Determination of Insulin-stimulated Hepatic Glucose Uptake by PET-CT Measurements

Insulin Resistance Clinical Trial

— ISGU  

Official title:

Determination of Insulin-stimulated Hepatic Glucose Uptake by PET-CT Measurements

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04938544
• Other study ID #: NL74609.068.20
• Status: Recruiting
• Start date: August 1, 2021
• Est. completion date: May 31, 2023

Study information

• Verified date: March 2023
• Source: Maastricht University Medical Center
• Contact: Jeremy B Sagarminaga, MSc
• Phone: 0638145779
• Email: jeremy.basset.s[@]gmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

In the absence of excessive alcohol consumption, increased levels of fat in the liver (>5%) are diagnosed as non-alcoholic fatty liver (NAFL). It has been shown that NAFL is strongly associated with impairments in metabolic health such as hepatic and whole-body insulin resistance. Insulin resistance is seen as the earliest hallmark in the development of type 2 diabetes.

Insulin has two main effects on the liver: suppressing endogenous glucose production (EGP) and increasing glucose uptake. While the former has been extensively studied and is known to be impaired in NAFL, no studies have yet examined whether insulin-stimulated hepatic glucose uptake is affected by NAFL.

Recent methodological developments allow us to visualize and quantify glucose uptake in any given tissue using dynamic Positron Emission Tomography (PET) with 18Fluorinated glucose tracer (FDG) during insulin stimulation.

In the present study, we will in a first instance optimize the insulin-stimulated whole-body PET protocol and apply the dose as reported in the literature 4 megabequerels per kg of body weight (MBq/kg) (±8 mSv) in the first three subjects. It will then be evaluated whether the dose can be decreased in the remaining measurements. Another twelve individuals will then undergo the optimized dynamic PET protocol to assess insulin-stimulated hepatic glucose together with whole-body glucose uptake measures. Liver fat content and composition will be assessed by proton magnetic resonance spectroscopy (1H-MRS). Fasted De Novo Lipogenesis (DNL) will also be measured by deuterated water. Additionally, a two-step clamp will be performed to measure whole-body insulin sensitivity and insulin-stimulated suppression of EGP. The identification of the contributing factors to insulin resistance during the development of NAFL is crucial in order to develop more effective strategies for the prevention and treatment of metabolic disorders.

Description:

Objective:

To determine the association between insulin-stimulated hepatic glucose uptake measured by dynamic PET and liver fat content in overweight/obese subjects.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 15
• Est. completion date: May 31, 2023
• Est. primary completion date: May 31, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 45 Years to 75 Years

Eligibility

Inclusion Criteria:

• Caucasian (people will be excluded when having a =50% racial African/Asian background)

• Male or postmenopausal female

• Aged 45-75 years at start of the study

• Body mass index (BMI) 27 - 38 kg/m2

• Stable dietary habits (no weight loss or gain >3kg in the past 3 months)

• Sedentary lifestyle (not more than 2 hours of vigorous exercise per week)

Exclusion Criteria:

• Type 2 diabetes (fasted blood glucose > 7 mmol/L)

• Any condition or medical history that would in the investigator's or dependent physician's opinion interfere with the study, with study outcomes or increase the risk of the study procedures

• Alcohol consumption of >2 servings per day

• Smoking

• Low Hb (men: <8.6 mmol/L; women <7.4 mmol/L)

• Use of medication known to interfere with the safety of study procedures

• Use of medication known to increase liver fat, like for instance corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen (Nolvadex), and methotrexate (Rheumatrex, Trexall).

• Subjects receiving thiazolidinediones (glitazones [pioglitazone, rosiglitazone]).

• Participation in research or medical examination that included PET/CT scanning in the last 3 months

• Contra-indication for MRI

Related Conditions & MeSH terms

• Insulin Resistance
• NAFLD
• Overweight
• Overweight and Obesity

Locations

Country	Name	City	State
Netherlands	Maastricht University	Maastricht

Sponsors (1)

Lead Sponsor	Collaborator
Maastricht University Medical Center

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Hepatic insulin sensitivity measured by hyperinsulinemic-euglycemic clamp	Hepatic insulin sensitivity is measured as % suppression of endogenous glucose production and peripheral insulin sensitivity is measured as Rd in µmol/kg/min. During the clamp, four blood samples in time are taken during each of the three steady states (basal, low insulin and high insulin phase). The average of these four blood samples will be taken for further calculations regarding glucose tracer kinetic: rate of appearance (Ra) and Rd.	10 hours
Other	Hepatic fatty acid composition by 1H-MRS	Liver fat will be quantified by 1H-MRS with which the water and fat resonances can be detected. The intensity of the fat resonance will be expressed relative to the water resonance (%). Hepatic fatty acid composition is measured as relative amount of SFA, MUFA and PUFA to the total amount of fatty acids determined by MRS.	1 hour
Other	De Novo Lipogenesis	DNL is measured as relative contribution of newly synthesized palmitate in the VLDL-TG pool expressed as %DNL. The fasted blood sample will be used for determination of newly synthesized palmitate in the VLDL-TG pool.	1 day
Primary	Insulin-stimulated glucose uptake measured by PET-CT measured by dynamic [18F]-FDG PET	Insulin-stimulated hepatic glucose uptake rate constant (Ki) will be determined by [18F]- FDG PET, by using the Patlak method (Patlak et al. 1983) in each voxel. Influx rate will be calculated in mL/cm3/min	1 hour
Primary	Hepatic fat content by 1H-MRS	Liver fat will be quantified by 1H-MRS with which the water and fat resonances can be detected. The intensity of the fat resonance will be expressed relative to the water resonance (%).	1 hour