Glucose transport and mitochondrial function in type 1 diabetes mellitus

Rationale: Type 1 diabetes mellitus (T1DM) is caused by immune-mediated
destruction of the insulin-producing pancreatic β-cells, resulting in lifelong
reliance on exogenous insulin (via multiple daily injections or insulin pump).
During exercise, glucose disposal increases via insulin-independent means in
healthy people and those living with T1DM. Some remnants of these cellular
features (such as increased NOX2 signalling) have also been described in animal
models of T1DM, but never for humans with T1DM. This insulin-independent
glucose signalling likely comes at a price of an impaired skeletal muscle
mitochondrial function. The observation that mitochondrial dysfunction and
exercise intolerance also occur in young, physically active, and otherwise
healthy individuals with T1DM confirms this suggestion. Since the cause of this
mitochondrial dysfunction in individuals with T1DM is unknown, this limits
preventive measures and effective treatment. Not only will we study the
intracellular metabolism in T1DM, we also expect that myokine secretion levels
are altered in T1DM, affecting inter-organ communication and whole-body glucose
and fat metabolism. In this project, we hypothesise that:
1) Individuals with T1DM will have larger NOX2-dependent cytosolic alterations
in metabolism in vastus lateralis biopsies compared to the individuals without
T1DM, and that these differences are exacerbated during exercise.
2) These alterations in insulin-independent glucose signalling contribute to
mitochondrial dysfunction, altered myokine secretion, and impaired exercise
tolerance in individuals with T1DM.
3) Aerobic exercise training will improve skeletal muscle glucose handling,
mitochondrial function and myokine secretion in T1DM.

Primary Aim: We aim to determine markers for NOX2-mediated insulin-independent
glucose uptake signalling pathways, mitochondrial function, myokine secretion
both at rest and after a bout of acute exercise in individuals with T1DM and
healthy controls, and secondly, to determine each of these variables both
before and after an exercise training intervention. The secondary objective of
this study is to obtain insight into the determinants of exercise intolerance
in T1DM by assessing the relationships between the measures obtained from
muscle biopsies (i.e. mitochondrial function) and whole-body exercise
tolerance, both before and after an exercise training intervention.

Study design: An exercise training intervention study in individuals with T1DM
and healthy controls will be performed to assess insulin-independent glucose
metabolism, mitochondrial function, and exercise tolerance by invasive as well
as non-invasive measurements.

4 weeks of moderate-intensity cycle exercise training on a cycle ergometer in
the laboratory. Sessions will consist of 3 x 30 minutes exercise in week 1, 3 x
40 minutes exercise in week 2, 3 x 50 minutes exercise in week 3, and 3 x 60
minutes in week 4.

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness: Participants in this study will be asked to
perform physical exercise tests, give muscle biopsies (4 samples), blood
samples (4 x 10-15 ml), and complete a 4-week exercise training intervention.
There is some extent of burden and risk associated with harvesting muscle
biopsies and blood samples, however this will be mitigated by the fact that
these procedures will only be carried out by highly trained physicians.
Moreover, the scientific gain from obtaining intracellular information
outweighs these relatively quick procedures with minimal discomfort afterwards.
The risks of the physical exercise measurements are negligible. The main risk
for the individuals with T1DM is the occurrence of hypoglycaemia during
exercise, which will be circumvented by observing strict pre-exercise
regulations for glucose concentrations: exercise will only commence if blood
glucose concentration is between 7-12 mmol.L-1.
There is a significant time investment on behalf of the participants, since
participants are required to visit the laboratory on 16 occasions for
approximately one-to-two hours per session. Although it cannot be guaranteed,
it is likely that participants in both groups will benefit from the exercise
training with regards to their physical fitness and overall health. Moreover,
participants will receive reimbursement for the biopsies. The outcome of the
research project is expected to provide insight in the critical physiological
determinants of exercise intolerance, insulin-independent glucose handling, and
mitochondrial dysfunction in T1DM. This will enable targeted interventions
(e.g. exercise training programmes, new drugs) aimed at ameliorating these
deleterious consequences of T1DM to be studied in future research.