Diabetes, Fish Oil, and Vascular Disease
William E. Connor, MD
15 December 1995 | Volume 123 Issue 12 | Pages 950-952
The major cause of death in patients with diabetes mellitus is macrovascular disease,
particularly coronary heart disease, stroke, and atherosclerosis of the lower extremities. Indeed,
the incidence of these ischemic complications is 1.7 to 4 times greater in men with diabetes than
in men without diabetes and is 2.7 to 6.4 times greater in women with diabetes than in women
without diabetes . The presence of diabetes even eliminates the usual protection from
coronary disease that premenopausal women have compared with men of similar age. Diabetic
persons of either sex have had a two- to four-fold increase in mortality in population studies
done throughout the world . The development of atherosclerosis is greatly accelerated in
persons with diabetes .
The reasons for increased vascular disease in diabetic persons are not completely known, but
certain risk factors are much more common in patients with diabetes, especially adult-onset
diabetes (non-insulin-dependent diabetes mellitus). These risk factors include hypertension,
hyperlipidemia, visceral obesity, and hyperinsulinemia and have been called the "deadly
quartet" or "syndrome x" [4, 5]. Several approaches may be taken to the prevention of coronary
disease and peripheral atherosclerosis in persons with diabetes. Better glucose control is
certainly one answer, but it is sometimes difficult to achieve in the free-living, affluent, and
sedentary U.S. population. Diet and drugs can be used to treat hypertension and
hyperlipidemia. All of these measures are helpful but may not completely solve the problem of
excessive vascular disease.
When evidence showed that Greenland Eskimos, because of their high intake of n-3 fatty acids,
had a much lower incidence of coronary disease than Danes [6, 7], a question was posed.
Would these fatty acids, found in fish and seal in the Eskimo diet, prevent coronary disease in
Western populations? These n-3 fatty acids are the very long chained and highly
polyunsaturated fatty acids: eicosapentaenoic acid (20:5) and docosahexaenoic acid (22:6).
They are present only in food from the oceans and fresh waters: fish, sea mammals, and
shellfish. Many studies then appeared showing that fish and fish oil preparations had many
diverse actions that could alleviate vascular disease [8, 9]. These included mild blood pressure
reduction, definite hypolipidemic effects, an antithrombotic action (achieved by inhibiting
thromboxane A2 synthesis in platelets), inhibition of cellular growth factors and monocyte
migration, and enhancement of nitric oxide production by the endothelium.
It seemed reasonable, then, that fish oil be used in patients with non-insulin-dependent and
insulin-dependent diabetes mellitus. Glucose homeostasis was achieved with no problems when
fish oil was used in persons with insulin-dependent diabetes mellitus [10, 11], and one study
actually showed less microvascular albumin leakage in the kidney . However, in some
studies, fish oil given to overweight patients with non-insulin-dependent diabetes mellitus caused
mild glucose intolerance compared with a control period [12, 13]. As Heine  has reviewed,
these adverse effects occurred in short-term experiments that had insufficient diet and weight
control when 15 g or more of fish oil (90 kcal) was added to the usual diet . A more recent
study comparing fish oil and olive oil (15 g given randomly over 12 months) showed no
difference in glucose homeostasis in persons who received fish oil compared with controls
according to five criteria: fasting glucose level, hemoglobin A1c level, plasma and urinary C-
peptide levels, and 24-hour urinary glucose excretion . At the same time, plasma triglyceride
and very-low-density lipoprotein (VLDL) levels markedly decreased during the fish oil period.
The randomized, double-blind, placebo-controlled approach taken by Toft and colleagues,
whose results are published in this issue , has provided more evidence for the absence of a
deleterious effect of fish oil on glucose metabolism. Toft and colleagues administered n-3 fatty
acids in a fish oil concentrate to 78 obese volunteers who had essential hypertension. Four 1-g
fish oil capsules provided both eicosapentaenoic acid and docosahexaenoic acid in a total
amount of 3.4 g/d. The placebo was 4 g of corn oil, which contained linoleic acid, an n-6
polyunsaturated fatty acid. After 16 weeks, fish oil had reduced the mean systolic blood pressure
by 4.4 mm Hg and the mean diastolic blood pressure by 3.2 mm Hg. This mild hypotensive
effect is similar to that shown in many other studies . Fish oil did not alter glucose control,
even in persons with mild glucose intolerance. The tests used were extensive: an oral glucose
tolerance test, a hyperglycemic clamp technique, and a euglycemic hyperinsulinemic clamp
technique. These tests measured insulin sensitivity and first- and second-phase insulin release.
At the same time, a mild hypolipidemic effect occurred, and plasma triglyceride and VLDL levels
decreased significantly. The high-density lipoprotein cholesterol level was also higher in the fish
oil group than in the corn oil group. The plasma cholesterol and low-density lipoprotein levels did
not differ between the fish oil and corn oil groups.
The hypotriglyceridemic effects of fish oil, which have been so universally observed, result from
a decrease in triglyceride synthesis in the liver and from an increase in the removal of
triglyceride from the blood. This has been documented in several studies done in humans and
animals [8, 16]. Because of these actions, fish oil has been useful in the treatment of
hypertriglyceridemic patients [16, 17], especially those with the types of hyperlipidemia (V, IV,
and IIb) so common in diabetic persons.
Both the epidemiologic evidence and the results of a subsequent clinical trial done in the United
Kingdom suggest that two to three fish meals per week might provide considerable protection
against coronary disease [8, 18]. The clinical trial of n-3 fatty acids involved several thousand
men who had recovered from myocardial infarction. The men who ate fish at least twice a week
for 2 years had a 29% reduction in total mortality, largely because they had fewer deaths from
coronary disease . Persons who could not eat fish were given three fish oil capsules per day
to supply the desired amount of n-3 fatty acids.
Practical advice for the patient with diabetes would be that he or she should consume fish
(prepared by poaching, grilling, baking, or broiling) two to three times per week. If eating fish is
not possible, the consumption of two to three fish oil capsules (1 g each) per day would provide
the equivalent amounts of eicosapentaenoic acid and docosahexaenoic acid.
Because the study by Toft and colleagues  indicates both that fish oil has no harmful effects
on glucose tolerance and that it has beneficial effects on blood pressure and plasma lipid levels,
fish or fish oil might now be considered useful in the prevention of vascular disease in patients
Author and Article Information
From Oregon Health Sciences University Portland, OR 97201.
Requests for Reprints: William E. Connor, MD, Department of Medicine, L465, Oregon Health
Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201-3098.
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