Targeting the beta-2 adrenergic pathway to improve skeletal muscle glucose uptake in healthy humans

Type 2 diabetes mellitus (T2DM) and its associated cardiovascular comorbidities
have developed into a leading cause of death in western countries. Medical and
non-medical treatments have failed to counter this *diabesity* epidemic,
fostering the need for novel therapies. In this context, we have recently
demonstrated robust improvements in insulin sensitivity in T2DM patients upon
10 days of mild cold acclimatisation, which proved to be primarily mediated
through an increased skeletal muscle glucose uptake and occurred independent of
improvements in classical regulatory pathways (i.e. insulin signalling or AMPK
activation). Given this background, it was recently shown that skeletal muscle
glucose uptake can be mediated through a novel pathway involving *2-adrenergic
receptors, through activation of mTORC2. As cold-exposure is well-known to
activate the sympathetic nervous system, this mechanism hence provides a likely
candidate to explain effects of cold acclimatisation on skeletal muscle glucose
disposal. Therefore, activation of this novel pathway could potentially be used
as a novel treatment to improve skeletal muscle glucose uptake in T2DM
patients. Indeed, we have recently observed dramatic improvements in glucose
homeostasis in diabetic rodents upon prolonged treatment with a low-dose of the
selective beta-2-agonist clenbuterol. Based on our data, activation of the
beta-2-mTORC2 pathway through supplementation with a selective beta-2-agonist
could significantly improve glucose tolerance in T2DM patients, thereby
contributing to a positive disease outcome. However, whether the beta-2-mTORC2
pathway can be activated in humans in vivo to improve glucose disposal and
thereby the glucose homeostasis, has thus far not been investigated.

To determine if short-term treatment with the selective beta-2-adrenergic
agonist clenbuterol improves glucose disposal via the mTORC2 pathway in lean,
healthy male individuals with normal physical activity

This study is a randomized, placebo-controlled, double-blinded, cross-over
study in which subjects will receive either the selective beta-2- agonist
clenbuterol (40 microg/day) or placebo supplementation for 2 weeks with a
4-week wash-out period.

For this study, subjects will consume clenbuterol (20 microgram/capsule) or
placebo tablets twice daily (40 microgram/day) for a total period of 4 weeks
(2x 2 weeks).

Participation in this study will not result in any health benefits for
subjects. This study will, however, expand our current knowledge regarding the
role of the beta-2 adrenergic receptor in skeletal muscle glucose uptake and
the glucose homeostasis in general. Furthermore, this study could potentially
open fundamentally new therapeutic avenues to prevent and treat T2DM.

Participation to this study will pose an intermediate risk to subject's health.
The main burdens for the subjects are:
- Burden of time: during this study, subjects will visit the University of
Maastricht at 6 different occasions (excl. screening and incl. 2 overnight
stays) in a period of 2 months. The total time which will be spend to the study
is approximately 67 hours, which is excluding travelling time.
- Potential side effects of clenbuterol: Despite the fact that clenbuterol is
supplemented at a low-dose, potential adverse effects could emerge, including
an increased heart rate/blood pressure, tremors, muscle spasms, dizziness and
headache.
- Invasive sample collection: During this study, several invasive sample
collections will be performed, including blood sample collection, muscle
biopsies and the hyperinsulinemic-eugluycemic clamp. These measurements could
be associated with local hematoma or bruise development. However, due to the
state-of-the-art techniques, risks for infection or prolonged bleeding will be
minimized.
- Unexpected medical findings: During the screening and measurements of the
study, unexpected medical findings might be found. Subjects will always be
informed regarding unexpected findings and this information will also be
communicated to the general physician.