Ketogenic diet therapy in patients with acromegaly

Acromegaly is caused by a tumour located at the base of the brain in the
pituitary gland that produces too much growth hormone (GH). Symptoms caused by
the excess of GH, and consequently increased insulin like growth factor 1
(IGF-1), are disproportionate growth of body parts, fluid retention, snoring
and excessive perspiration. The various metabolic changes that occur due to
acromegaly increase the risk for insulin resistance, diabetes mellitus,
arterial hypertension, sleep apnoea and thus an increased risk of
cardiovascular disease if left untreated. The result is signs and symptoms,
increased mortality, morbidity, and greatly reduced quality of life (QoL).
Normalisation of GH and IGF-1 gives a normalisation of mortality, however
morbidity and QoL do not (completely) normalise. After surgery, a somatostatin
analogue is the primary medical treatment, however, normalisation occurs in
only 40% of patients.
Recently, in a proof-of-principle study, we showed that a 2-week ketogenic diet
(low in carbohydrates) in patients with somatostatin analogues could
significantly reduce IGF-1 values. Patients felt better and sometimes even
needed less somatostatin analogues. This proof of concept led to the new
hypothesis that acromegaly patients with somatostatin analogues should possibly
be treated with a eucaloric low-carbohydrate ketogenic diet for a longer period
of time to improve their biochemistry, symptoms and QoL. Additionally, this
diet can make a significant contribution in the treatment of insulin resistance
and glucose intolerance that often occur in this patient group.

In active acromegaly, glucose levels tend to be elevated, which is accompanied
by high insulin levels. This GH-driven hyperinsulinemia results in an unwanted
situation; the liver becomes even more GH sensitive. Redundant GH impairs
insulin secretion and reduces glucose uptake, on behalf of lipolysis, release
of free fatty acid (FFA), and hepatic glucose production. Insulin resistance is
characteristic for the development of diabetes mellitus in patients with
acromegaly.
Treatment with somatostatin analogs (SSAs) will suppress GH secretion from the
adenoma and insulin secretion from pancreatic B cells. SSAs reduce insulin
levels and increase HbA1c and postprandial glucose, with neutral effects on
fasting plasma glucose (FPG). The effect of ketogenic diet therapy on glucose
tolerance in acromegaly patients treated with SSAs is currently unknown.
Another treatment option for uncontrolled acromegaly is the GH receptor blocker
pegvisomant. Pegvisomant treatment has favorable effects on glucose metabolism,
lowering plasma glucose (FPG) and HbA1c. Unknown is whether under the
circumstances of a ketogenic diet,if proteolysis or ketogenesis will prevail in
acromegaly patients treated with pegvisomant, thus what will be the effect of
the ketogenic diet.

To determine the effect of a 6-month eucaloric very-low-carbohydrate ketogenic
diet on IGF-I levels in adult acromegaly patients.

A single-centre randomised controlled trial

A eucaloric ketogenic diet (30-40 g carbohydrate per day) for 3 months,
followed by a less strict ketogenic diet (50-60 g carbohydrate per day) for
another 3 months. The control group will receive a eucaloric diet according to
the national healthy food guidelines/Mediterranean diet.

The extent of the burden of our study is considered low. Dietary restriction
and the ketogenic diet have been proven feasible and safe in previous studies.
For this study, three extra blood samples by 3 venepunctures are taken. No
extra visits to the hospital or imaging studies are needed in order to obtain
all the information required for this study. Several standardized
questionnaires are asked to be filled in during and after the diet. Mentioned
questionnaires take about 30 minutes to complete. No other risks concerning the
dietary intervention are to be expected.