuming 400 mL of decaffeinated coffee (equivalent to 2.5 mmol of chlorogenic acid per liter) significantly increased glucagon-like peptide 1 (GLP-1) secretion after meals compared to controls.60

The association between chlorogenic acid and GLP-1 is particularly remarkable. Several GLP-1-related pharmaceutical agents are mimicking this hormone as a treatment for type II diabetes mellitus, including the recently FDA-approved GLP-1 analog BYETTA™ (exenatide). Chlorogenic acid acts to increase GLP-1 and delay glucose absorption, thereby maintaining the responsiveness of the insulin-producing beta cells of the pancreas.61

Ferulic acid, another water-soluble coffee extract, improves blood vessel relaxation and decreases levels of homocysteine, an independent cardiovascular risk factor.62


You are not doomed to disease by “bad genes”!

Phenotypic nutrition enables you to choose dietary strategies and nutrients that influence powerful biochemical and genetic factors to help control the expression of your genetic code to your benefit.

In a prevention program to guard against metabolic syndrome, the first step is identifying if you are at high risk. This can easily be accomplished by checking simple blood tests of triglycerides, insulin, HDL, CRP, and DHEA. Next, select specific nutritional strategies to beneficially influence the expression of your genetic code and biochemical make-up to decrease your disease risk.

It is up to you—help control your own genetic destiny, or roll the dice and hope for the best.


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55. Available at: Accessed September 6, 2005.

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