Insulin-induced microvascular dilatation during a physiological stimulus - Studies in hypertension and obesity.

Title: Insulin-induced microvascular activity during a physiological stimulus -
Studies in hypertension and obesity.

One of mechanism involved in the insulin-mediated regulation of blood glucose
levels is the vasodilatory response by resis-tance vessels and preterminal
arterioles. These hemodynamic effects of insuline contribute to glucose uptake
(for approx. 40%) and several studies demonstrated impaired insulin-induced
hemodynamic effects in hypertension and obesity. However, in these studies the
hyperinsulinemia was artificially induced by a hyperinsulinemic euglycemic
clamp. Till so far it is unknown if these hemodynamic effects of insulin will
also occur with a physiological stimulus. In this study we will examine if the
insulin-induced microvascular effects will occur after a physiological stimulus
(i.e. a liquid high carb or high fat meal (MTT)). With that the physiological
importance of the insulin-induced microvascular dilatation can be elucidated.

Hypothesis:
We hypothesize that liquid meal intake and consequently the endogenous induced
hyperinsulinemia will lead to insulin-induced microvascular dilatation in
healthy normotensive subjects. Moreover, we suggest that the postprandial
plasma insulin concentration shows a positive correlation to insulin-induced
microvascular dilatation while the postprandial free fatty acid concentration
shows a negative correlation. Furthermore, we suggest that the insulin-mediated
microvascular dilatation, resulting from this fysiological induced
hyperinsulinemia, will be less in hypertensive and obese subjects compared to
the healthy controls.

1 : Will the intake of a liquid meal lead to insulin-induced microvascular
dilatation in healthy subjects?
2: Does meal composition (high fat meal vs. high carb meal) play a role in the
occurence of insulin-induced microvascular dilatation in healthy subjects?
3: Is this insulin-induced microvascular dilatation after a physiological
stimulus (liquid high carb meal and liquid high fat meal) impaired in obese and
hypertensive subjects compared to the healthy controls?

All subjects will bring 3 visits to the AZM. The following interventions will
be applied:
- microcirculation measurement - intake liquid high carb meal -
microcirculation measurement
- microcirculation measurement - intake liquid high fat meal - microcirculation
measurement
- microcirculation measurement - intake placebo - microcirculation measurement

During the visits 1 catheter will be inserted in the antecubital vein of the
lower dominant arm. Subsequently a set of microcirculation measurements will be
performed (t=0 min.). After this set of measurements (t=90 min.) subjects will
drink a liquid high carb meal, a liquid high fat meal or a placebo drink. 30
minutes after intake (t=120 min.) a second set of microcirculation measurements
will be performed.

During the study days the heart rate and blood pressure will be monitored and 8
venous blood samples of 5 ml and 8 venous blood samples of 1 ml will be taken.
The intake of glucose or placebo will be randomly assigned.

The hypertensive subjects will be asked to discontinu the intake of
antihypertensive medication 3 weeks prior to the study.
All subjects will be asked to collect urine during 24hrs prior to the first and
second study day. Microcirculation measurements: 1) perfused capillary density
and functional capillary recruitment in the nailfold, visualized by a capillary
mi-croscope, 2) endothelium- (in)dependent vasodilation of finger skin
microcirculation, evaluated with laser Doppler measurements in combination with
iontophoresis of acetyl-choline and sodium nitroprusside, and 3) densities and
diameter of arterioles, capillaries and venules in the bulbar conjunctiva,
measured with conjunctival microscopy.
The high carb meals and high fat meals will be taken orally. During the visit
several blood samples will be taken, blood pressure and heart rate will be
monitored.

Discontinuing the antihypertensive medication can lead to symptoms and/or
unwarranted increases in blood pressure (>220/120 mmHg). When this will occur,
the medication will be started again and participation to the study will be
stoped. All methods used for measuring microcirculation are non-invasive. The
burden of these measurements is therefore negligible. Inserting the catheters
can be alittle bit painful and after removal sometimes bruises can appear. The
liquid high carb and high fat meals will be taken orally, no health risks are
involved. The used dose of acetylcholine and sodium nitroprusside is very low
and appeared to have side effects only in very rare cases (for example during
an allergic reaction). The effect is only local in the skin an whenever a side
effect will occur, the study will be immediately stopped. There will be taken
48 ml of blood during one study day. No burden or risk is involved with this
amount. De subject will be sober during the study day. Previous studies showed
that this isn't a big burden for a subject.