Life Extension Magazine August 2008
Insulin Resistance—A Lethal Link Between Metabolic Disease and Heart Attack
By William Davis, MD
By William Davis, MD
Due to multimillion dollar advertising and marketing campaigns by the pharmaceutical industry, patients and physicians alike seem to associate heart attack and stroke risk only with cholesterol. Drugs that lower cholesterol (statins), have created a windfall of profit for pharmaceutical companies, with a single company’s statin drug often exceeding several billion dollars in annual sales. However, cardiovascular risk entails far more than just elevated cholesterol levels.
In fact, the phenomenon known as insulin resistance offers a direct link between metabolic disease and cardiovascular risk, and is an often overlooked culprit underlying diabetes and heart disease. Learn how and why these two common diseases are intimately related and how to untangle them from your life.
How are Blood Sugar and Plaque Related?
Diabetes and heart disease are intertwined from the start, sharing a complex panel of hidden phenomena that lay the foundation for both conditions. If diabetes is present, heart disease is much more likely to develop. If heart disease develops, it is far more likely that diabetes will also.
The shared misfortune of diabetes and heart disease emerged with Dr. Steven Haffner’s 1998 report from the University of Texas that people with diabetes who do not have heart disease have the same risk for heart attack as people with established heart disease—the risk is one and the same.1 In 1999, the American Heart Association went on to label diabetes “a cardiovascular disease.”
Since then, more studies have established this link. A 2001 study of people with stable heart disease but no previous history of diabetes found that approximately 50% of subjects had newly diagnosed disturbances of glucose metabolism (16% had full-blown diabetes and 36% had impaired glucose tolerance).2 Another recent study in persons hospitalized with more advanced, unstable heart disease symptoms (“unstable angina”) uncovered that 66% of those who met the criteria for diabetes were not diagnosed as such by their treating physician.3 In addition, the more extensive the heart disease identified, the higher the blood sugars tended to be. These insights provide us with strategies that could help diminish the likelihood of both diabetes and heart disease.
Insulin Resistance—Root of the Problem
The majority of people with heart disease and diabetes have, often buried years earlier in their past, a pattern of poor responsiveness to insulin, or “insulin resistance.” Once this phenomenon becomes established, the stage is set.
Insulin is the hormone that helps the cells and tissues of the body use glucose. An autoimmune process, whereby the body’s immune system attacks the insulin-producing cells of the pancreas, is the defect behind type 1 diabetes. This is a different process from so-called ‘adult-onset’, or type 2, diabetes.
Type 2 diabetes in adults represents a metabolic imbalance of both insulin secretion and insulin action at the cellular level, as opposed to the absolute deficiency of insulin observed with type 1 diabetes. In patients with type 2 diabetes, a number of factors lead to a poor response to insulin in muscle, fat, and liver. In essence, tissue cells become less responsive to insulin. This triggers the pancreas to overcompensate by producing greater quantities of insulin. Blood levels of insulin double, triple, even quadruple as the pancreas struggles to overpower the body’s poor responsiveness to insulin. This is the situation called “insulin resistance.”
For reasons that have yet to be understood, an overworked pancreas cannot meet the increased demand for insulin for long. After just a few years, the insulin-producing beta cells of the pancreas begin to “burn out” and blood sugar rises. Rising blood sugar is therefore a sign of insulin resistance.
Insulin resistance is present in 90% or more of people with diagnosed diabetes.4 In all practicality, adult-onset, or type 2, diabetes is synonymous with poor sensitivity to insulin.
Insulin resistance is an underlying cause of a number of metabolic abnormalities that are grouped together in a condition called the metabolic syndrome. This disorder is associated with a host of undesirable consequences such as rising blood sugar, increased triglycerides, which lead to a reduction in beneficial high-density lipoprotein (HDL) and an increase in dangerous, small low-density lipoprotein (LDL) particles, greater risk for blood clotting, and high blood pressure.4,5
The list of metabolic phenomena triggered by insulin resistance should appear familiar—these are also risk factors for coronary atherosclerosis.4
More About Metabolic Syndrome
Metabolic syndrome is known by a number of different names—insulin resistance syndrome, syndrome X, borderline diabetes, among others and is typically associated with increased triglycerides, reduced HDL, heightened inflammation, three-fold or greater risk of heart attack,6 greater risk for stroke, and diabetes.
Metabolic syndrome can drive the growth of atherosclerotic plaque even when everything else, like LDL, is corrected to perfect levels. Even with excellent LDL levels, for instance, hidden atherosclerotic heart disease can continue to grow at an alarming rate.
The first step in guarding against insulin resistance and metabolic syndrome is to gauge one’s risk through simple tests such as triglycerides, insulin, blood pressure, HDL, C-reactive protein, and dehyroepiandro-sterone (DHEA). You and your doctor should suspect insulin resistance and metabolic syndrome if:
The likelihood of developing metabolic syndrome also escalates sharply above a body mass index (BMI) of 27. Keep in mind that these cut-offs are somewhat arbitrary and that lesser degrees of insulin resistance can be present before these cut-off points are fully reached.
Some leading researchers advocate detecting risk of insulin resistance and metabolic syndrome by measuring waist size. If waist circumference is >35 inches in a female or >40 inches in a male, then metabolic syndrome is a high risk.7,8
Insulin Resistance and Inflammation
Insulin resistance is also associated with inflammation, as reflected by increased levels of the inflammatory markers nuclear factor-kappa B, interleukin-6, and C-reactive protein (CRP).5,9 C-reactive protein is the blood test that has emerged as a valuable tool to gauge hidden, imperceptible inflammation. Studies have consistently shown that the higher the CRP, the brighter the flame of inflammation that burns in the body and the greater the likelihood of heart attack and diabetes.10-12
In addition, insulin resistance triggers abnormalities in a recently recognized group of signaling molecules called adipokines.13 Fat cells, particularly those in the abdomen (“central obesity”), assume a life of their own and begin to act just like an independent new organ of the body, producing dozens of these unique substances. The adipokine, leptin, for instance, is produced by abdominal fat cells and causes white blood cells called macrophages to grab cholesterol particles, a phenomenon believed to add to coronary atherosclerosis. Tumor necrosis factor-alpha (TNF-alpha), another potent adipokine, activates inflammatory responses in vascular tissue and increases release of adhesive molecules, both of which add to atherosclerosis.5,14,15 Increased adipose tissue mass contributes to increased secretion of proinflammatory cytokines, especially TNF-alpha.15
Increasing Insulin Sensitivity and Reducing Inflammation
The key to reducing or eliminating many of the threats of both metabolic syndrome/insulin resistance and heart disease is to chip away at the root cause of both and increase insulin sensitivity. Correct this fundamental defect and correction of multiple other phenomena will follow—HDL will increase, small LDL particles will be reduced, and triglycerides will plummet. The blood-clotting protein fibrinogen will also drop while physical stamina and energy will increase.
Likewise, hidden inflammation that fuels both heart disease and metabolic syndrome will be powerfully reduced.
In most cases, insulin resistance, inflammation, and CRP can usually be reduced effectively and dramatically—usually to normal—just by using the nutritional supplements and lifestyle strategies discussed below. Furthermore, achieving glycemic control in patients with insulin resistance through lifestyle and nutritional interventions can effectively prevent or delay the development of cardiovascular problems and complications.
As you will read, given the right kind of information, drugs are not always necessary, perhaps rarely.
Lifestyle strategies that help correct insulin sensitivity, reduce hidden inflammation (CRP), and thereby contribute to reducing the likelihood of heart disease and diabetes include:
Exercise. For improvement of insulin sensitivity, at least 30 minutes of physical activity per day is required for benefit, preferably 60 minutes. Also, the more frequent your efforts, the better. Exercise can scale down inflammation, as well. An Israeli experience in 28 patients with coronary heart disease showed that 12 weeks of aerobic exercise at 70–80% of maximum heart rate reduced CRP by 19% in non-diabetics and by 40% in diabetics.16 Strength training with weights or resistance machines also helps by increasing basal metabolic rate and accelerating fat loss. Twenty minutes twice a week of strength training can accelerate progress tremendously.
Weight loss (if overweight). Weight loss yields the most dramatic effect of all for both improving insulin response and reducing inflammation. Weight reduction yields dramatic drops in CRP.17-19 The principal determinant is the amount of weight lost, not the means by which you achieve it.18–20
Healthy foods. Choose foods rich in soluble fiber and lower in glycemic load (i.e. the total amount of sugar and carbohydrate calories). The best foods are raw nuts and seeds, oat bran, lean proteins, and omega-3 fatty acids. Some dietary approaches may pack a greater effect than others (see below). Dietary strategies such as replacing saturated fat with healthy oils like olive, canola, and flaxseed (for monounsaturates); selecting lower glycemic-load foods such as lean proteins, whole grain products, and vegetables; and avoiding foods like processed white flour and white sugar-laden foods like cookies, crackers, candies, and cakes will help subdue inflammation and improve insulin response.21-23
The Mediterranean diet is one effective approach to improve insulin responses and reduce inflammation. The Greek ATTICA Study of over 3,000 men and women yielded 20% reduction of CRP in participants who most closely adhered to a traditional Mediterranean diet. The diet includes plentiful olive oil (a rich source of monounsaturated fat), vegetables and fruits, nuts, and fish, with little or no processed foods.24 Several other studies have demonstrated improvement in insulin responses and reduction of blood sugar on the Mediterranean diet.23,25,26
A major boost in soluble fiber intake may also increase success in reducing inflammation and insulin responses. David Jenkins, MD, PhD, DSc, at the Clinical Nutrition & Risk Factor Modification Center in Toronto has acquired a fascinating experience using an approach he calls “the dietary portfolio” of cholesterol-lowering foods.
In one study, 46 participants followed a four-week nutrition program that added the following nutrients per 1,000 kcal of subjects’ total intake: 1.0 gram of phytosterols (high in plant sterols), 9.8 grams viscous, or soluble, fibers such as oat bran and oat products, barley, and psyllium seed, 21.4 grams soy protein, and 14 grams raw almonds. (An average 2,400 kcal diet would provide 2.4 grams phytosterols, 24 grams viscous fiber, 51 grams soy protein, and 34 grams almonds.) Participants averaged a fiber intake of 78 grams/day, which is five times more fiber than the average American consumes.27 A control group followed a very low saturated fat, dairy, and whole grain cereal diet, rather than foods containing viscous fibers and plant sterols.28
Dr. Jenkins’ dietary portfolio achieved an LDL reduction of 29% and a 28% reduction in CRP, compared with the control group who achieved only 8% reduction in LDL and 10% reduction in CRP. Another treatment group on the control diet received treatment with the cholesterol drug, lovastatin (Mevacor®), but performed no better than the dietary portfolio group.28
Dr. Jenkins’ dietary portfolio and other studies have also shown that abundant fiber intake, especially viscous or soluble fibers, slows the release of sugars into the bloodstream and thereby blunts excessive insulin responses. Improvements in insulin sensitivity and blood glucose responses have also been demonstrated in several other studies.29,30
Sleep. Chronic lack of a full night’s sleep impairs insulin function and contributes to the visceral (within abdominal contents) fat accumulation peculiar to metabolic syndrome.31 Maintaining seven to eight hours of sleep per night helps enhance insulin responses.31,32 Melatonin supplementation to restore normal sleep-wakefulness cycles may help improve metabolic syndrome and inflammation.33
The following supplements can help reduce insulin resistance and inflammation in the body:
Fish oil. Omega-3 fatty acids contained in fish oil help in numerous ways.34 Omega-3s effectively reduce the inevitably elevated triglycerides of metabolic syndrome, raise HDL, and reduce inflammation.35-38 Of all their benefits, the triglyceride-reducing power of omega-3s represents their most powerful effect, which is likely responsible for the dramatic reduction in heart attack and stroke seen with supplementation.39-41 Approximately 1,400 mg eicosapentaenoic acid and 1,000 mg docosahexaenoic acid are recommended each day for maintaining a healthy heart.
Chromium. Doses of supplemental chromium ranging from 200 mcg/day to 1,000 mcg/day improve blood sugar by enhancing the effects of insulin.42,43 Chromium supplements also offer a useful adjunct to diabetic patients on sulfonylurea therapy, which is normally associated with weight gain when taken alone. In a recent study in adult diabetics, the usual weight gain seen with sulfonylurea therapy was significantly reduced by supplementing with chromium picolinate, 1,000 mcg/day.43 Other studies have demonstrated that chromium supplementation safely reduces cholesterol and triglyceride levels, and may reduce requirements for oral antidiabetes medication.44
White bean extract. This extract of the common white bean, Phaseolus vulgaris, is a starch blocker that blocks intestinal carbohydrate absorption by up to 66%. A recent randomized, placebo-controlled study showed that 445 mg of white bean extract twice daily in overweight adults led to 6.4 pounds of weight loss (while maintaining lean body mass) after 30 days compared with only 0.8 pounds in non-treated subjects.45
White bean extract also improves insulin responses by reducing sugar absorption and through weight loss.45
DHEA. When taken at bedtime, this adrenal gland hormone enhances mobilization of abdominal fat that contributes to metabolic syndrome, insulin resistance, and inflammation.46 Life Extension recommends the usual dose range for aging men and women is 15-75 mg daily. Ideally, DHEA-S blood levels should be obtained three to six weeks after dosing to assess individual response.46 Men and women with hormone-responsive cancers should only supplement with DHEA after clearance by their personal physician.
Vitamin D. Numerous exciting reports about vitamin D’s myriad beneficial effects include recent observations that vitamin D deficiency contributes to insulin resistance and raises blood pressure (by increasing the blood pressure-raising hormone renin).47 Vitamin D deficiency is exceedingly common, particularly in northern climates, where up to 90% of people have moderate-to-severe deficiency. In sun-deprived climates, 1,000–4,000 IU/day may be required to raise blood levels to normal, occasionally more. Most people who lack sun exposure can safely take 2,000 IU/day.48 However, adequate sun exposure does not necessarily guarantee optimal vitamin D levels.49 Vitamin D status can be assessed by having one’s blood tested. Optimal levels are considered to be in the range of 30-50 ng/mL (75-125 nmol/L) of 25-hydroxyvitamin D in the blood. (Discuss vitamin D supplementation with your doctor if you have kidney disease, kidney stones, or a history of high calcium levels.)
Vitamin D is also gaining recognition as a crucial modulator of inflammation. A University of London study demonstrated a dramatic reduction in the inflammatory proteins CRP and matrix metalloproteinase (MMP), after supplementation in 171 healthy adults, with a startling 68% reduction in MMP.50
Magnesium. This mineral is needed for more than 300 biochemical reactions and is recognized as an important mediator of insulin action and in reducing inflammation. In several studies, daily oral magnesium supplementation substantially improved insulin sensitivity by 10% and reduced blood sugar by 37%.51-53 The Women’s Health Study including nearly 12,000 participants showed that people who fail to take the recommended adequate intake of magnesium of 320-420 mg/day are more prone to have both metabolic syndrome and increased CRP.54 Improved sensitivity to insulin generated by magnesium replacement can dramatically reduce triglycerides by as much as 75 mg/dL.53 Reduced triglyceride availability, in turn, reduces the triglyceride-rich particles, very low-density lipoprotein (VLDL) and small LDL, which are powerful contributors to heart disease. Magnesium supplementation can also raise levels of beneficial HDL.55,56
Magnesium deficiency is common not only from a dietary standpoint, but is also becoming an even larger issue as people turn to bottled water, which contains hardly enough magnesium, and as municipal water treatment more intensively “softens” its water by removing magnesium.
Even the federal government admits that many Americans do not obtain the recommended amount of magnesium, which is 320 mg/day for women and 420 mg/day for men.57 Magnesium supplementation is therefore a basic requirement for health for most people. (Discuss this with your doctor if you have kidney disease or electrolyte disorders.)
Flavonoids. Naturally occurring flavonoid compounds are important for suppressing inflammation. Emerging research suggests that some flavonoids also enhance insulin response and reduce insulin resistance. Of the thousands of known flavonoids identified, several, including polyphenols and resveratrol, stand out for these benefits.
Polyphenols derived from green tea, cocoa, and apples are emerging as powerful facilitators of insulin responses as well as being potent anti-inflammatory compounds.58-60 A study comparing the effects of dark chocolate, containing beneficial cocoa polyphenols, with white chocolate (non-cocoa), 100 grams per day for 15 days, showed that only dark chocolate improved insulin sensitivity.61 Another study in 10 healthy volunteers showed that 37 grams of dark chocolate (containing 148 mg of procyanidins) yielded a 29% decrease in inflammatory leukotrienes and a 32% increase in the anti-inflammatory prostacyclin compared with subjects who received chocolate containing only 33 mg of procyanidins.58 This net decrease in the plasma leukotriene-prostacyclin ratio, a measure of proinflammatory-anti-inflammatory eicosanoid balance, dissipated six hours after subjects ingested the chocolate, suggesting that consumption of flavonoid sources several times a day is more likely to yield maximum benefit.58
Cocoa polyphenols also work in synergy with beta glucans, which offer an excellent source of low-glycemic carbohydrates. Beta glucans are an excellent form of soluble dietary fiber that help modulate the body’s response to carbohydrate-containing foods,62-64 promote satiety and weight loss,65 and lower CRP levels.66
Researchers have also found that cinnamon helps to diminish the dangerous after-meal surge in blood glucose,67 due to water-soluble polyphenols contained in this spice.68
Resveratrol, a flavonoid found in grape skins and concentrated in red wine, has also attracted a good deal of research attention. Red wine, 12 oz/day, has been found to improve insulin responses in people with diabetes. Resveratrol suppresses inflammatory mediators and powerfully inhibits matrix metalloproteinase, a trigger for atherosclerotic plaque rupture that results in heart attack and stroke.69 In data extrapolated from animal studies, resveratrol doses of at least 20 mg/day are necessary to protect against heart disease.70 A glass of red wine (about 6 oz or 180 mL) averages just 500 mcg of resveratrol.71 In addition, resveratrol content in red wines varies enormously depending on type of grape, soil characteristics, methods of barreling, etc., but averages around only 2.5 mg/L.71 Non-drinkers and those seeking protection for a healthy heart can obtain resveratrol as a standalone supplement, or mixed with other flavonoids.
The powerful antioxidant supplement, lipoic acid, is also a useful strategy to curtail inflammatory responses and improve insulin responses.72-78 Although much of the research on lipoic acid 600-1,800 mg/day has focused on the improvement of painful nerve conditions associated with type 2 diabetes, lipoic acid also suppresses inflammatory mediators, such as interleukin-6 and plasminogen activator-1.79
Break the Insulin Resistance Connection and Lower Your Risk of Heart Disease and Diabetes
Choosing low glycemic-load foods rich in soluble fiber, getting a full night’s sleep as consistently as possible, exercise, and taking nutritional supplements like fish oil, vitamin D (especially if you are sun-deprived), lipoic acid, magnesium, cinnamon, beta glucans, resveratrol, and polyphenols found in cocoa, green tea, and apples are part of a powerful integrative plan for breaking the insulin resistance connection.
You can chart your progress by periodically measuring a variety of important metabolic and cardiovascular factors.
You want to achieve:
If you have had a lipoprotein analysis, e.g., a VAP® (vertical auto profile) or NMR (nuclear magnetic resonance) test, reducing small LDL to <15% of total LDL can be a helpful secondary measure. Achieving a blood pressure of ≤130/85 mmHg is another important goal.
Remember, decreasing heart disease risk is far more than simply taking a statin drug or making sure that your LDL is within an optimal range. By focusing on improving insulin sensitivity, you can help reduce the risk of heart attack and break the lethal connection between cardiovascular and metabolic diseases!
Dr. William Davis is a practicing cardiologist in Milwaukee, Wisconsin. He is founder of the Track your Plaque program, a heart disease prevention program that shows how to use CT heart scans to control coronary plaque. He can be contacted through www.TrackYourPlaque.com.
If you have any questions on the scientific content of this article, please call a Life Extension Health Advisor at 1-800-226-2370.
1. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998 Jul 23;339(4):229-34.
2. Kowalska I, Prokop J, Bachorzewska-Gajewska H, et al. Disturbances of glucose metabolism in men referred for coronary arteriography. Postload glycemia as predictor for coronary atherosclerosis. Diabetes Care. 2001 May;24(5):897-901.
3. Conaway DG, O’Keefe JH, Reid KJ, Spertus J. Frequency of undiagnosed diabetes mellitus in patients with acute coronary syndrome. Am J Cardiol. 2005 Aug 1;96(3):363-5.
4. Bansilal S, Farkouh ME, Fuster V. Role of insulin resistance and hyperglycemia in the development of atherosclerosis. Am J Cardiol. 2007 Feb 19;99(4A):6B-14B.
5. Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R. Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation. 2005 Mar 22;111(11):1448-54.
6. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002 Dec 4;288(21):2709-16.
7. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-97.
8. Grundy SM, Hansen B, Smith SC, Cleeman JI, Kahn RA. Clinical Management of Metabolic Syndrome. Circulation. 2004;109:551-6.
9. Bluher M, Fasshauer M, Tonjes A, et al. Association of interleukin-6, C-reactive protein, interleukin-10 and adiponectin plasma concentrations with measures of obesity, insulin sensitivity and glucose metabolism. Exp Clin Endocrinol Diabetes. 2005 Oct;113(9):534-7.
10. Dandona P. Effects of antidiabetic and antihyperlipidemic agents on C-reactive protein. Mayo Clin Proc. 2008 Mar;83(3):333-42.
11. Ridker PM. Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: implications for longevity. Nutr Rev. 2007 Dec;65(12 Pt 2):S253-9.
12. Sabatine MS, Morrow DA, Jablonski KA, et al. Prognostic significance of the Centers for Disease Control/American Heart Association high-sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronary artery disease. Circulation. 2007 Mar 27;115(12):1528-36.
13. Calabro P, Yeh ET. Intra-abdominal Adiposity, Inflammation, and Cardiovascular Risk: New Insight into Global Cardiometabolic Risk. Curr Hypertens Rep. 2008 Feb;10(1):32-8.
14. Ferroni P, Basili S, Falco A, Davì G. Inflammation, insulin resistance, and obesity. Curr Atheroscler Rep. 2004 Nov;6(6):424-31.
15. Sonnenberg GE, Krakower GR, Kissebah AH. A novel pathway to the manifestations of metabolic syndrome. Obes Res. 2004 Feb;12(2):180-6.
16. Goldhammer E, Tanchilevitch A, Maor I, et al. Exercise training modulates cytokines activity in coronary heart disease patients. Int J Cardiol. 2005 Apr 8;100(1):93-9.
17. Clifton PM, Keogh JB, Foster PR, Noakes M. Effect of weight loss on inflammatory and endothelial markers and FMD using two low-fat diets. Int J Obes (Lond). 2005 Dec;29(12):1445-51.
18. Esposito K, Pontillo A, Di PC, et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA. 2003 Apr 9;289(14):1799-804.
19. Due A, Toubro S, Stender S, Skov AR, Astrup A. The effect of diets high in protein or carbohydrate on inflammatory markers in overweight subjects. Diabetes Obes Metab. 2005 May;7(3):223-9.
20. Gardner CD, Kiazand A, Alhassan S, et al. Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women: the A TO Z Weight Loss Study: a randomized trial. JAMA. 2007 Mar 7;297(9):969-77.
21. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA. 2004 Sep 22;292(12):1440-6.
22. Zhao G, Etherton TD, Martin KR, et al. Dietary alpha-linolenic acid reduces inflammatory and lipid cardiovascular risk factors in hypercholesterolemic men and women. J Nutr. 2004 Nov;134(11):2991-7.
23. Serra-Majem L, Roman B, Estruch R. Scientific evidence of interventions using the Mediterranean diet: a systematic review. Nutr Rev. 2006 Feb;64(2 Pt 2):S27-S47.
24. Chrysohoou C, Panagiotakos DB, Pitsavos C, Das UN, Stefanadis C. Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: The ATTICA Study. J Am Coll Cardiol. 2004 Jul 7;44(1):152-8.
25. Paniagua JA, de la Sacristana AG, Sánchez E, et al. A MUFA-rich diet improves posprandial glucose, lipid and GLP-1 responses in insulin-resistant subjects. J Am Coll Nutr. 2007 Oct;26(5):434-44.
26. Tzima N, Pitsavos C, Panagiotakos DB, et al. Mediterranean diet and insulin sensitivity, lipid profile and blood pressure levels, in overweight and obese people; the Attica study. Lipids Health Dis. 2007 Sep 19;6:22.
27. Available at: http://www.eatright.org/ada/files/Metamucil_Fact_Sheet.pdf. Accessed April 1, 2008.
28. Jenkins DJ, Kendall CW, Marchie A, et al. Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive protein. JAMA. 2003 Jul 23;290(4):502-10.
29. Savaiano DA, Story JA. Cardiovascular disease and fiber: is insulin resistance the missing link? Nutr Rev. 2000 Nov;58(11):356-8.
30. Jenkins DJ, Axelsen M, Kendall CW, et al. Dietary fibre, lente carbohydrates and the insulin-resistant diseases. Br J Nutr. 2000 Mar;83 Suppl 1S157-63.
31. Jennings JR, Muldoon MF, Hall M, Buysse DJ, Manuck SB. Self-reported sleep quality is associated with the metabolic syndrome. Sleep. 2007 Feb 1;30(2):219-23.
32. Gottlieb DJ, Punjabi NM, Newman AB, et al. Association of sleep time with diabetes mellitus and impaired glucose tolerance. Arch Intern Med. 2005 Apr 25;165(8):863-7.
33. Plante GE. Sleep and vascular disorders. Metabolism. 2006 Oct;55(10 Suppl 2):S45-9.
34. Available at: http://www.americanheart.org/presenter.jhtml?identifier=4632. Accessed April 1, 2008.
35. Calder PC. n-3 fatty acids and cardio-vascular disease: evidence explained and mechanisms explored. Clin Sci (Lond). 2004 Jul;107(1):1-11.
36. Stark KD, Park EJ, Maines VA, Holub BJ. Effect of a fish-oil concentrate on serum lipids in postmenopausal women receiving and not receiving hormone replacement therapy in a placebo-controlled, double-blind trial. Am J Clin Nutr. 2000 Aug;72(2):389-94.
37. Tsitouras PD, Gucciardo F, Salbe AD, Heward C, Harman SM. High Omega-3 Fat Intake Improves Insulin Sensitivity and Reduces CRP and IL6, but does not Affect Other Endocrine Axes in Healthy Older Adults. Horm Metab Res. 2008 Mar;40(3):199-205.
38. Barre DE. The role of consumption of alpha-linolenic, eicosapentaenoic and docosahexaenoic acids in human metabolic syndrome and type 2 diabetes--a mini-review. J Oleo Sci. 2007;56(7):319-25.
39. Ciubotaru I, Lee YS, Wander RC. Dietary fish oil decreases C-reactive protein, interleukin-6, and triacylglycerol to HDL-cholesterol ratio in postmenopausal women on HRT. J Nutr Biochem. 2003 Sep;14(9):513-21.
40. Dewailly E, Blanchet C, Lemieux S, et al. n-3 Fatty acids and cardiovascular disease risk factors among the Inuit of Nunavik. Am J Clin Nutr. 2001 Oct;74(4):464-73.
41. Albert CM, Campos H, Stampfer MJ, et al. Blood Levels of Long-Chain n–3 Fatty Acids and the Risk of Sudden Death. N Engl J Med. 2002;346(15):1113-8.
42. Anderson RA, Cheng N, Bryden NA, et al. Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes. 1997 Nov;46(11):1786-91.
43. Martin J, Wang ZQ, Zhang XH, et al. Chromium picolinate supplementation attenuates body weight gain and increases insulin sensitivity in subjects with type 2 diabetes. Diabetes Care. 2006 Aug;29(8):1826-32.
44. Broadhurst CL, Domenico P. Clinical studies on chromium picolinate supplementation in diabetes mellitus—a review. Diabetes Technol Ther. 2006 Dec;8(6):677-87.
45. Celleno L, Tolaini MV, D’Amore A, Perricone NV, Preuss HG. A Dietary supplement containing standardized Phaseolus vulgaris extract influences body composition of overweight men and women. Int J Med Sci. 2007;4(1):45-52.
46. Villareal DT, Holloszy JO. Effect of DHEA on abdominal fat and insulin action in elderly women and men: a randomized controlled trial. JAMA. 2004 Nov 10;292(18):2243-8.
47. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006 Mar;81(3):353-73.
48. Holick MF. Vitamin D deficiency. N Engl J Med. 2007 Jul 19;357(3):266-81.
49. Binkley N, Novotny R, Krueger D, et al. Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab. 2007 Jun;92(6):2130-35.
50. Timms PM, Mannan N, Hitman GA, et al. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM. 2002 Dec;95(12):787-96.
51. Guerrero-Romero F, Tamez-Perez HE, Gonzalez-Gonzalez G, et al. Oral magnesium supplementation improves insulin sensitivity in non-diabetic subjects with insulin resistance. A double-blind placebo-controlled randomized trial. Diabetes Metab. 2004 Jun;30(3):253-8.
52. Rodriguez-Moran M, Guerrero-Romero F. Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Diabetes Care. 2003 Apr;26(4):1147-52.
53. Yokota K, Kato M, Lister F, et al. Clinical efficacy of magnesium supplementation in patients with type 2 diabetes. J Am Coll Nutr. 2004 Oct;23(5):506S-9S.
54. Song Y, Ridker PM, Manson JE, et al. Magnesium intake, C-reactive protein, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care. 2005 Jun;28(6):1438-44.
55. Rasmussen HS, Aurup P, Goldstein K, et al. Influence of magnesium substitution therapy on blood lipid composition in patients with ischemic heart disease. A double-blind, placebo controlled study. Arch Intern Med. 1989 May;149(5):1050-3.
56. Farvid MS, Siassi F, Jalali M, Hosseini M, Saadat N. The impact of vitamin and/or mineral supplementation on lipid profiles in type 2 diabetes. Diabetes Res Clin Pract. 2004 Jul;65(1):21-8.
57. Available at: http://dietary-supplements.info.nih.gov/factsheets/magnesium.asp. Accessed April 1, 2008.
58. Schramm DD, Wang JF, Holt RR, et al. Chocolate procyanidins decrease the leukotriene-prostacyclin ratio in humans and human aortic endothelial cells. Am J Clin Nutr. 2001 Jan;73(1):36-40.
59. Ohta Y, Funayama M, Seino H, et al. Apple polyphenol improves lipid metabolism and insulin independence in obese rats. Nippon Shokuhin Kagaku Kogaku Kaishi. 2007;54(6):287-94.
60. Serisier S, Leray V, Poudroux W, et al. Effects of green tea on insulin sensitivity, lipid profile and expression of PPARalpha and PPARgamma and their target genes in obese dogs. Br J Nutr. 2007 Dec 6;1-9.
61. Grassi D, Lippi C, Necozione S, Desideri G, Ferri C. Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons. Am J Clin Nutr. 2005 Mar;81(3):611-4.
62. Queenan KM, Stewart ML, Smith KN, et al. Concentrated oat beta-glucan, a fermentable fiber, lowers serum cholesterol in hypercholesterolemic adults in a randomized controlled trial. Nutr J. 2007;6:6.
63. Poppitt SD, van Drunen JD, McGill AT, Mulvey TB, Leahy FE. Supplementation of a high-carbohydrate breakfast with barley beta-glucan improves postprandial glycaemic response for meals but not beverages. Asia Pac J Clin Nutr. 2007;16(1):16-24.
64. Biorklund M, van Rees A, Mensink RP, Onning G. Changes in serum lipids and postprandial glucose and insulin concentrations after consumption of beverages with beta-glucans from oats or barley: a randomised dose-controlled trial. Eur J Clin Nutr. 2005 Nov;59(11):1272-81.
65. Greenway F, O’Neil CE, Stewart L, Rood J, Keenan M, Martin R. Fourteen weeks of treatment with Viscofiber increased fasting levels of glucagon-like peptide-1 and peptide-YY. J Med Food. 2007 Dec;10(4):720-4.
66. McCarty MF. Low-insulin-response diets may decrease plasma C-reactive protein by influencing adipocyte function. Med Hypotheses. 2005;64(2):385-7.
67. Hlebowicz J, Darwiche G, Bjorgell O, Almer LO. Effect of cinnamon on postprandial blood glucose, gastric emptying, and satiety in healthy subjects. Am J Clin Nutr. 2007 Jun;85(6):1552-6.
68. Anderson RA, Broadhurst CL, Polansky MM, et al. Isolation and characterization of polyphenol type-A polymers from cinnamon with insulin-like biological activity. J Agric Food Chem. 2004 Jan 14;52(1):65-70.
69. Oak MH, El BJ, Anglard P, Schini-Kerth VB. Red wine polyphenolic compounds strongly inhibit pro-matrix metalloproteinase-2 expression and its activation in response to thrombin via direct inhibition of membrane type 1-matrix metalloproteinase in vascular smooth muscle cells. Circulation. 2004 Sep 28;110(13):1861-7.
70. Thirunavukkarasu M, Penumathsa SV, Koneru S, et al. Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: Role of nitric oxide, thioredoxin, and heme oxygenase. Free Radic Biol Med. 2007 Sep 1;43(5):720-9.
71. Folts JD. Potential health benefits from the flavonoids in grape products on vascular disease. Adv Exp Med Biol. 2002;505:95-111.
72. Jacob S, Ruus P, Hermann R, et al. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic Biol Med. 1999 Aug;27(3-4):309-14.
73. Jacob S, Henriksen EJ, Schiemann AL, et al. Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Arzneimittelforschung. 1995 Aug;45(8):872-4.
74. Konrad T, Vicini P, Kusterer K, et al. alpha-Lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes Care. 1999 Feb;22(2):280-7.
75. Estrada DE, Ewart HS, Tsakiridis T, et al. Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway. Diabetes. 1996 Dec;4(12):1798-804.
76. Henriksen EJ. Exercise training and the antioxidant alpha-lipoic acid in the treatment of insulin resistance and type 2 diabetes. Free Radic Biol Med. 2006 Jan 1;40(1):3-12.
77. Henriksen EJ, Jacob S, Streeper RS, Fogt DL, Hokama JY, Tritschler HJ. Stimulation by alpha-lipoic acid of glucose transport activity in skeletal muscle of lean and obese Zucker rats. Life Sci. 1997;61(8):805-12.
78. Kamenova P. Improvement of insulin sensitivity in patients with type 2 diabetes mellitus after oral administration of alpha-lipoic acid. Hormones (Athens). 2006 Oct-Dec;5(4):251-8.
79. Sola S, Mir MQ, Cheema FA, et al. Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study. Circulation. 2005 Jan 25;111(3):343-8.
80. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003 Jan 28;107(3):499-511.
81. Davis W. Cholesterol and statin drugs: separating hype from reality. Life Extension. 2004 Nov;10(11):42-52.
82. St-Pierre AC, Bergeron J, Pirro M, et al. Effect of plasma C-reactive protein levels in modulating the risk of coronary heart disease associated with small, dense, low-density lipoproteins in men (The Quebec Cardiovascular Study). Am J Cardiol. 2003 Mar 1;91(5):555-8.
83. Available at: http://www.diabetes.org/pre-diabetes/pre-diabetes-symptoms.jsp. Accessed April 1, 2008.
84. Wen CP, Cheng TY, Tsai SP, Hsu HL, Wang SL. Increased mortality risks of pre-diabetes (impaired fasting glucose) in Taiwan. Diabetes Care. 2005 Nov;28(11):2756-61.
85. Cowie CC, Rust KF, Byrd-Holt, et al. Prevalence of Diabetes and Impaired Fasting Glucose in Adults in the U.S. Population. National Health and Nutrition Examination Survey 1999–2002. Diabetes Care 2006; 29:1263-8.