The study consists of two separate parts: the dose escalation study and the part studying
the effects of emotions and insulin on blood flow.
All participants will first undergo a screening visit starting with signing an informed
consent form. Then they will undergo a physical examination, are interviewed about their
medical history. Finally, some routine laboratory tests are collected, and a 75 g oral
glucose tolerance test is performed. The participants who are eligibile for the study
will continue to the PET studies.
The dose escalation study will be completed first. In this 8 participants will be studied
once with Siemens Biovision Quadra PET/CT scanner. They will receive eight doses of
oxygen-15 labelledradiowater (H2[15O]O) ranging from 25 to 700 MBq, with each dose
repeated twice to evaluate repeatability of each dose. These participants will not
undergo any further studies.
For the other subjects, there will be two more PET study visits.
On the first visit, the effects of emotions, evoked by short movie clips or cold exposure
of one leg, on whole-body blood flow will studied with oxygen-15 labelled radiowater.
Each participant will be studied 8 times in one session, with repeated H2[15O]O boluses
of 400 MBq followed by 7.5 min dynamic PET scans with Siemens Biovision Quadra PET/CT
scanner and a 5 min recovery and wash-out period.
On the other visit the effects of insulin on circulation will be studied by performing a
hyperinsulinemic, euglycemic clamp during the PET scan. During the clamp, fast-acting
insulin (NovoRapid, NovoNordisk) is administered intravenously at a fixed rate (40 mU/m2
body surface area/min). Plasma glucose is monitored every 5-10 minutes, and 20 % glucose
is administered at a varying rate to maintain euglycemia (5.0 mmol/L).
At the scanner a fasting H2[15O]O PET/CT scan (400 MBq) will be performed first. After
this, the hyperinsulinemic, euglycemic clamp is started, and the radiowater scans are
repeated 10 minutes and 50 minutes into the insulin infusion. 60 minutes after the start
of clamp, 100 MBq of glucose analogue tracer [18F]fluorodeoxyglucose is administered and
a 50 min dynamic PET scan is started. After the scan, insulin infusion is discontinued
and participants are monitored until plasma glucose levels are adequate for safe
discharge.
For a subgroup of participants, skeletal muscle microvascular bloodflow will also be
assessed with contrast-enhanced ultrasound performed during fasting and 30 minutes after
the start of clamp. The participants will be administered intravenous contrast agent, and
after steady plasma concentration is reached (2.5 min), the contrast agent micro bubbles
are destroyed with a high-intensity ultrasound signal, and the rate at which small
arterioles are refilled is measured.
Data will be analysed using in-house developed programs. Regions of interest will be
drawn manually for peripheral tissues (skeletal muscle, visceral, brown and subcutaneous
adipose tissue, liver, kidney, intestines) and using automated segmentation tools for the
brain.