Total-body Glucose Utilization in Obesity (TOTAL)

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.

Study Overview

• Status: Recruiting
• Conditions: Obesity and Overweight
• Intervention / Treatment: Radiation: H2[15O]O PET/CT; Behavioral: Movies; Behavioral: Cold; Drug: Hyperinsulinemic euglycemic clamp; Radiation: [18F]FDG PET/CT; Drug: CEUS or Contrast enhanced Ultrasound

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Aino Latva-Rasku, MD, PhD; Phone Number: 358+23139857; Email: aehyyp@utu.fi
• Study Contact Backup: Name: Sanna Himanen, RN; Phone Number: 358+469200200; Email: sanna.himanen@varha.fi

Study Locations

• Finland
  • Turku, Finland, 20521
    • Recruiting
    • Turku PET Centre
    • Contact: Pirjo Nuutila, Professor; Phone Number: 35823131868; Email: pirjo.nuutila@utu.fi
    • Contact: Sanna Himanen, RN; Phone Number: +358469200200; Email: sanna.himanen@varha.fi
    • Sub-Investigator: Aino Latva-Rasku, MD, PhD
    • Sub-Investigator: Harri Harju, MA
    • Sub-Investigator: Nelli Tuomola, MD
    • Sub-Investigator: Miikka Honka, MD, PhD
    • Sub-Investigator: Hidehiro Iida, professor
    • Principal Investigator: Pirjo Nuutila, professor
    • Principal Investigator: Lauri Nummenmaa, professor
    • Sub-Investigator: Jouni Tuisku, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TOTAL dose test; The aim of the studies performed in this arm (8 subjects) is to test the lowest dose of H2[15O]O (radiowater) for the Siemens Quadra PET/CT scanner. Each participant will be studied once with the scanner with 4 different doses (25-700 MBq) of H2[15O]O, each repeated 2 times	Radiation: H2[15O]O PET/CT; H2[15O]O PET/CT, with a dose of 25-700 MB/bolus repeated 2-8 times per scan.
Experimental: TOTAL; The participants in this arm will undergo two PET visits. On one visit the effects of visual stimuli or cold on whole body perfusion will be studied with H2[15O]O PET/CT. On the second visit whole-body insulin sensitivity is studied with [18F]fluorodeoxyglucose PET/CT, and the acute and delayed effects of intravenous insulin on blood flow will be studied with H2[15O]O PET/CT.	Radiation: H2[15O]O PET/CT; H2[15O]O PET/CT, with a dose of 25-700 MB/bolus repeated 2-8 times per scan.; Behavioral: Movies; Participants will watch eight short movie clips, and the changes different emotions evoked by the clips will be studied using H2[15O]O PET/CT.; Behavioral: Cold; Participants will be studied with H2[15O]O PET/CT while one of their legs will be exposed to cold to study the effects of cold stimulus on whole-body blood flow.; Drug: Hyperinsulinemic euglycemic clamp; Participants will be administered intravenous fast acting insulin (NovoRapid, Novo Nordisk, 1 mU/m2 body surface area/min) together with 20 % glucose to maintain normal glucose values (5.0 mmol/L) to study the effects of insulin on whole body blood flow with H2[15O]O PET/CT, and to assess tissue insulin-stimulated glucose uptake with [18F]FDG PET/CT.; Radiation: [18F]FDG PET/CT; Whole-body [18F]FDG PET/CT scan to study tissue glucose uptake, dose 100 MBq; Drug: CEUS or Contrast enhanced Ultrasound; Contrast-enhanced ultrasound of left forearm muscles is performed during fasting and after 30-40 minutes of hyperinsulinemia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin-induced change in tissue blood flow	Brain, liver, skeletal muscle and brain blood-flow (ml/100 g/min) measured with H2[15O]O PET/CT	Change from fasting condition to 10 minutes and 50 minutes after the start of insulin infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects of insulin on skeletal muscle microvascular perfusion	The difference in the rate of refill of skeletal muscle small capillaries measured as contrast agent wash-in using contrast-enhanced ultrasound during fasting and during hyperinsulinemic, euglycemic clamp	Change from fasting condition to 10 minutes and 50 minutes after the start of insulin infusion
Tissue insulin-stimulated glucose uptake	Skeletal muscle, adipose tissue, liver and brain glucose uptake (micromol/100g/min) during hyperinsulinemic, euglycemic clamp measured with [18F]FDG PET/CT	Measured from 60 to 110 minutes after the start of insulin infusion
Effects of emotions on whole-body blood flow	Distribution of whole-body blood flow after visual stimuluses or cold exposure	Measured during 60-second activation blocks (visual stimuli) or during 5 min cold-exposure
Range of effective and feasible radiowater doses with whole-body PET/CT	Repeatability and reliability of different doses of H2[15O]O in assessing tissue blood flow in the brain, skeletal muscle, myocardium, liver and adipose tissue	During repetitive H2[15O]O scans (a total of 120 minutes)

Collaborators and Investigators

• Sponsor: Turku University Hospital
• Investigators: Principal Investigator: Lauri Nummenmaa, Professor, University of Turku; Principal Investigator: Pirjo Nuutila, professor, University of Turku, Turku University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2023
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: September 29, 2024
• First Submitted That Met QC Criteria: December 12, 2024
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 12, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: obesity; PET; radiowater
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Obesity
• Other Study ID Numbers: T335/2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No