William Lands

NIAAA, Bethesda, MD, USA


Blood lipoprotein profiles mediated by liver metabolism are indirect   associative markers of risk for cardiovascular disease.  However, vascular   inflammation, thrombosis, and ventricular arrhythmia may be mediated more   directly by excessive actions of n-6 eicosanoids than by blood lipoproteins.  During eicosanoid formation, highly unsaturated fatty   acids (HUFA) are mobilized from tissue lipids.  Thus, the percent of n-6 HUFA in tissue HUFA is a surrogate clinical marker for the probable intensity of n-6 eicosanoid-mediated events.  The percent of n-6 HUFA in tissue HUFA is also a marker of relative dietary intakes, reflecting known competitions among dietary n-3 and n-6 FA in maintaining levels of tissue HUFA (Lands et al,  Biochim. Biophys. Acta 1992; 1180: 147-162).  This quantitative competition permits planning diverse diets to meet a desired surrogate clinical outcome.  To aid food choices during clinical   interventions, the equation was embedded in an interactive personalized   computer software application called KIM (Keep It Managed) - downloadable from  KIM manages n-3 and   n-6 information on 9,214 different food servings, interpreting and displaying it in terms of multiple daily food choices understandable by the general public.  Ethnic food combinations for Greenland, Japanese, Mediterranean, and American populations give proportions of n-6 in tissue   HUFA near 30%, 50% 60% and 80%, respectively.  These surrogate clinical outcomes are associated with cardiovascular mortalities of 20, 50, 90, and 200 per 100,000, respectively.  This strong association combines with knowledge of the fatal mechanisms to support the recent Am. Heart Assoc. advice that "..foods rich in omega-3 FA, specifically EPA and DHA, confer cardioprotective effects beyond those that can be ascribed to improvements in blood lipoprotein profiles."




Sven Ebbesson

University of Alaska, Anchorage, Alaska, USA


This diabetes prevention study was initiated to explore potential avenues to prevent the development of NIDDM in Alaskan Eskimo populations with recent dramatic increases in impaired glucose tolerance (IGT) and NIDDM. The study involved 1) an initial screening in 1994 of 454 individuals in 4 villages for diabetes and associated risk factors, 2) a 4 year intervention and 3) a second screening in 1998.  The intervention focused on a) increased physical activity, b) weight reduction when indicated and c) increased consumption of traditional foods rich in omega 3 fatty acids and decreased consumption of saturated fats.  We report here that personal counseling resulted in significant (p=0.0001) reductions in plasma concentrations of total cholesterol, LDL, fasting glucose and 2h glucose. 72% had improved glucose and lipid levels.  Although average weight decreases were about 2 kg, the decreases were not statistically significant.   None of the 39 participants originally diagnosed with IGT developed NIDDM after the 4 years of intervention.  Funded by 2 RO1 DK47099




Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico


Roberto Marchioli

Santa Maria Imbaro, Italy

BACKGROUND: There is conflicting evidence on the benefits of foods rich in vitamin E (alpha-tocopherol), n-3 polyunsaturated fatty acids (PUFA), and their pharmacological substitutes. We investigated the effects of these substances as supplements in patients who had myocardial infarction. METHODS: From October, 1993, to September, 1995, 11,324 patients surviving recent (< or = 3 months) myocardial infarction were randomly assigned supplements of n-3 PUFA (1 g daily, n=2836), vitamin E (300 mg daily, n=2830), both (n=2830), or none (control, n=2828) for 3.5 years. The primary combined efficacy endpoint was death, non-fatal myocardial infarction, and stroke. Intention-to-treat analyses were done according to a factorial design (two-way) and by treatment group (four-way). FINDINGS: Treatment with n-3 PUFA, but not vitamin E, significantly lowered the risk of the primary endpoint (relative-risk decrease 10% [95% CI 1-18] by two-way analysis, 15% [2-26] by four-way analysis). Benefit was attributable to a decrease in the risk of death (14% [3-24] two-way, 20% [6-33] four-way) and cardiovascular death (17% [3-29] two-way, 30% [13-44] four-way). The effect of the combined treatment was similar to that for n-3 PUFA for the primary endpoint (14% [1-26]) and for fatal events (20% [5-33]). INTERPRETATION: Dietary supplementation with n-3 PUFA led to a clinically important and statistically significant benefit. Vitamin E had no benefit. Its effects on fatal cardiovascular events require further exploration.



Roberto Marchioli

Santa Maria Imbaro, Italy




Martha Daviglus

Northwestern University, Chicago, IL


OBJECTIVE: Dietary fish and omega-3 fatty acids (n-3 FAs) are associated with a reduced risk of CHD mortality.  However, enthusiasm for the intake of fish and n-3 FAs in type 2 diabetics has been tempered by reports of impaired glucose homeostasis.  Most studies showing this negative impact of fish intake and n-3 FAs on glycemic control have been feeding or supplement studies conducted for short time periods.  There are little data on the relationship of fish and n-3 FA intake to glucose levels in free-living diabetic populations.  This study examines the associations of dietary fish and n-3 FAs with blood glucose levels among participants with type 2 diabetes from the Coronary Artery Risk Development in Young Adults (CARDIA) Study. METHODS: A total of 43 diabetic (i.e., fasting glucose levels >125 mg/dl) black and white men and women average age 33.6 years in 1992 to 1993 were included in analyses.  Data on fish and n-3 FAs [a-linolenic acid (ALA, 18:3n-3), eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3)] were obtained from an interviewer administered diet history questionnaire.  RESULTS: Average amount of fish consumed was 25.34 oz/mo.  Mean intake of ALA, EPA, and DHA was 2.2 g/d, 0.07 g/d, and 0.13 g/d, respectively.  Spearman rho correlations show a nonsignificant direct association of glucose with intake of fish (p=0.10), ALA (p=0.18), EPA (p=0.24), and DHA (p=0.11).  For diabetics who consumed fish (n=29), mean glucose was 196.1 mg/dl compared to 208.9 mg/dl for the non-consumers (n=14).  Average glucose levels were highest for the highest tertile of n-3 FAs, e.g., for DHA intake (from lowest to highest) 191.1 mg/dl, 211.5 mg/dl, and 213.0 mg/gl.  However, with adjustment for age, BMI, race, sex, education, alcohol and smoking this pattern changed, mean glucose levels were lowest for highest tertile of DHA intake, i.e., (from lowest to highest) 202.1 mg/dl, 215.9 mg/dl, and 196.3 mg/dl. CONCLUSION: In this cohort of free living young diabetics with typical low to moderate fish consumption, no significant differences in blood glucose levels were observed with intake fish or n-3 FAs.  Fish consumption at moderate levels does not appear to be associated with poor glycemic control.





David Siscovick

University of Washington, Seattle, WA, USA


There is mounting evidence that modest dietary intake of fatty fish and low-dose, long-chain, n-3 polyunsaturated fatty acid (PUFA) supplementation are associated with a reduced risk of out-of-hospital primary cardiac arrest, also known as sudden cardiac death.  In contrast, modest intake of long-chain n-3 PUFAs is not associated with a reduced risk of non-fatal myocardial infarction.  In this presentation, we discuss the potential role of modest intake of n-3 PUFAs in the prevention of sudden cardiac death in the community.  We suggest that differences in the findings from prior epidemiologic studies of fish and long-chain n-3 PUFA intake and the risk of coronary heart disease may relate to differences in the primary focus of the research, the distribution of long-chain n-3 PUFA intake and other dietary FA in the population, and the outcomes examined.  We illustrate these issues with data from a population-based case-control study of dietary intake and cell-membrane levels of long-chain n-3 PUFAs and the risk of primary cardiac arrest.  Prior research has not examined whether modest dietary intake of fatty fish or low-dose n-3 PUFA supplementation is associated with a reduced risk of sudden cardiac death and/or non-fatal myocardial infarction in patients with type II diabetes mellitus.  Based upon evidence from epidemiologic studies and clinical trials, we suggest several methodological issues that should be considered in the design of a clinical trial to examine the effects of modest intake of long-chain n-3 PUFAs on cardiovascular outcomes among patients with type II diabetes mellitus.  




Steven Haffner


University of Texas at San Antonio, USA


Type 2 diabetes is associated with a two-fold increased risk for CHD.  In most studies, the relative risk of CHD is greater in women than men.  In addition, the case fatality of myocardial infarction is greater in type 2 diabetic subjects than in non-diabetic subjects. The relation between glycemia and CHD in diabetic subjects is statistically significant but only in relatives.  One explanation for the relatively modest relation between glucose and CHD in diabetic subjects is the existence of an atherogenic pre-diabetic state.




Henry N. Ginsberg

Columbia University, NY, NY, USA


Patients with diabetes mellitus have 3-5 times higher rates of all forms of atherosclerotic cardiovascular disease than the general population.  Although much of the risk in the diabetic population can be explained by well-described risk factors such as hypertension, LDL cholesterol, and smoking, there is a significant proportion of the increased risk that seems unique to diabetics.  In the area of lipoproteins, diabetics appear to have a characteristic set of lipid abnormalities that have been loosely designated as the diabetic dyslipidemia. This includes hypertriglyceridemia, low HDL cholesterol, and heterogeneous LDL with increased small dense LDL. The pathophysiologic basis of this dyslipidemia  appears to be closely linked to the insulin resistance that is common in type 2 diabetics.  Studies completed over the past 30 years have provided strong support for increased free fatty acid flux from the adipose tissue to the liver as a major driving force for increased assembly and secretion of triglyceride-rich VLDL particles by the liver.  More recent studies suggest that hyperinsulinemia can drive hepatic lipogenesis and further increase VLDL secretion.  Once plasma VLDL triglycerides are increased, exchange of triglycerides for LDL and  HDL cholesteryl esters, mediated by cholesteryl ester transfer protein (CETP), results in triglyceride-rich LDL and HDL that are good substrates for lipases. Hydrolysis of the triglycerides in LDL and HDL lead to small dense LDL and small HDL.  Additionally, CETP mediated exchange results in cholesteryl ester-enriched VLDL, which may be more atherogenic.  Small dense LDL may also be more atherogenic.  Small HDL has a lower affinity for apoprotein A-I leading to dissociation of the latter protein and its rapid clearance from the plasma.  This results in fewer HDL particles in the blood.  Finally, all of the above can occur when intestinal particles, chylomicrons, are increased postprandially.  The latter is common in type 2 diabetics because of modest reductions in lipoprotein lipase and because of the competition between VLDL and chylomicrons for lipoprotein lipase.  All aspects of the diabetic dyslipidemia have the potential to increase the atherogenic risk of the patients.  Treatments of each component of the dyslipidemia have been associated with reduced risk. Treatment of insulin resistance may add further benefit.



Norberta W. Schoene         

Beltsville Human Nutrition Research Center, USDA, Beltsville, MD, USA  


Known risk factors estimate only 25 to 50% of the observed coronary heart disease (CHD) observed in type 2 diabetics.   Dysfunctional regulation of coagulation, fibrinolytic, and inflammatory processes maybe added factors in diabetic CHD.   Numerous studies in type 2 diabetics have demonstrated imbalances among these processes.  Examples include increased fibrinogen and tissue plasminogen activator inhibitor (PAI-1) levels in addition to the presence of hyperactive platelets in the circulation.  Studies with diabetic subjects suggest that dietary omega-3 FA can normalize the signaling mechanisms in hemostatic functions.   However, more evidence is needed from clinical trials to further substantiate the positive effects of dietary omega-3 FA on these additional risk factors for CHD in type 2 diabetics.  Such evidence will assist in the development of dietary approaches to prevent and delay the incidence of CHD and type 2 diabetes.  The coexistence of these two diseases within individuals may reach near epidemic numbers in the next 25 years as the US populations ages and grows ever more obese.   Primary prevention strategies must be devised and implemented soon to avoid the consequences of this prediction.   



James R. Sowers

State University of New York – Downstate Medical Center, Brooklyn, NY USA


There is increasing evidence that essential hypertension is associated with a panoply of metabolic abnormalities. Included in these abnormalities are insulin resistance, dyslipidemia, enhanced coagulation, and decreased fibrinolytic activity, microalbuminuria, and platelet abnormalities and endothelial dysfunction. Visceral obesity appears to be the most common and predictive underlying factor for all of these metabolic abnormalities accompanying hypertension as well as increased cardiovascular disease (CVD) risk. As the prevalence of obesity is increasing, there is cause for concern that CVD increases will parallel this risk factor, particularly in especially high-risk populations, such as African-American women. Other important risk factors, such as increased oxidative stress, may require special therapeutic strategies.




James H. O’Keefe

Mid America Heart Institute, Kansas City, MO, USA


Diabetes Mellitus disrupts normal autonomic nervous system function.  Diabetic autonomic neuropathy, though typically asymptomatic, is associated with a poor prognosis, with 5 year mortality rates approximately 25-50%.  Like other microvascular diabetic complications (retinopathy and nephropathy) neuropathy appears to be due to small vessel disease.  However, the causes of death in diabetics with autonomic dysfunction are largely due to macrovascular complications such as myocardial infarction, stroke and sudden cardiac death.    Studies show that in addition to duration of diabetes, serum cholesterol and triglyceride levels are correlated with increased risk of autonomic neuropathy.


The insulin resistance syndrome predisposes to heightened sympathetic reactivity, especially in response to alpha adrenergic stimulation.  This is manifest as increased norepinephrine induced vasoconstriction. Later in the course of diabetes, dysfunction of the sympathetic nerves is demonstrable. Diabetic autonomic neuropathy is associated with impaired vasodilator response of coronary resistance vessels to sympathetic stimulation.


Although abnormalities of the sympathetic nervous system are commonly observed in diabetic patients or those with insulin resistance syndrome, the cardinal lesion of diabetic autonomic neuropathy relates to loss of normal parasympathetic activity.  An important marker of parasympathetic disease is the absence of normal beat to beat variability of heart rate (heart rate variability).  Also, the attenuation of parasympathetic dominance at night predisposes to a loss of the normal drop in heart rate and systolic blood pressure during sleep.  This has been hypothesized to contribute to the diastolic dysfunction and left ventricular hypertrophy commonly seen in diabetic patients.


Diabetic autonomic neuropathy has been correlated with urinary albumin excretion, hyperinsulinemia, hypertriglyceridemia, silent myocardial ischemia, diastolic dysfunction, left ventricular hypertrophy and chronotropic incompetence (lack of appropriate increase in heart rate during exercise) and delayed heart rate recovery (a delay in the recovery of heart rate after exercise).


Electrocardiographic markers of parasympathetic dysfunction in diabetic autonomic neuropathy include a lengthened Q-T interval and Q-T dispersion.  These abnormalities of myocardial repolarization increase vulnerability to malignant dysrhythmias.  The heightened sympathetic tone and predisposition to ischemia (coronary vasoconstriction, prothrombotic state) increase the irritability of the myocardium.  This constellation of abnormalities markedly increases the risk of sudden cardiac death in diabetic patients.


Effective therapy for diabetic neuropathy is not yet available.  Over 30 compounds have reached phase III clinical trials and have all failed to establish efficacy.



John Miles

Saint Luke's Hospital and University of Missouri-Kansas City, Kansas City, MO  USA


It is generally recognized that Insulin resistance is a prominent feature of Type 2 diabetes. This resistance to the action of insulin is viewed by most in the context of insulin’s effects on glucose metabolism. However, a significant and well documented abnormality is also present in insulin’s major effect on adipocyte metabolism, suppression of hormone sensitive lipase. This antilipolytic effect of insulin is under normal circumstances the most sensitive of all metabolic processes to this hormone. Insulin resistance in fat cells results in elevated plasma concentrations of nonesterified fatty acids (NEFA). Increases in NEFA produced experimentally in humans have been shown to mimic the insulin resistance seen in obesity and type 2 diabetes. This insulin resistance manifests as impaired glucose transport in skeletal muscle and impaired suppression of endogenous glucose production. Moreover, under some circumstances, decreases in plasma NEFA concentrations in insulin resistance states through the use of antilipolytic drugs has returned insulin action to normal. The weight of evidence supports the concept that abnormally elevated NEFA concentrations are the chief factor in the insulin resistance of type 2 diabetes. Preliminary evidence indicates that administration of n-3 fatty acids at a dose of 3.4 g/day does not have a significant effect on plasma NEFA concentrations or turnover.





Insulin Resistance and n-3 FA’S:  Animal and cell culture


M. T. Clandinin

University of Alberta

Edmonton, Alberta, Canada


Feeding animals with diets high in saturated fat induces insulin resistance, and replacing saturated fat isocalorically with polyunsaturated fat, especially long-chain n-3 fatty acids, will prevent the development of insulin resistance in skeletal-muscle tissue.  To investigate the mechanism, rats were fed high fat (20%, w/w) semipurified diets for 6 weeks.  Diets containing ratios of polyunsaturated/saturated (P/S) fatty acid of 0.25 (low-P/S diet) and l.0 (high-P/S diet) were used to study the effect of the level of saturated fat.  To study the effects of n-3 fatty acids, diets with a low-P/S ratio containing either 0 (low-n-3 diet) or 3.3% (high-n-3 diet long-chain n-3 fatty acids from fish oil were fed.  Plasma membrane from skeletal muscle was purified.  The content of fatty acids in sarcolemmal phospholipid was significantly related to the dietary composition.  Insulin binding to intact sarcolemmal vesicles prepared from rats fed diets high in n-3 fatty acids increased 14-fold compared with animals fed the low -n-3 diet.  Increased insulin binding was due to increased receptor number at the low-affinity high-capacity binding site.  Dietary effects on insulin binding were eliminated when studies were carried out on detergent-solubilized membranes, indicating the importance of the phospholipid fatty acyl composition for insulin binding.  When muscle protein synthesis was determined dietary n-3 fatty acids were found to alter net protein synthesis.  The results suggest that dietary n-3 and polyunsaturated fatty acids increase insulin binding to sarcolemma by changing the fatty acyl composition of phospholipid surrounding the insulin receptor, and this might be the mechanism by which dietary fatty acids modify insulin action.




William L. Isley

Saint Luke's Hospital and University of Missouri-Kansas City, Kansas City, MO  USA



Early studies in small numbers of poorly controlled patients with type 2 diabetes mellitus treated for short periods of time with large doses (5+ g/d) of w3 fatty acids revealed a deterioration of glycemic control.  More recent studies with more moderate doses (£3 g w3 fatty acids have shown no change in glycemia.  Measures of insulin sensitivity have generally shown little change with fish oils, or in one case, improved insulin sensitivity (Popp-Snijders 1987).  Fasting and postprandial insulin concentrations have been found to be elevated by fish oils in some studies.  Hepatic glucose production has also been found to be increased by fish oil therapy in some studies.  Studies comparing equal caloric placebos have been more likely to show no differences between placebo and fish oil therapy.  Fish oils appear to have no effect on insulin sensitivity, but may compromise

insulin release in poorly controlled patients with type 2 diabetes mellitus.





James M. Ntambi

University of Wisconsin, Madison, Wisconsin USA


Dietary factors can influence which lipid-regulating genes are activated or deactivated, and could thus contribute to hypertriglyceridemia. Many studies have shown that dietary fish oil rich in n-3 polyunsaturated FA, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has a hypotriglyceridemic effect but the mechanism of its action is not fully understood. Thus we investigated the effects of a fish oil-rich diet on the regulation of one particular gene whose protein product controls the de novo synthesis of FA. We used a mouse model that over expresses this protein (and its associated mRNA) and as a result, is both severely diabetic and hypertriglyceridemic. Mice were divided into two groups and were given a high fat diet (30% of total energy) as soybean oil or fish oil. Compared with soybean oil feeding, fish oil feeding decreased hepatic mRNA levels for this protein , and in addition, reduced plasma levels of triglycerides and glucose. These data suggest that fish oil exerts an antidiabetic and hypotriglyceridemic effect in this mouse strain by inhibiting the expression of specific genes that control fatty acid synthesis.  



Donald B. Jump

Michigan State University, East Lansing, MI, USA


The liver plays a central role in whole body lipid metabolism. Recent studies have shown that two transcription factors: peroxisome proliferator activated  receptor (PPARa) and sterol response element binding protein (SREBP1c), play  a critical role in the balance between hepatic fatty acid/triglyceride  synthesis and fatty acid oxidation. N3-polyunsaturated FA (PUFA) activate hepatic PPARa to enhance mitochondrial, peroxisomal and microsomal fatty acid oxidation. In contrast, N3-PUFA suppresses hepatic SREBP1c levels  leading to a decline in fatty acid and triglyceride synthesis. In a mouse model of obesity (ob/ob), which displays insulin resistance, N3-PUFA activates PPARa, but fail to suppress SREBP1c. Analysis of microsomal fatty acid metabolism in livers of lean and obese mice has revealed a significant  decline in the metabolism of PUFA through NADPH-dependent pathways. The most significant effect is the decline in the generation of epoxy-FA and  the expression of a key enzyme involved in epoxy fatty acid synthesis, i.e.  CYP2C23. We speculate that obesity associated changes in hepatic fatty acid metabolism may contribute to the dysregulation of SREBP1c. Failure of N3-PUFA to down-regulate SREBP1c may contribute to elevated hepatic lipid synthesis/storage.




Bengt Vessby

University of Uppsala, Uppsala, Sweden. 


Epidemiology suggests that a high intake of fish may reduce the risk of developing glucose intolerance in elderly people. The incidence of diabetes in Greenland, where people have had a high intake of marine fats, is low. Long-chain w3 FA (FAs) in the diet can prevent the development of insulin resistance in experimental animals fed a high fat diet. A moderate fish intake, compared with a low fish intake, seems to reduce the risk of developing cardiovascular disease in humans. Addition of fish oil or fatty fish to the diet has reduced the incidence of cardiac death in subjects with coronary heart disease.  The reason for the cardioprotective effect of w3 FAs is not clearly established but the current view favours an antiarrythmic, and possibly antithrombogenic, effect. There are as yet few data supporting an antiatherosclerotic effect of w3 FAs in humans. Also, the possible mechanism behind the suggested antidiabetogenic effect of fish or w3 FAs is not well characterized. In contrast to animal experiments, no clear positive effects of long-chain w3 FAs on insulin secretion or insulin sensitivity has been documented in controlled trials in humans. Several studies have shown a tendency for blood glucose concentrations to increase, both in the fasting and post-prandial states after addition of w3 FAs or fatty fish to the diet, other studies have shown no impairment of the glucose control. It has been discussed whether the dose of w3 fatty FAs, as well as the degree of impairment of insulin secretion, could be factors influencing these results. On average, the changes of the blood glucose levels, or HbA1c, have been numerically small and recent meta-analyses have not verified a significant negative over-all effect of n-3 fatty FAs on blood glucose control.  Other concerns regarding dietary fish oil supplementation are the conflicting reports on LDL cholesterol levels and particle size and of increasing PAI-1 concentrations (in spite of lowered triglyceride levels and unchanged insulin levels) potentially increasing the CHD risk. Even if these are not consistent findings they call for a certain conservatism in prescribing fish oil in higher doses in diabetes before we have more convincing documentation. There are still many questions to answer. Should all patients with diabetes (type 1 and typ 2, with or without documented CHD) take w3 supplements and if so – which dose? Should patients with newly detected diabetes and those with poor glucose control and severly reduced capacity for glucose stimulated insulin secretion be treated in the same way?  As for now there are good arguments for an increased proportion of (fat) fish in the diabetic diet (epidemiological support, cheap price, controlled dose, good antioxidant protection, “displacement” effect, other protective factors?) while the place of fish-oil supplementation remains controversial while we are waiting for the results of further intervention studies. 



Angella A. Rivellese

Federico II University Medical School, Naples, Italy


The Italian Fish Oil Multicenter Trial was performed in order to elucidate in a large sample of hypertriglyceridemic patients with and without glucose intolerance or diabetes, the metabolic effects of a moderate amount of long chain w3 FA (2580 mg EPA+DHA for the first two months and 1720 mg for the following 4 months). This randomized, double blind, placebo controlled study was performed in 935 patients, 470 assigned to w3 FA and 465 to placebo; 55% had either impaired glucose tolerance or type 2 diabetes.  The main results of the study were:  No negative effects on blood glucose control; a significant reduction in plasma triglycerides (-21%) of the same level in patients with and without abnormalities in glucose tolerance; a modest, but significant increase in LDL cholesterol; no effect on HDL cholesterol in the whole group, while in male type 2 diabetic patients there was a significant greater increase in HDL cholesterol compared to that observed in normoglycemic individuals. Moreover, in the context of this trial, our center performed additional evaluations in a small group of type 2 diabetic patients with hypertriglyceridemia in order to evaluate the effects of w3   in particular on insulin resistance. w3   had no effect on the insulin resistance of these patients, as well as it has been shown more recently also in healthy people.

Diabetic control is not adversely affected by fish oil


William E. Connor

Oregon Health Sciences University, Portland, OR, USA


 In the 1960s and 1970s the favorable effects of fish oil consumption in diabetics was stressed by the Danish workers studying disease patterns in the Greenland Eskimos.  Subsequently fish oil feeding to diabetic rats led to improvement in insulin sensitivity.  Similar results occurred in type 1 diabetics and glucose control was improved or unaffected.  However, the administration of fish oil to type 2 diabetics led to impaired glucose control in studies without a placebo control of an equivalent amount of fat calories.  Later it was concluded that these early type 2 diabetic studies were problematic.  Long-term (up to 1 year) studies were conducted with fish oil and a placebo oil randomly allocated.  Fasting blood glucose levels, Hb-A1c values, plasma peptide C levels and 24-hour urinary glucose were unchanged by fish oil.  In all of these studies there were beneficial changes in plasma triglyceride levels and in LDL size without any changes in HDL.  LDL increases were dependent upon the amount of plasma triglyceride lowering which occurred after fish oil.       It was concluded that fish oil did not adversely diabetic control in type 2 diabetics and perhaps improved glucose control in type 1 diabetics.  There should be no hesitation in using fish oil for its beneficial effects upon vascular disease in diabetic patients. 



Mark Deeg

Indiana University, Indianapolis, IN, USA


Early studies examining the effect of omega 3 FA in diabetic patients suggested that this class of FA worsened glycemic control.  However, many of those studies were not randomized trials or controlled properly and used high doses of omega 3 FA.  Since then, 18 trials in type 2 diabetic patients ( 800 patients in total) have utilized  a parallel or crossover design of 3 to 24 weeks in duration with generally  lower doses of omega 3 FA (3-10 gm/day).  A recent meta analysis of 12 of these trials showed that omega 3 FA did not significantly affect fasting blood glucose or HbA1c.  Thus, omega 3 FA do not need to be held from type 2 diabetic patients in fear of worsening glycemic control.   

w3 FAs


Christie Ballantyne

Baylor College of Medicine, Houston, Texas USA


Hypertriglyceridemia may contribute to the development of atherosclerosis by increasing expression of cell adhesion molecules (CAMs). Although the cellular expression of CAMs is difficult to assess clinically, soluble forms of CAMs (sCAMs) are present in the circulation and may serve as markers for CAMs. In this study, we examined the association between sCAMs and other risk factors occurring with hypertriglyceridemia, the effect of triglyceride reduction on sCAM levels, and the role of soluble vascular cell adhesion molecule-1 (sVCAM-1) in monocyte adhesion in vitro. Compared with normal control subjects (n=20), patients with hypertriglyceridemia and low HDL (n=39) had significantly increased levels of soluble intercellular adhesion molecule-1 (sICAM-1) (316+/-28.8 versus 225+/-16.6 ng/mL), sVCAM-1 (743+/-52.2 versus 522+/-43.6 ng/mL), and soluble E-selectin (83+/-5.9 versus 49+/-3.6 ng/mL). ANCOVA showed that the higher sCAM levels in patients occurred independently of diabetes mellitus and other risk factors. In 27 patients who received purified n-3 fatty acid (Omacor) 4 g/d for > or =7 months, triglyceride level was reduced by 47+/-4.6%, sICAM-1 level was reduced by 9+/-3.4% (P=.02), and soluble E-selectin level was reduced by 16+/-3.2% (P<.0001), with the greatest reduction in diabetic patients. These results support previous in vitro data showing that disorders in triglyceride and HDL metabolism influence CAM expression and treatment with fish oils may alter vascular cell activation. In a parallel-plate flow chamber, recombinant sVCAM-1 at the concentration seen in patients significantly inhibited adhesion of monocytes to interleukin-1-stimulated cultured endothelial cells under conditions of flow by 27.5+/-7.2%. Thus, elevated sCAMs may negatively regulate monocyte adhesion.





Trevor A Mori 

University of Western Australia and the West Australian Heart Research Institute

Perth, Western Australia, Australia 


In recent studies in humans we have shown significant benefits of w3 fatty acids on blood pressure (BP). The first, was a randomised, controlled trial examining the independent and combined effects of dietary fish and weight-loss on 24hr ambulatory BP in 63 treated, overweight hypertensives,  for 16-wks. Fish and weight-loss had significant independent and additive effects on 24hr ambulatory BP. The second study, examined the independent effects of EPA or DHA, using a double-blind, randomised, placebo-controlled parallel design. Fifty-six mildly hyperlipidaemic but otherwise healthy men, took 4g daily of purified EPA, DHA, or olive oil capsules for 6 weeks. DHA, but not EPA, reduced 24hr and awake ambulatory BP. We have demonstrated that a daily fish meal as part of a reduced-fat diet, had additive effects on BP reduction in obese treated hypertensives.  Furthermore, DHA, but not EPA, significantly reduced ambulatory BP. Thus, DHA may be the principal w3 fatty acid that lowers BP in humans.




Ingrid Toft

University Hospital, Tromsø, Norway 


N-3 FA may beneficially influence endothelium mediated vasodilatation as well as renal microcirculation. Diabetic patients often develop endothelial dysfunction and hypertension secondary to nephropathy.  Theoretically, n-3 FA may therefore be more effective in reducing the blood pressure in diabetic patients than in non-diabetic persons. Fish oil studies on diabetic patients have been focused on effects on lipid and  glucose metabolism, and not so much on changes in blood pressure. In the relatively few placebo controlled studies done on diabetic patients who were not treated with antihypertensive drugs during fish oil intake, systolic and diastolic blood pressure were reduced by  4 - 8  and 3 - 5 mmHg,  respectively. No added benefit of fish oils on blood pressure control could be detected in diabetic patients on antihypertensive medication. It is not known if fish oils may be effective in preventing the development of hypertension in diabetic patients. Conclusion: Blood pressure reduction during fish oil intake in diabetic patients with untreated mild hypertension seems to be slightly higher, or at least similar to that what is observed in non-diabetic persons. Future studies are necessary in this field.         



Gary McVeigh

Queen's University of Belfast, Ireland


Omega-3-FA favorably influence many of the mechanisms   involved in atherogenesis and may reduce mortality from coronary heart disease. We found that dietary supplementation with omega-3-FA improved endothelium-dependent responses to the infusion of acetylcholine into the brachial artery. These responses were accompanied by improved compliance characteristics of the arterial circulation. These data support   the hypothesis that the direct vascular effects of omega-3-fatty  acids on arterial reactivity and wall characteristics may contribute to their cardioprotective actions in humans.      



Clemens von Schacky

University of Munich, Germany 


A number of biologic modulators of inflammation (e.g. cytokines, growth factors and adhesion molecules), are reduced by w-3 fatty acids. In vitro this was true for e.g. vascular cellular adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, interleukin (IL)-1, -6 and -8 on a protein level. Ex vivo, after dietary supplementation to humans, this has been observed for platelet-derived growth factor-A, and -B, and monocyte chemoattractant protein-1 on an mRNA level and for leukotriene B4, tumor necrosis factor a, interleukin-1b, and -6 on a compound level. Clinically, as demonstrated in adequate intervention trials with dietary w-3 fatty acids in patients, this seems to translate into a more benign course of chronic inflammatory diseases like chronic polyarthritis, IgA-nephritis, chronic inflammatory bowel disease, and coronary atherosclerosis.



Ernst J. Schaefer

Tufts University, Boston, MA,USA


Remnant-like lipoprotein particles are produced as a result of the

catabolism of triglyceride-rich lipoproteins of both intestinal and

liver origin. ApoB-100 and apoB-48 containing remnant particles have a

residence time of about 5 hours in plasma, are cholesterol-enriched, and

are atherogenic. These particles are increased in patients with

diabetes, renal disease, and premature coronary heart disease (CHD).

Elevated remnant-like lipoprotein (RLP) cholesterol > 10 mg/dl is a

significant independent CHD risk factor, especially in women. This assay

is now FDA approved for the diagnosis of type III hyperlipoproteinemia

or dysbetalipoproteinemia as well as for CHD risk assessment. In the VA

HIT study in men with low HDL and CHD, RLP cholesterol was 3 fold

elevated as compared to controls, while TG levels were similar. Moreover

in this study, baseline RLP C values were significantly related to the

development of new CHD events. RLP C values can be significantly reduced

by control of diabetes, weight loss, n3 fatty acids (especially EPA and

DHA), fibrates, and statins, especially simvastatin and atorvastatin.

Elevated RLP C values increase brachial artery reactivity.



William S. Harris

Mid America Heart Institute, Kansas City, MO, USA


Fish oils rich in marine w3 FA have clear effects on serum lipid and lipoprotein levels. When consumed in relatively large doses (i.e., 3-6 g/d), w3 FA reduce fasting triglyceride levels by 20-40%. However, at lower intakes (i.e., 1 g/d), minimal effects are noted. Similarly, at high doses, LDL-C levels often rise 10-20% (especially in the short-term and in hypertriglyceridemic patients), but not at lower intakes. Although these findings have largely come from studies In non-diabetic patients, current evidence suggests that the same is true in type 2 diabetes. In 14 data sets taken from placebo-controlled, randomized trials in patients with type 2 diabetes, an average of 3.7 g of w3 FA was given per day. The mean triglyceride decrease was 33%, and the decrease was statistically significant in every study. LDL-C levels increased an average of 10%, but in only 3 data sets were the increases statistically significant. When considering the effects of low intakes of w3 FA on LDL-C, no studies have yet been reported in diabetic subjects. In non-diabetic subjects, intakes of 2 g or less have produced a 3% increase in LDL-C on average, similar to that seen in the GISSI Prevenzione study. Thus, both moderate (3-4 g) and low (<2 g) low w3 FA intakes have a minor impact on LDL-C levels. Whether this is clinically significant is unclear, but the positive results of several clinical trials focusing on total mortality would argue that the impact is negligible.



Christine M Williams

University of Reading, Reading, UK 


The atherogenic lipoprotein phenotype (ALP), is a collection of blood lipid abnormalities that include moderately raised triglycerides, low HDL and raised small dense LDL (LDL3).  It is believed to represent the dyslipidemia of insulin resistance, although it can occur in the absence of carbohydrate intolerance and may be present in up to 25% of middle aged males in developed countries. Omega-3 FA might be expected to be beneficial in countering the lipid abnormalities of the ALP, since raised triglycerides appear to be the primary metabolic defect that drive changes in LDL particle size and density. The few studies that have investigated effects of oemga-3 FA in ALP populations, support this proposition. Our own studies in this group have shown that 2.5 g/d of omega-3 FA lead to reductions in triglycerides of 30% and reductions in small dense LDL of 23%. In this study we also observed that increases in total LDL following omega-3 FA were confined exclusively to subjects with an apo E4 genotype.



Arne Nordøy

University Hospital, Tromsø, Norway

Dyslipidemia is common in diabetics and in patients with coronary heart  disease (CHD) In two double blind parallel  studies  patients with dyslipidemia were  treated with the combination of  Simvastatin or Atorvastatin and omega-3  FA (FA) in two dosages and placebo.  The addition of omega-3 FA   increased the lipid lowering effects of statins, reduced the concentration of  small, dense LDL particles and reduced postprandial hyperlipemia.  In  addition the postprandial  activation of factor VII which was pronounced in  these subjects were abolished.  No significant changes in blood glucose or  insulin levels were observed during the treatment.  In conclusion omega-3 FA  in combination with statins represent an important and safe alternative  treatment to patients with dyslipidemia with or without combination of  diabetes.    




Howard R. Knapp

Deaconess Billings Clinic Research Division, Billings, MT, USA


Considerable controversy exists on the effects of many PUFA on hemostasis, since extrapolation of in vitro findings or animal studies to human clinical situations is difficult. The effect of background diet and other cultural factors also appears to have an influence; the positive clinical findings in ASCVD with 18:3n-3 enrichment in a “Mediterranean Diet” is in contrast to a large negative study of 5-6g/day 18:3n-3 supplementation of several thousand middle-aged men in Oslo.  The reported dramatic decline in cardiovascular events and post-operative thrombosis in Norway during the war years did coincide with marked dietary changes, but also with numerous other life-style alterations. The prospective DART and GISSI trials, however, provide good evidence that even low doses of n-3 PUFA likely benefit hemostasis in patients with vascular disease. Studies during 1985-95 achieved some consensus that dietary long-chain n-3 PUFA, but not other LC-FA, prolong template bleeding time, reduce accelerated eicosanoid synthesis (such as TxA production during platelet aggregation), modestly retard platelet aggregation, and reduce vascular tone. More recent studies have clarified that these changes are not associated with an increase in clinical bleeding (e.g. post-CABG), but there has also been more appreciation that post-prandial events are significant for both atherogenesis and thrombosis. Post-prandial changes do occur in clotting factor activation, but there is not agreement that this relates to thrombin formation. Evidence also exists for post-prandial platelet activation, and part of the beneficial effects of n-3 PUFA may relate to their reduction  of post-prandial lipemia. Further work will help to define appropriate markers for beneficial changes in hemostasis induced by n-3 PUFA in patients with vascular disease.



Erik Berg Schmidt

Aalborg Hospital, Aalborg, Denmark


Heart rate variability (HRV), a measure of cardiac autonomic nerve balance, is associated with a reduced risk of sudden cardiac death.  We have studied the association between fish consumption, cellular levels of  omega-3 FA and HRV, measured by 24-hour Holter monitoring. We have studied healthy subjects, patients with CHD, patients with diabetes mellitus and patients on hemodialysis. We have undertaken intervention studies with fish oils in patients with CHD, renal disorders and healthy volunteers.  We conclude that fish consumption, cellular levels of omega-3 FA (in particular DHA) and fish oil supplementation are positively associated with HRV. This suggests that marine omega-3 FA may decrease the risk of sudden cardiac death.



Peter L McLennan

Univ of Wollongong, NSW, Australia


  Dietary fish oil prevents fatal cardiac arrhythmias and sudden death in many animal models. Arrhythmia vulnerability appears inversely associated with the incorporation of docosahexaenoic acid (DHA 22:6n-3) into cardiac membrane phospholipids. In the rat, the time-course of antiarrhythmic activity of dietary fish oil follows the time-course of membrane fatty acid changes.  In diabetic rats, cardiac membrane long-chain PUFA (especially DHA) are put at risk by reduced activity of fatty acid desaturases. With increasing evidence of an essential role for myocardial DHA in optimal heart function, dietary supplementation with omega-3 FA may be important for reducing risk of cardiac dysfunction in diabetes.



Alexander Leaf

Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA


There is much evidence that n-3 polyunsaturated fatty acids (PUFAs) will prevent fatal ventricular arrhythmias in animals, and increasing clinical evidence that the same protection occurs in humans. The mechanism for this prevention of sudden cardiac death is that these PUFAs act by modulating ion currents responsible for electrical activity in excitable tissues, both heart and brain. At present it seems that the inhibitory actions of the PUFAs on the voltage-dependent fast sodium channels and on the L-type calcium channels are most important for these beneficial effects. The evidence for these effects will be briefly reviewed and some simple dietary suggestions will be offered.  Since the incidence of ischemic coronary heart disease is very prevalent among middle aged diabetics, this preventive action of the PUFAs may have considerable public health benefit for diabetic subjects.



Artemis P. Simopoulos

The Center for Genetics, Nutrition and Health, Washington, D.C., USA 


Studies on the evolutionary aspects of diet indicate that major changes have taken place in our physical activity and diet, particularly in the type and amount of essential FA (omega-6 and omega-3) and antioxidant intake.  Assuming 35% of energy came from animals and 65% from plants, the estimated intake of essential FA from animal and vegetable sources in the Late Paleolithic period shows that the ratio of linoleic acid to a-linolenic acid (LA:ALA) is 0.70, whereas the ratio of longer chain omega-6:omega-3 is 1.79, giving a ratio of total omega-6:omega-3 of 0.79.  In the United States, again considering the same subsistence ratio of animal sources:plants sources of 35:65, the current diet would provide a ratio of 16.74, which is close to estimates of 15-20:1 of other investigators.  Considering other populations, i.e., in Japan the omega-6:omega-3 ratio is 4:1, and in the United Kingdom this ratio is 15:1, whereas 20 years ago it was 10:1.  Similar ratios have been suggested for northern Europe and Holland with lower ratios in southern Europe due to higher consumption of olive oil instead of corn and safflower oils.  In the past 20 years the ratio changed from 10:1 to 15:1 in England and northern Europe.  The shift in the decrease in omega-3 fatty acid intake is reflected in the declining concentrations of docosahexaenoic acid (DHA) and rising concentrations of LA in human milk.  The traditional diet of Greece prior to 1960 had a ratio of 1-2:1.  In general, there are a few reliable estimates of the intake of longer chain omega-3 PUFA. The increase in the omega-6:omega-3 ratio is a totally new phenomenon in the diet of human beings.  Current intake differs from our ancestors’ intake who consumed omega-6 and omega-3 FA in roughly equal amounts.  Such an enormous change in a short period of time does not allow time for adaptation. The omega-3 and omega-6 essential FA are not interconvertible in the human body and are important components of practically all cell membranes.  Omega-6 and omega-3 FA influence eicosanoid metabolism, gene expression, and intracellular cell communication.  Because the PUFA composition of cell membranes is to a great extent dependent on dietary intake, appropriate amounts of dietary omega-6 and omega-3 FA need to be considered in making dietary recommendations, and these two classes of PUFAs should be distinguished because they are metabolically and functionally distinct and have opposing physiological functions.  Their balance is important for homeostasis and normal development.  A balanced omega-6:omega-3 ratio in the diet is essential for normal growth and development and should lead to decreases in cardiovascular disease, other chronic diseases and improve mental health.   



Sonja L. Connor

Oregon Health Sciences University, Portland, OR, USA


Incorporating n-3 FA (FA) into diabetic diets is fraught with the same problems as incorporating n-3 FA into the diet generally.    n-3 FA are not the magic bullet.  Simply adding n-3 FA to an otherwise unhealthy diet will not overcome health-risks associated with other nutrients.  For example, seafood available for consumption in 1997 was about 100 grams a day in Estonia, Finland and Spain while the CHD mortality/100,000 men, age-standardized, was highly variable (583 in Estonia, 329 in Finland and 216 in Spain).  Therefore, in addition to increasing the intake of n-3 FA, it is necessary to reduce the intake of pathogenic dietary factors (cholesterol, saturated and trans FA, n-6/n-3) and increase the intake of protective dietary factors (n-3 FA, carotenoids, vitamins E and C, folate and fiber).  Which is best -- linolenic acid or EPA and DHA?  EPA, DPA and DHA available for consumption in 1997 increased as CHD mortality decreased (Eastern and Central European countries 0.10% kcal/578 deaths per 100,000 men, Western European countries 0.12/297, Mediterranean countries 0.14/230 and Asian countries 0.22/121.  Linolenic acid did not increase as CHD mortality decreased (Eastern and Central European countries 0.60% kcal, Western European countries 1.20, Mediterranean countries 0.67 and Asian countries 0.66).  Because linolenic acid can be converted to EPA and DHA, and has been associated with the prevention of fatal arrhythmias, it is important to include linolenic acid as well as EPA and DHA in the diet.  The intake of linolenic acid increased in the United States with the introduction of Canola oil and Canola oil margarine and would increase even more if people would purchase meat from animals that had grazed on grass and increase consumption of leafy vegetables.    Diet vs lifestyle.  Both the public and health professionals are, for the most part, in a “diet mode”.  Many think CHD prevention or treatment means changing abruptly to a diet that minimizes the intake of meat, cheese, ice cream and chocolate while doubling the intake of grains, beans, vegetables and fruits.  The culture needs to change to an “eating style mode” that focuses on trying new foods and recipes.  This will result in gradually modifying one’s eating style as opposed to changing one’s diet on the spot.    So Much Science, So Little Seafood.  Even though the strength of the science is substantial, there are significant barriers to incorporating seafood into the diet. People generally have experienced seafood only in the form of fish sticks or canned tuna. have little knowledge about how to identify high quality fresh seafood.  don’t know how to cook seafood. complain that cooking fish leaves a lingering smell.  worry that seafood may not be safe to eat.    Health professionals can help in a number of ways.  Promote buying frozen seafood, much of which has been flash frozen at sea and will be top quality when cooked from the frozen state or as soon as it is thawed. List the ways to identify high quality fresh seafood. Advise people to wash seafood and pat it dry with paper towels before cooking it. Provide simple recipes – seafood is the fast food of lower fat cooking. Let people know about seafood cooking and tasting opportunities. To minimize any fish smell when cooking, suggest running the kitchen exhaust fan and/or heat water containing lemon juice or vanilla. Put seafood safety in context with the safety of other foods. Promote working on environmental issues that will make our waters free of contamination. Remember something has to be heard 7 times before it sinks in.