The effect of Glucocorticoid Receptor Polymorphisms and Metabolically Active Genetic Variants on Glucose Metabolism in the Skeletal Muscle

Glucocorticoids (GCs) such as the stress hormone cortisol are produced in the
adrenal glands. In order to exert their effects in the human body, they need to
be bound to the glucocorticoid receptor (GR), which makes the GR an essential
factor in mediating cortisol effects. GC's are well known for thier effects in
the human body such as anti-inflammatory and immunosuppressive actions, and
their effects on glucose and protein metabolism. The efficacy of GCs and the
prevalence as well as the severity of side effects are highly variable between
individuals whereas sensitivity to GCs in the same patient seems to be rather
stable, suggesting genetic factors to play a role in GR sensitivity.

Recently it was found that a polymorphism (= genetic variation) in the GC gene
(more specifically BclI) is associated with an increased response to GCs,
hereby confirming the hypothesis that the BclI indeed is a functional
polymorphism.

In follow up of this finding, we tested patients of the big a combined cohort
study (CODAM and Hoorn Studies) and found that homozygous carriers of the BclI
polymorphisms have increased total body fatness and insulin resistance. This
finding is of major importance because it might (partly) explain why some
patients might be more susceptible to weight gain and the development of
insulin resistance, ultimately leading to type 2 diabetes. Understanding the
underlying mechanisms through which this polymorphism might act to induce these
effects can contribute to a better understanding, treatment and prevention of
type 2 diabetes. Unfortunately, at present, the exact mechanism through which
the BclI polymorphism leads to hypersensitivity of the GR and its subsequent
metabolic and body compositional effects remains poorly understood.

The group of Prof. Schrauwen has performed a variety of studies, investigating
the effects of ectopic lipid accumulation in several organs (in obesity and
type 2 diabetes) and the relationship with the development of insulin
resistance. Doing so, the glucose and fat metabolism in the skeletal muscle of
these subjects has been quite well characterised. Furthermore so, biopsy
material and plasma samples are available from these studies for further
research.

Genotyping subjects (both obese and type 2 diabetic subjects) from these
studies for GR polymorphisms and other genetic variants influencing
energy-metabolism would provide an excellent opportunity to investigate the
effects of these polymorphisms on substrate metabolism in the skeletal muscle
in a minimally invasive manner since no new human tissue has to be obtained and
all measurements have already been performed. It only requires a new blood
sample for genetic determination.

At the time of inclusion, almost all subjects have given their consent that
their tissue may be used for further research in line with the initial research
and that they can be approached for additional research.

The major objective is to investigate the effects of the GR polymorphisms on
metabolism in the skeletal muscle, in order to unravel the pathophysiological
mechanisms underlying previously observed clinical effects in carriers of this
polymorphisms. This will be done by investigating the following (already
obtained) parameters:
-Body composition (underwater weighing)
-Insulin sensitivity (hyperinsulinemic-euglycemic clamp)
-Substrate oxidation (indirect calometry during the clamp)
-Skeletal muscle oxidative capacity
-VO2max-test
-Skeletal muscle lipid accumulation in muscle biopsies.

Blood plasma samples will be obtained to genotype each subject for the GR
polymorphisms and other genetic variants influencing energy metabolism.

In this observational study, all subjects enrolled will be approached and asked
to give one blood sample (if DNA is not already available) in which genotyping
for the GR polymorphisms and genetic variants influencing energy-metabolism can
be performed. Subjects will be divided per genotype the above mentioned
parameters will be compared among the different genotypes of the GR
polymorphisms.

Combining the four studies, provides an excellent opportunity to investigate
the effects of these polymorphisms on glucose and protein metabolism in the
skeletal muscle in a minimally invasive manner since no new human tissue has to
be obtained and all measurements have already been performed. Only one vial of
blood from each subject needs to be obtained.