Up to 80% of women with breast cancer (BC) develop metabolic disorders, such as insulin
resistance, obesity, hyperinsulinemia, and glucose intolerance, during or after their
treatment. Such disorders increase BC mortality and the likelihood of relapse 2- and 3-fold,
respectively. However, it is not known why BC and/or the treatment hereof causes metabolic
disorders and very few studies have investigated the underlying biological causes.
Aims:
determine the involvement of insulin resistance in skeletal muscle in the metabolic
disorders prevalent in BC survivors
identify BC-and/or treatment-induced molecular changes in skeletal muscle
BC is a common cancer with 2.1 million new cases each year, and BC also causes the largest
number of cancer-related deaths among women worldwide. Fortunately, more people are now
surviving their cancer. In Denmark, the majority of the 300.000 cancer survivors, constitute
a group of ~ 70,000 women who have survived BC. However, there is a severe lack of research
into the physiological sequelae of cancer and/or treatment, including the metabolic health
consequences of BC. Recent epidemiological studies have revealed that 60-80% of women with BC
develop metabolic disorders that are similar to those observed in conditions such as type 2
diabetes (T2D) during or following their treatment. However, unlike T2D, the underlying
biological causes for the development of metabolic disorders with BC and/or the treatment are
poorly investigated. It is important to address this knowledge gap, as metabolic disorders
increase mortality among women with BC 2-fold and increase the likelihood of BC recurrence up
to 3-fold.
The investigators hypothesize that metabolic disorders in BC survivors are due to cancer
and/or treatment-mediated molecular rewiring of skeletal muscle, which causes insulin
resistance.
Scientific breakthroughs in obesity and diabetes research have shown that hyperinsulinemia
and hyperglycemia are most often caused by insulin resistance in skeletal muscle, fat, and
liver. In particular, skeletal muscle is essential for maintaining a normal metabolism as it
is responsible for up to 75% of the uptake of glucose from the blood in response to insulin.
It is thus likely that skeletal muscle insulin resistance causes metabolic perturbations in
BC survivors but this has not been investigated directly. Insulin-resistant skeletal muscle
does not respond normally to insulin, causing severe metabolic disorders. These include
hyperglycemia, hyperinsulinemia, dyslipidemia and hypertension; all conditions that are
increasingly being documented in women with BC and BC survivors It is likely that insulin
resistance in skeletal muscle is causing the metabolic disorders often present in BC
survivors. Since muscle plays key roles in metabolic regulation by keeping blood glucose and
insulin levels normal, it is extremely relevant to clarify the precise involvement of
skeletal muscle in BC-related metabolic disorders.
12 premenopausal women (Body Mass Index = 25-30) who were operated for BC (stage I-III) will
be included. Especially overweight premenopausal women develop markedly metabolic dysfunction
as determined by an oral glucose tolerance test. The subjects will be studied 3-10 weeks
after completing adjuvant chemotherapy. Twelve healthy weight-, activity- and age-matched
subjects will be recruited as controls (matched by bicycle exercise test, grip strength, dual
x-ray absorptiometry, and using the international physical activity questionnaire). Exclusion
criteria are as follows: Post-menopause at the time of BC diagnosis, metastatic cancer, < 4
or > 5 series of paclitaxel treatment, alcohol intake of > 7 items/week, smoking, known T2D
or metabolic syndrome, known cardiovascular disease and medical treatment thereof, or
impaired mobility. Insulin sensitivity will be measured via the hyperinsulinemic-euglycemic
clamp method. In short, basal muscle (from the vastus lateralus muscle) biopsies are taken
after 1 hour rest after which insulin (1.4 mU/kg/min) is administered while maintaining
euglycemia by continuous glucose infusion. Insulin-stimulated biopsies are taken after 1.5
hours.