The effect of acute whole-body heat exposure on liver insulin sensitivity and substrate metabolism

In a recent study, for the first time it has been shown that repeated exposure
to heat beneficially affects liver metabolism and induces a change in
whole-body substrate use. After 10 days of mild heat acclimation (6h per day,
10 consecutive days), rate of [glucose] disappearance (Rd) and endogenous
glucose production (EGP) were reduced in a fasted state, indicating improved
glucose homeostasis. Additionally, fat oxidation was increased after
acclimation. Importantly, although it has been shown that parameters of liver
metabolism improve after repeated whole-body heat exposure, it is unknown what
the acute effects of whole-body heat exposure are on the hepatic insulin
sensitivity. In order to get a superior understanding of the underlying
mechanisms and relationships between heat and metabolism, and how acclimation
effects build up and are established, the present study aims to assess the
effect of acute whole-body heat exposure on hepatic insulin sensitivity,
substrate use and related blood parameters in healthy obese volunteers.

To gain insight into the full spectrum of temperature-induced changes in
glucose homeostasis, the present study will be aimed at assessing the effect of
acute whole-body heat exposure on liver insulin sensitivity, substrate
oxidation and plasma metabolites in healthy overweight adults between 45 and 65
years, a population group at risk for development of metabolic disorders.

The study will be set up in a randomised cross-over design. The study will
consist of 2 test days in which the test subjects will be exposed to heat on
one day and to a neutral temperature on the second day. The two conditions will
be offered in random order

Heat exposureby means of a water-perfused suit. Water temperature during heat
exposure will initially be set at 39*C and adjusted as the test subject's core
temperature changes. In the neutral condition, the water temperature will be
set to 32*C.

We will take frequent blood samples, which can be dangerous in case of anemia.
This is why people with a low Hb will be excluded from participation. The total
amount of blood that will be taken in 2 days is maximal ~210mL (2x ~100mL
during clamp and 10ml during the screening). Blood sampling itself and the
infusions can cause bruises. Subjects that use anti-coagulants are excluded
from the study. Infections or continued bleeding are very rare.
Hyperinsulinemic-euglycemic clamping is a procedure we perform routinely in our
laboratory without notable complications. In rare occasions, subjects exhibit
symptoms of hypoglycemia (even if their blood glucose levels are still above 3
mmol/L). After successfully performing the clamp, blood glucose values will be
monitored for an additional 30-60 minutes with glucose infusion stand-by if
glucose levels happen to drop. Solid food and sugar-drinks will be provided
directly after finishing the clamp, to avoid the experience of hypoglycemia.

Heat exposure might be perceived as uncomfortable. Especially during the heat
condition, core temperature will be closely monitored during the procedures, as
described under 6.3.2 of the protocol C1. Maintaining core temperature at a
certain level (also called core temperature clamping) has been applied in many
previous studies, and has been reported as being a useful and safe tool for
standardization of a thermal strain in humans. Investigators will communicate
with the participants throughout the procedures to check comfort and well-being
of the participants. It will be ensured that a potential fluid dysbalance cause
by sweating during the measurement procedures will be compensated by isotonic
fluid intake during and after the clamp.

The Blanketroll ® III system, as described in section 7 of the study protocol
C1., is widely used in daily clinical routine to control body temperature
and/or maintain a desired temperature. The system works through conductive heat
transfer. Investigators involved in the study have obtained sufficient
(year-long) experience, with the Blanketroll ® III Hyper-Hypothermia system,
which means they can safely use and control it. By closely monitoring the
participant*s core temperature as described under 6.3.2 and section 7 of the
protocol C1., the risk for hyperthermia above the desired level of mild
hyperthermia of ~37.5*C should be negligible.