Skeletal muscle glucose uptake in patients with chronic myeloid leukemia on tyrosine kinase inhibitor therapy

Disturbances in glucose metabolism upon treatment with the tyrosine kinase
inhibitor (TKI) nilotinib frequently occur in patients with chronic myeloid
leukemia (CML), causing diabetes mellitus and metabolic syndrome. It is
suggested that insulin resistance plays a role in the pathophysiology of
nilotinib-induced hyperglycaemia, however the underlying mechanism remains
unclear. Since skeletal muscle insulin resistance is considered to be the
initiating defect in the development of diabetes type II, even before *-cell
failure and overt hyperglycemia develops, it is of highly clinical interest to
study the effects of TKIs on skeletal muscle. Recently, we showed a reduction
in glucose uptake upon incubation with nilotinib in skeletal muscle cells in
vitro. Interestingly, we also showed a reduction in glucose uptake upon
incubation with imatinib (another TKI used in the treatment of CML), despite
the fact that imatinib treatment is actually associated with better glycaemic
control in patients with diabetes mellitus. This study aims to confirm these in
vitro findings in skeletal muscle of CML patients and to assess its clinical
relevance. In order to be able to study glucose uptake in skeletal muscle
tissue in vivo, it is necessary to stimulate the glucose uptake by either an
exercise or insulin stimulus. Interestingly, the mechanism by which exercise
and insulin stimulate glucose uptake is different. Therefore, we designed a
study to examine skeletal muscle glucose uptake under both exercise and
hyperinsulinemic conditions to further explore glucose dysregulation in TKI
users.

The current study aims to compare skeletal muscle glucose uptake after 1) an
exercise stimulus and 2) under hyperinsulinemic conditions between CML patients
on nilotinib, CML patients on imatinib and non-CML controls.

Cross-sectional exploratory study

During this study CML patients will not be exposed to a major risk, as standard
care will not be withheld: patients will not be taken off their medication and
will be carefully screened by a medical doctor. Contra-indications for the
maximal aerobic cycling test and [18F]FDG PET/CT will be checked during the
medical screening procedure and are listed as exclusion criteria for the study.
Venous blood withdrawal can induce a local hematoma (<5%). However, this is
completely reversible within 2 weeks and will not induce permanent damage.
[18F]FDG PET/CT is a procedure with minimal radiation burden. The clamp
procedure is considered a safe procedure to control plasma glucose levels, and
will be performed under continuous supervision of a physician.

We applied the risk classification as outlined in the document
*Kwaliteitsborging mensgebonden onderzoek 2.0*, formulated by the NFU
(Nederlandse Federatie van Universitair Medische Centra). For this study, we
have classified the risk as negligible for the participating patients.