Total-body Glucose Utilization in Obesity

There are three goals for this study. One is to investigate how different emotions and exposure to cold affect blood flow in the body. The second aim is to study how insulin affects blood flow and tissue glucose uptake, and to study whether this effect is altered in obesity. Last, the study focuses on establishing the lowest dose of a PET radiotracer, oxygen-15 labelled water, that can be used in clinical studies with a new whole-body PET scanner.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Age 20-60 years
2. BMI either 18.5-25 kg/m2 or above 30 kg/m2
3. Use of hormonal contraception for women in child bearing age

Exclusion Criteria:

1. In the lean group history of obesity or type 2 diabetes
2. In the group with obesity: current or previous use of GLP-1-agonists or insulin
3. History of eating disorders
4. Smoking, use of narcotics, excessive use of alcohol
5. Previous participation in PET studies
6. Previous significant exposure to radiation
7. Claustrophobia
8. Active plans for concieving (both sexes)
9. Any other condition that in the opinion of the investigator could create a hazard to the subject safety, endanger the study procedures or interfere with the interpretation of study results