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Fats and Cholesterol Omega-6 to omega-3 fatty acid ratio

Apr 23, 2002

The increased prevalence of diabetes has paralleled a rise in consumption of n-6 (relative to n-3) fatty acids and trans fatty acids found in partially hydrogenated oil. 66-68 Both can change cellular membrane phospholipid composition and decrease fluidity—a state associated with altered insulin receptors, decreased insulin sensitivity, and subsequent insulin resistance and hyperinsulinemia 69-73 . A large dietary glycemic load exacerbates the hyperinsulinemia.

Since 1850 the n-6 to 3 ratio in the Western diet has risen from 4:1 to greater than 20:1 as fats from fish, wild game, and leaves were replaced by the consumption of linoleic acid (LA)-rich oils from seeds. Changes in feeding poultry and livestock have altered the n-6 and n-3 content of the animal protein consumed 74-76 . This imbalance leads to a high proportion of arachidonic acid (AA)-derived eicosanoids such as thromboxane A2, leukotrienes, and the production of inflammatory mediators, e.g., cytokines and interleukins 74 , 75, 77 . One of the most important functions of the vascular endothelium is to regulate inflammatory reactions, and too much linoleic acid can induce marked injury to endothelial cells. 78

Excessive intake of the n-6 linoleic acid and relative n-3 deficiency have been postulated to be the major causes of the increasing western-type cancers, cardiovascular and cerebrovascular diseases and allergic hyperreactivity 79 .

Several studies show an association between low intake of n-3 (relative to n-6) and a decrease in mortality from all causes, especially CHD. 80-84 Populations that consume a diet rich in omega 3s have a lower prevalence of diabetes 85 . Epidemiological evidence from the Multiple Risk Factor Intervention Trial (MRFIT) of 12,866 American males revealed significant inverse relationships between dietary n-3 PUFA and mortality from CHD, cancer, and all-causes 86 . These effects could be improved by simply lowering the n-6 to n-3 ratio 87 . A study of 43,757 U.S. health care professionals followed for six years from 1986 found that diets high in n-3 acids are associated with a reduced risk of CHD independently of other dietary and non-dietary risk factors 118 Prior to the last world war the prevalence of diabetes and CHD was climbing in Norway paralleling a rise in the n-6/n-3 ratio and consumption of more highly processed high glycemic foods 88 . Following a significant reduction in n-6/n-3 fat ratio during the war Norway recorded a sharp decrease of almost fifty percent in the incidence of diabetes and cardiovascular mortality. Unfortunately, reversion to the previous dietary fat intake and n-6/n-3 fat ratio was followed by an equally rapid rise in both diabetes and CHD 88 .

In the last 20 years there has been a dramatic increase in the prevalence of type 2 diabetes and CHD in urban and upper socioeconomic groups in India. This rise has paralleled an increase in the consumption of n-6 fatty and the n-6 to n-3 ratio 89 . Simply changing the composition of the dietary fat to increase the n-3 while decreasing the n-6 PUFA in patients with type 2 diabetes had a significant impact. This improved insulin action and reduced the required dosage of hypoglycemic agents 89 . The response was maximal when the n-6/n-3 ratio in dietary lipids was adequately lowered.

The United States has experienced a sharp and sustained fourfold rise in the number of diagnosed cases of diabetes since 1960. This rise has paralleled the increased consumption of n-6 fats mostly in the form of seed oils which has risen after reports that n-6 PUFA lowered plasma cholesterol 89 . Adequate n-6 fatty acids are critical, especially in patients with type 2 diabetes who have an impaired delta 6 desaturase which is key in the first step of n-6 metabolism to eicosanoids. However, Toborek et al provide compelling evidence that too much linoleic acid can induce profound inflammatory responses in cultured human endothelial cells—most markedly among all the unsaturated fatty acids studied. 78

Greater than eighty percent of insulin mediated glucose disposal takes place in skeletal muscle 90 . In adult humans insulin resistance is associated with low proportions of polyunsaturated fatty acids (PUFAs) in muscle membrane structural lipid whereas a higher percentage unsaturated fat, especially long-chain polyunsaturated fatty acids (the omega-3s), is associated with greater insulin sensitivity 69, 71, 91, 92 . N-3 PUFAs may improve insulin sensitivity by increasing membrane fluidity 71-73 . Dietary intake has been shown to influence the adipose 70 and muscle membrane phospholipid fatty acid (FA) composition 93 , however endogenous factors also play a role. Some adult populations with similar diets demonstrate wide ranges in muscle membrane FA profiles, and mothers at higher risk of the metabolic syndrome (as determined by fasting insulin and triglyceride levels) have children with a muscle membrane characterized by a lower proportion of n-3 PUFAs 94 . This suggests there may be genetic differences in the ability to incorporate n-3s into membranes, or perhaps the concurrent ingestion of trans and saturated fats along with other environmental factors is preventing the incorporation of n-3s. This underscores the importance of increasing the amount of n-3s in the diet relative to n-6s to ensure optimal FA muscle membrane composition and insulin sensitivity.

Omega 3 PUFAs, especially those found in fish oil, enhance endothelial nitric oxide production, improve endothelial relaxation, inhibit production of pro-inflammatory cytokines, lower cholesterol levels, prevent atherosclerosis, and help prevent stroke and osteoporosis. 16, 95 Omega 3 supplementation has been shown to reduce markers of endothelial dysfunction, e.g., vWF and tissue-type plasminogen activator antigen. 96, 97 Consumption of the n-3 fatty acid docosahexaenoic acid (DHA; 22:6n-3) found in fish oil reduced endothelial expression of vascular cell adhesion molecule 1 (VCAM-1), E-selectin, intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), and IL-8 in response to IL-1, IL-4, tumor necrosis factor, or bacterial endotoxin, in the range of nutritionally achievable plasma concentrations. 98 Omega 3s also have anti-arrhythmic properties, and the available evidence suggests a role in secondary prevention of CHD. Their established role in primary prevention will have to await future clinical trials but there is substantial evidence to support it. 16 Fish oil has been shown to significantly improved endothelial function in peripheral small arteries in hypercholesterolemia patients, 99 and Abe et al demonstrated that fish oil is particularly effective in improving endothelial function (i.e., reducing endothelial activation) among patients with elevated triglycerides and diabetes. 100 While concerns have been raised that fish oil may worsen glycemic control, recent meta-analyses suggest that fish oil has no substantial effect on fasting glucose or glycosylated hemoglobin concentrations. 101, 102

Saturated Fat

Saturated fats are stable, resist rancidity, and therefore do not usually tax the body’s antioxidants or oxidize endothelial cells. Saturated fats also have a role in numerous important physiological processes, e.g., saturated fat makes up the majority of phospholipids in cell membranes, brain tissue, and lung surfactant. In a compelling review in Science, Taubes concludes that, “Despite decades of research, it is still a debatable proposition whether the consumption of saturated fats above recommended levels…by anyone who’s not already at high risk of heart disease will increase the likelihood of untimely death…Nor have hundreds of millions of dollars in trials managed to generate compelling evidence that healthy individuals can extend their lives by more than a few weeks, if that, by eating less fat.” 103

While several studies suggest a detrimental effect of saturated fat on hyperinsulinemia and hyperglycemia, other studies have been unable to confirm these results. Some of these inconsistencies of saturated fat studies may be due to lack of adjustment for confounding by other dietary and non-dietary risk factors. In six years of follow up of a cohort of male health professionals, Willett’s group did not observe significant associations between major types of fat and risk of type 2 diabetes. 11 After extending this prospective analysis of 42,504 participants to twelve years of follow-up, the researchers found that intakes of total fat and saturated fat were associated with a higher risk of type 2 diabetes, but these associations disappeared after additional adjustment for BMI, 104 Consumption of unprocessed red meat (e.g., beef, lamb, pork) and of poultry was not substantially associated with risk for type 2 diabetes. On the other hand, frequent consumption of processed meat (e.g., sausage, bacon) has been positively associated with risk of type 2 diabetes, possibly because they are a major sources of nitrosamines which may contribute to beta cell toxicity and insulin resistance. Frequent consumption of processed meats could also reflect other lifestyle factors or other components that may be toxic. 104 This may be but one example of the vilification of an innocent saturated fat due to its association with a confounding factor. Diets high in saturated fat could be also be associated with low fiber, over-consumption of total calories, and as part of a high glycemic load.

If you eat a diet low in fat (and high in carbohydrates) versus a high fat diet, your liver will manufacture saturated fat. 105, 106 107 Consider the marbled, fatty steak that comes from a cow. The cow was likely fed a very low fat high carbohydrate diet, so where did all the fat come from? Not from the diet but from the excess carbohydrate calories that ultimately were stored as fat. The same thing occurs in humans.

It appears that C-reactive protein is a better marker than lipid profiles suggesting a critical, diffuse inflammatory process in diabetes and CHD. 108, 109 Could it be that saturated fat, LDL, and other lipids are fairly benign unless they are in a pro-oxidant environment, and maybe it is the anti-inflammatory effects of the statins that are most beneficial?

Plotnick et al demonstrated that a single high-fat meal transiently reduces endothelial function (as measured by flow-mediated brachial artery vasoactivity) for up to four hours in healthy, normocholesterolemic subjects 110 . The 900 calorie meal included 14 grams of saturated fat, 225 mg of cholesterol, and an unspecified but significant amount of trans fats. Endothelial impairment was not seen after a low fat meal or when the single high fat meal was immediately preceded by the ingestion of antioxidant vitamins (1,000 mg C and 800 IU E). The researchers suggest that continual exposure to high saturated fat meals and large postprandial TG load may initiate the atherosclerotic cascade of (1) endothelial injury (2) proliferation of macrophages, lymphocytes, and platelet adhesion of cholesterol and other lipids, and (4) fatty streak development 111 112 . Plotnick al’s study demonstrates this may be possible despite normal cholesterol levels. Perhaps it is the excess calories that are often consumed along with saturated fat (rather than the saturated fat per se) that generate free radical production and exacerbate endothelial dysfunction. 113, 114 And in Plotnick’s study, trans fats most likely also contributed to endothelial dysfunction. Saturated fat consumption has been associated with a rise in HDL 115 and a lowering of Lp(a). 116 Identifying the background diet is often lacking in studies. For example, fiber, which may be low in a high saturated fat diet, has been shown to be a better predictor of insulin levels, weight gain, and other risk factors for CHD than total or saturated fat consumption. 117

Meta-analyses of controlled and randomized trials that have used modification of dietary fat as the only type of intervention have been unable to demonstrate a significant lowering of incidence of nonfatal CHD nor coronary or total mortality. 118, 119

Trans Fatty Acids

Trans fatty acids are formed by partially hydrogenating liquid vegetable oils to make margarine and vegetable shortening. Because of their long shelf life, low cost, and suitability for commercial frying these ubiquitous trans fats are added to most fast, fried, and snack foods, cookies, and other bakery items. Trans fatty acids raise total cholesterol and LDL, lower HDL, reduce n-3 incorporation into cell membranes, and are associated with tens of thousands of premature deaths per year 66, 67 . The Nurses’ Health Study showed a positive association between trans fat intake and risk of type 2 diabetes. 12 An in vitro study of cultured endothelial cells suggests that a diet high in trans fats and deficient in magnesium increases the calcification of endothelium. 120

Dietary Cholesterol

Cholesterol is critical for maintaining brain and nerve tissue integrity. It also plays a role in hormone and membrane structure, the immune system, and numerous critical physiological processes. Just as your body makes saturated fat, it also makes approximately 2000 mg of cholesterol daily. More than 80 percent of cholesterol in the body is manufactured by it and almost entirely unrelated to dietary intake. Over 50 years of cholesterol-feeding studies show that dietary cholesterol has a negligible effect on plasma cholesterol concentrations. The 167 cholesterol-feeding studies in over 3,500 subjects in the literature indicate that a 100 mg change in dietary cholesterol changes plasma total cholesterol by 2.2 mg/dL. Addition of 100 mg cholesterol per day to the diet increases total cholesterol with a 1.9 mg/dL increase in LDL cholesterol and a 0.4 mg/dL increase in HDL cholesterol. On average, the LDL:HDL ratio change per 100 mg/day change in dietary cholesterol is from 2.60 to 2.61, which would be predicted to have little effect on heart disease risk even by the debatable NCEP standards 121 Carbohydrates stimulate insulin release, which, in turn, stimulates HMG-CoA reductase, the liver enzyme that plays a key role in cholesterol production and is the target of cholesterol-lowering drugs.


Cholesterol, as with other lipids, is benign unless it contains extra oxygen atoms (oxy-cholesterol or OxChol). Prolonged heating of cholesterol, e.g., butter heated for 24 hours, can form oxy-cholesterol. While cooking oils and fast foods often contain trans fats, re-used frying oils, rancid fats, and other oxidized food derivatives pose a potential threat to the endothelium. While cholesterol is relatively resistant to oxidation, food processing often accelerates its oxidation creating OxChol derivatives in fatty foods. Spray dried egg yolks made in the process of making powdered eggs contain OxChol, and these are used in many packaged baked goods such as cookies, crackers, etc. Unfortunately, they are labeled simply as “eggs.” Frying in the re-used oil in many fast food restaurants produces French fries, fried chicken, etc. laden with toxic OxChol. Especially in patients with type 2 diabetes, consumption of oxidized dietary lipids may lead to increased circulating oxidized plasma lipids and accelerated atherosclerosis. 122

Monounsaturated Fats

Garg conducted a meta-analysis of nine studies of monounsaturated dietary fat (MUFA) in patients with type 2 diabetes. 6 Total dietary fat as a percentage of total calories ranged from 37 to 50 percent, and calorie contribution from MUFA ranged from 22 to 33 percent. Overall, high MUFA-enriched diets improved glycemic control, reduced fasting plasma TG and VLDL-cholesterol concentrations by 19% and 22%, respectively, and caused a modest increase in HDL-cholesterol concentrations without adversely affecting LDL-cholesterol concentrations. Furthermore, there was no evidence that high-monounsaturated-fat diets induce weight gain in patients with diabetes mellitus provided that energy intake is controlled. Of course some of these benefits attributed to the MUFA may be due to substituting MUFA for carbohydrates and reducing the glycemic load.

In a randomized, double-blinded, cross-over study, with healthy subjects with normal cholesterol, Kris-Etherton et al compared an Average American diet (AAD—34% fat; 16% saturated fatty acids; 11% MUFAs) with those of 4 cholesterol-lowering diets: an American Heart Association/National Cholesterol Education Program Step II diet and 3 high-MUFA diets [olive oil (OO), peanut oil (PO), and peanuts and peanut butter (PPB). [Kris-Etherton, 1999 #1469]The high-MUFA diets lowered total cholesterol by 10% and LDL cholesterol by 14%. This response was comparable with that observed for the Step II diet. Triglyceride concentrations were 13% lower in subjects consuming the high-MUFA diets and were 11% higher with the Step II diet than with the AAD. The high MUFA diets did not lower HDL cholesterol whereas the Step II diet lowered it by 4% compared with the AAD. Using standard (and debatable) CVD risk determinations, the OO, PO, and PPB diets decreased CVD risk by an estimated 25%, 16%, and 21%, respectively, whereas the Step II diet lowered CVD risk by 12%. However, using the TG/HDL ratio, which may stronger CVD risk predictor, 123, 124 clearly the Step II diet increased risk while the high-MUFA diets reduced it. Correctly, the study concludes that a high- MUFA, cholesterol-lowering diet may be preferable to a low-fat diet because of more favorable effects on the CVD risk profile. This is consistent with other studies showing high MUFA diets improve markers of endothelial function in healthy subjects 125 , and a diet enriched in oleic acid markedly decreases LDL susceptibility to oxidation. 126

Eric S. Freedland, MD graduated from University of Rochester School of Medicine in 1982, trained in internal medicine at Mt. Auburn Hospital in Cambridge, MA, and emergency medicine at Harbor-UCLA Medical Center in Torrance, CA, and has held faculty positions at Harvard Medical School (1990-1991) and Boston University School of Medicine (1992-1997). Dr. Freedland has developed a nutrition-centered model of disease with a special emphasis on diabetes. A staunch advocate for prescribing lifestyle changes before drugs, Dr. Freedland has written and lectured extensively on this subject.


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