The influence of metformin and a hypocaloric diet on thyroid radioactive iodide uptake in healthy volunteers: a pilot study.

Treatment with radioactive iodide (RAI) is a widely used and highly efficient
treatment for benign and malignant thyroid diseases, such as differentiated
thyroid cancer (TC). Specific thyroid iodide uptake is needed to assure
effective RAI treatment in TC, which is facilitated by the expression of a
sodium-iodide symporter (NIS) on the thyroid cell. Factors that influence
either positively or negatively the NIS expression and function could affect
the response to RAI treatment. We, and others have shown that that activation
of AMP-activated-protein-kinase (AMPK) leads to decreased NIS expression and
iodide uptake in in vitro studies and animal models. For this reason we will
focus in this study on modulators of AMPK activity in relation to thyroid
iodide uptake in humans. The first important modulator of AMPK is metformin, a
well known drug in the treatment of type 2 diabetes mellitus (DM). Because
there is evidence that thyroid disease and DM are closely linked and metformin
is investigated as important adjunct in the treatment of TC, we estimate that
there is a large group of patients that use metformin who undergo RAI
treatment, making it interesting to investigate the effects of metfromin on
thyroid iodide uptake. Secondly, we want to investigate the effects of a
hypocaloric diet, since hypocaloric conditions also induce AMPK activation.
During RAI treatment for TC, patients undergo thyroid hormone withdrawal or
administration of rhTSH to stimulated thyroid iodide uptake. Thyroid hormone
withdrawal results in symptomatic hypothyroidism, leading to complaints such as
weight gain and nausea, which could result in reduced food intake and thus
hypocaloric conditions. Since this could influence AMPK activation and thus
thyroid iodide uptake and RAI efficacy, it is relevant to investigate the
effect of altered caloric intake on thyroid iodide uptake.

To assess the physiological effects of metformin and hypocaloric dieting on
thyroid iodide uptake and thyroid function in healthy volunteers.

This is an investigator initiated interventional pilot study.

The first group of 7 subjects will follow a two week course of metformin
according a specific dosing scheme. Group 2 with 7 subjects will follow a
hypocaloric diet (40% caloric restriction, high fat, low carbohydrate content)
for two weeks. There will be a control group of 3 subjects to assess the degree
of intra-individual variation in thyroid iodide uptake.

Subjects will not benefit directly from this research but by participating they
could have an important contribution to optimizing RAI treatment to improve
efficacy and reduce adverse events. The risk of adverse effects is minimized by
choosing a healthy study population who will be screened for health problems.
We only use a short intervention period of twee weeks. The expected risk for
both interventions and control group are considered very low and we do not
expect any serious side effects from both interventions. All subjects will
donate blood and urine at 3 different time points, including blood donation for
health screening. Furthermore, subjects will undergo 123I uptake testing twice,
which is not associated with any side effects and radiation dose will remain
below recommend values.