HOW DO WE DIE - MARKERS OR MEDIATORS?
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 http://intramural.niaaa.nih.gov/eicosanoids/ 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."
DIABETES IN NATIVE AMERICANS: DIETARY APPROACHES TO REDUCING CVD RISK
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
THE GISSI PREVENZIONE STUDY- PRINCIPAL FINDINGS
Gruppo Italiano per lo
Studio della Sopravvivenza nell'Infarto miocardico
Roberto Marchioli
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.
EFFECTS OF N-3 FATTY ACIDS IN DIABETIC
PATIENTS IN THE GISSI PREVENZIONE STUDY
Roberto Marchioli
ASSOCIATION OF
DIETARY FISH AND OMEGA-3 INTAKE WITH PLASMA GLUCOSE IN THE CARDIA STUDY
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.
PREVENTION OF SUDDEN
DEATH BY LOW INTAKES OF N-3 POLYUNSATURATED FA
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.
DIABETES AS A RISK
FACTOR FOR CHD
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.
DIABETES, LIPOPROTEINS, AND ATHEROSCLEROSIS
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.
HEMOSTATIC ABNORMALITIES IN TYPE 2
DIABETES
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.
ALTERATIONS IN BLOOD PRESSURE AND
ENDOTHELIAL FUNCTION IN TYPE 2 DIABETES
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.
DIABETES AND
AUTONOMIC DYSFUNCTION: A CAUSE OF INCREASED CHD RISK?
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.
THE ROLE OF NONESTERIFIED FATTY ACIDS IN THE PATHOGENESIS OF THE
INSULIN RESISTANCE OF TYPE 2 DIABETES MELLITUS
John Miles
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.
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.
INSULIN RESISTANCE
AND w3 FAs: HUMAN
REGULATION OF LIPOGENIC GENE EXPRESSION BY FISH OIL.
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.
PPAR,
SREBP and N3-PUFA.
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.
HISTORICAL CONCERNS
REGARDING THE USE OF w3
FA:S IN DIABETIC PATIENTS
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.
MULTICENTER TRIAL OF w3 FA IN TYPE 2 DIABETIC PATIENTS.
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.
GLYCEMIC CONTROL AND MARINE w3 FA: A META-ANALYSIS
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.
CIRCULATING ADHESION MOLECULES AND w3 FAs
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.
EFFECTS OF w3 FA ON BLOOD PRESSURE
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.
FISH OILS AND BLOOD PRESSURE IN DIABETIC PATIENTS
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.
MODULATION OF ENDOTHELIAL HEALTH BY w3 FATTY ACIDS
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.
DIMINISHING INFLAMMATORY
RESPONSES WITH w-3 FATTY ACIDS
Clemens von Schacky
University of Munich, Germany
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.
EFFECTS OF w3 FATTY ACIDS ON LDL-CHOLESTEROL IN DIABETIC PATIENTS
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.
OMEGA-3 FA IN THE
TREATMENT OF THE ATHEROGENIC LIPOPROTEIN PHENOTYPE
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.
OMEGA-3
FA AND STATINS: COMBINED THERAPY FOR
DYSLIPIDEMIA
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.
OVERVIEW OF w3 FAs, HEMOSTASIS AND 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.
CAN OMEGA-3 FA IMPROVE HEART RATE VARIABILITY?
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.
OMEGA-3 FA AND
ARRHYTHMIAS: ANIMAL STUDIES
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.
ALTERING METABOLIC FUNCTIONS OF EXCITABLE TISSUES
BY w-3 FATTY ACIDS
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.
EVOLUTIONARY ASPECTS OF OMEGA-3 FATTY
ACID INTAKE
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.
INCORPORATING N-3
FATTY ACIDS INTO DIABETIC DIETS
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.