Effect of N3-polyunsaturated fatty acids on peripheral insulin sensitivity

Fatty acids (FA) are no longer considered solely as a source of energy but also
as potent regulators of intermediary metabolism. N3 poly unsaturated fatty
acids (N3 PUFA) have been shown to be associated with a lower prevalence of
cardiovascular diseases. FA are also involved in obesity induced insulin
resistance and DM2. Thus saturated fatty acids are known for their negative
interference on insulin stimulated glucose uptake in peripheral tissues. We
recently studied the effect of two different intravenous lipid emulsions
containing a mixture of MUFA, PUFA and saturated fatty acids on insulin
sensitivity (MEC 05-295) and found insulin resistance but no difference between
the two different lipid emulsions. Whether N3 PUFA have the same effect on
glucose metabolism in humans is not completely known. Lipid emulsions for
parenteral nutrition based on fish oil are now available. We hypothesize that
the fish oil based lipid emulsion SMOFlipid® has a less profound effect on
insulin sensitivity compared to the two earlier studied lipid emulsions.
To differentiate between the effect of similar FFA and similar lipid infusion
dose, we will administer a similar dose of 500 ml SMOFlipid® and Intralpid® in
an additional group of healthy subjects and measure the reduction in insulin
sensitivity compared to a control study day with saline infusion.

to measure peripheral insulin sensitivity and intramyocellular concentrations
of different FA metabolites (ceramide, gangliosides, diacylglycerol and
triacylglycerol) known to interfere with the insulin signalling cascade during
infusion of SMOFlipid® compared to iv saline.

Cross over intervention study

Hyperinsulinemic euglycemic clamp with stable isotopes and concomitant infusion
of fish oil containing lipid emulsion, SMOFlipid®, on one occasion, and control
saline infusion on the other occasion. At the end of both clamps a muscle
biopsy from the musculus vastus lateralis will be performed. Each participant
will serve as its own control. Studies will be performed in random assignment.
To differentiate between the effect of similar FFA and similar lipid infusion
dose, we will administer a similar dose of 500 ml SMOFlipid® and Intralpid® in
an additional group of healthy subjects and measure the reduction in insulin
sensitivity compared to a control study day with saline infusion. In this group
of participants no musle biopsies will be perfomed. Each participant will serve
as its own control. Studies will be performed in random assignment.

Participant will visit the AMC 3 times after an overnight fast: one inclusion
visit (2,5 hours) and two study days (each 9,5 hours). On every study day, 2
intravenous catheters will be inserted, one for infusion of labelled glucose
and insulin and one to draw blood samples. Stable isotopes are safe and have no
side effects. Hypoglycemia during infusion of insulin will not occur because we
measure bedside plasma glucose every 10 minutes. The fish oil containing
intravenous lipid emulsion, SMOFlipid® Fresenius Kabi Nederland B.V, is
registered for use as the lipid component of total parenteral nutrition.
During the muscle biopsy, subjects should not experience any discomfort,
because the biopsy area will be adequately anaesthetized. The day after the
muscle biopsy subjects may experience a sore feeling at the biopsy location,
which will resolve in a few days after the biopsy. Safety measures will be
taken to reduce the risk for a haematoma (pressure bandage). In our experience,
muscle biopsy is tolerated well and leaves minimal scarring. The total amount
of blood that will be withdrawn is 320 ml. This amount is not considered to be
of negative influence to the subject*s health.

To differentiate between the effect of similar FFA and similar lipid infusion
dose, we will administer a similar dose of 500 ml SMOFlipid® and Intralpid® in
an additional group of healthy subjects and measure the reduction in insulin
sensitivity compared to a control study day with saline infusion. The
intravenous lipid emulsion Intralipid® Fresenius Kabi Nederland B.V, is
registered for use as the lipid component of total parenteral nutrition, and
the most clinically used lipid emulsion in the Netherlands. Participnats in the
additional group will visit the AMC 4 times (one extra study day with
Intralipid infusion) In this addtional group of participants no muscle biopies
will be performed. The amount of blood that will be withdrawn in these
participants is 470 ml.
This amount is not considered to be of negative influence to the subject*s
health.