Hi,

I would like to direct the attention of the l
ist members to a paper (1) that closes a crucial
gap in our understanding of the sequence of metabolic
events finally resulting in diabetic blindness.

There is growing evidence that an accumulation
of omega-6 fatty acids and especially their
elevated blood levels (free fatty acids, FFAs)
are causative factors in the development of
endothelium dependent vascular diseases (1,2).

The paper (1) convincingly shows that
these FFAs in concentrations actually present
in the blood of diabetics (literature in 1)
and persons with a high cardiovascular risc (2)
specifically induce the expression of certain
endothelial surface molecules. The enhanced
expression of these factors is a well known
starting point for the attachment of blood cells
('leukocyte rolling') which are responsible for
the induction and perpetuation (3) of
inflammatory processes resulting in atheroslerosis.

As FFAs are not only elevated in diabetes but in
many high-risk states like obesity, stress, and
insulin resistance, too, the omega-6 content
of the adipose tissue could be responsible for
the high blood levels as these fats are
always primarily released.

Diabetics are not only unable to keep their
blood glucose levels low. The increase of the
FFAs is often more severe and precedes the
increase of glucose. Additionally, the
diabetic liver is unable to extract and
adequately metabolize omega-6 acids
thus leading to high blood levels and
consecutively to diabetic retinopathy and
blindness (1).

The actions of omega-6 FAs are in part dependent
on their enzymatic conversion into hormonally
active hydroxy acids (1). One receptor that is
activated by these hormones (4) is the
receptor for the thiazolidinedione class of
antidiabetic drugs. A well known adverse effect
of these drugs is weight gain. The increase of
omega-6 consumption in westernized populations
could to some extent be responsible for the
obesity epidemic.

Since about 100 years pathologists knew that the
deposition of so called amyloid in pancreatic
islets is typical for human, feline, and simian
diabetes. Amyloid is an aggregation product of
the hormone amylin which is stoichiometrically
cosecreted with insulin. One of the best inducers
of amyloid deposition are omega-6 FFAs (5,
for Alzheimer-amyloid see 6).

A very interesting reading in this context is the
the paper of Staffan, Loren, et. al. (7),
highlighting a principal difference between the
nutrition in Kitava and Sweden. The intake of
polyunsaturated omega-6 and monounsaturated fats
in Kitava is very low (not more than 2% each
compared to 16% mono and 5% poly in Sweden), while
the intake of carbs is very high (70%). But
vascular risk and body weight are both very low,
in spite of low protein intakes.

Such a diet is not very 'paleo' and points to the
possible role of omega-6 uptake. It could even be
more important than consumption of carbs.

Omega-6 FAs disturb and interfere with delicate
hormonal control systems (prostaglandins,
leukotrienes, lipoxins, hydroxy-FAs, omega-3-FA
interconversion) and are merely one enzymatic
(lipogygenase-) step away from hormonally active
substances.

roland

(1)
Chen W, et. al.: Dyslipidemia, but not hyperglycemia,
induces inflammatory adhesion molecules in human
retinal vascular endothelial cells.
Invest Ophthalmol Vis Sci. 2003 Nov;44(11):5016-22.

(2)
Yli-Jama P, et. al.: Serum free fatty acid
pattern and risk of myocardial infarction:
a case-control study.
J Intern Med. 2002 Jan;251(1):19-28.

(3)
Ross R.: Atherosclerosis--an inflammatory disease.
N Engl J Med. 1999 Jan 14;340(2):115-26.

(4)
Shankaranarayanan P, et. al.: IL-4 induces
apoptosis in A549 lung adenocarcinoma cells:
evidence for the pivotal role of
15-hydroxyeicosatetraenoic acid binding to
activated peroxisome proliferator-activated
receptor gamma transcription factor.
J Immunol. 2003 Jan 15;170(2):887-94.

(5)
Ma Z, Westermark GT. et. al.: Effects of free
fatty acid on polymerization of islet amyloid
polypeptide (IAPP) in vitro and on amyloid fibril
formation in cultivated isolated islets of
transgenic mice overexpressing human IAPP.
Mol Med. 2002 Dec;8(12):863-8.

(6)
Wilson DM, et. al.: Free fatty acids stimulate
the polymerization of tau and amyloid beta peptides.
In vitro evidence for a common effector of
pathogenesis in Alzheimer's disease.
Am J Pathol. 1997 Jun;150(6):2181-95.

(7)
Lindeberg S, et. al.: Determinants of serum
triglycerides and high-density lipoprotein
cholesterol in traditional Trobriand Islanders:
the Kitava Study.
Scand J Clin Lab Invest 2003;63(3):175-80.