Diabetic persons and fish
oil
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 (1). 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 (2). The
development of atherosclerosis is greatly accelerated in persons with
diabetes (3).
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 A(sub 2) 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
(11). 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 (13) 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 (13). 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 A(sub 1C) level, plasma and urinary
C-peptide levels, and 24-hour urinary glucose excretion (14). 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 (15), 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 (8). 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 (18). 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 (15) 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 with diabetes.
William E. Connor, MD
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