The primary aim of this study is to determine the causal relationship between the accumulation and inflammation of perivascular adipose tissue (PVAT) and insulin-stimulated glucose uptake in skeletal muscle, measured using dynamic PET-CTA, in…
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Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome parameter is insulin-stimulated 18F-FDG uptake in quadriceps
muscle (expressed as Ki) as measured by means of [18F]-FDG PET and PVAT
quantity and inflammation measured by CT angiography.
Secondary outcome
Secondary study parameters are:
- Skeletal muscle blood flow measured by contrast enhanced ultrasonography
(CEUS);
- Hepatic, myocardial, and whole-body glucose uptake rate (Ki) measured with
PET-CT;
- Skeletal muscle mitochondrial function measured by means of Oroboros in
skeletal muscle biopsies;
- Skeletal muscle intracellular insulin signalling pathways measured by Western
blot in muscle biopsies.
Background summary
Insulin resistance, defined as insulin-stimulated glucose uptake in the body,
is primary factor underlying postprandial glucose clearance and a major
hallmark in the development of type 2 diabetes mellitus (T2DM). In this
context, approximately 70-80 percent of glucose uptake takes place in skeletal
muscle, which is therefore an important determinant of T2DM risk. As such, the
muscles microcirculation contributes to skeletal muscle glucose uptake by
hitherto unclarified mechanisms. A recently identified part of this
microvascular bed is so-called perivascular adipose tissue (PVAT), and this
tissue has been shown in mice and isolated human muscle arterioles to regulate
muscle blood flow and glucose uptake.
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.
Furthermore, quantity and inflammation of PVAT can be determined in man using
CT angiography. During the current study, we will therefore evaluate whether
PVAT properties differ between prediabetic and healthy individuals and relate
to the effects of insulin on skeletal muscle glucose uptake and blood flow.
For this purpose, PVAT properties will be compared between fifteen individuals
with prediabetes and fifteen healthy controls matched for age and sex and
related to skeletal muscle glucose uptake and blood flow. All subjects will
then undergo the optimized dynamic PET protocol to assess insulin-stimulated
skeletal muscle glucose together with whole-body glucose uptake measures. A
one-step hyperinsulinemic, euglycemic clamp will be performed to measure
whole-body insulin sensitivity. Detailed characterization of PVAT in
prediabetes can provide a new target for preventing T2DM and provide a basis
for modeling prediabetes in vitro.
Study objective
The primary aim of this study is to determine the causal relationship between
the accumulation and inflammation of perivascular adipose tissue (PVAT) and
insulin-stimulated glucose uptake in skeletal muscle, measured using dynamic
PET-CTA, in healthy and prediabetic men and (postmenopausal) women.
Study design
Observational cross-sectional study design.
Study burden and risks
This study will not provide direct benefits to the participants, and the main
burden will be the time investment. In total, participants will visit
Maastricht University twice (including the screening) for measurements. To
minimize the required number of participants, we will conduct an observational
cross-sectional study involving 32 individuals: 16 healthy controls (with an
allowance for dropouts) and 16 individuals with prediabetes (with an allowance
for dropouts). The study requires at least 30 participants to complete the
study.
The measurements performed are low-risk, though bruising may occur from blood
draws or muscle biopsies. These risks are minimized through state-of-the-art
techniques and sterilization of the equipment. The contrast used during
ultrasonography carries minimal risk. Risks associated with the clamp and
PET-CT are low due to the clear exclusion criteria and the experience of the
researchers conducting the tests. For the PET scan, an 18F-FDG bolus will be
injected into the participants. This is a radioactive glucose tracer commonly
used in current medical practice. The total radiation exposure is approximately
5.94 mSv per participant (PET-CT= ~ 5.64 mSv + CTA= ~ 0.29 mSv = 5.94 mSv,
compared to the normal background radiation in the Netherlands of about 2.9 mSv
per year). Additionally, a contrast fluid used during the CT scan also has a
low risk.
Universiteitssingel 50
Maastricht 6229 ER
NL
Universiteitssingel 50
Maastricht 6229 ER
NL
Listed location countries
Age
Inclusion criteria
1. Caucasian (people will be excluded when having a >=50% racial African/Asian
background);
2. Male or (postmenopausal; defined as 1 year after the last cycle) female;
3. Age between 40-75 years;
4. BMI: 25-35 kg/m2;
5. Pre-diabetes in one the following criteria:
a. Impaired glucose tolerance: plasma glucose values >= 7.8 mmol/l and <= 11.1
mmol/l, 120 minutes after glucose drink consumption during OGTT in screening;
b. Impaired fasting glucose: Fasting plasma glucose >= 6.1 mmol/l and <= 6.9
mmol/l;
c. Insulin resistance: glucose clearance rate <= 360 ml/kg/min, as determined
using OGIS120;
d. HbA1c of 5.7-6.4%;
6. Stable dietary habits (no weight loss or gain >3kg in the past 3 months);
7. Sedentary lifestyle (not more than 2 hours of vigorous exercise per week).
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded
from participation in this study:
1. Not meeting all inclusion criteria;
2. Type 2 diabetes (fasted blood glucose > 7 mmol/L or non-fasted > 11mmol/L);
3. Any condition, disease or abnormal laboratory test result that, in the
opinion of the Investigator, would interfere with the study outcome, affect
trial participation or put the subject at undue risk.
4. Alcohol consumption of >2 servings per day;
5. Currently smoking, or having quit recently or a longer time ago;
6. Low Hb (men: <8.6 mmol/L; women <7.4 mmol/L);
7. Subjects using anticoagulant medication (antiplatelet agents can be used,
but other medications should be excluded);
8. Subjects who have participated in another biomedical study within the last 3
months that could interfere with the study results;
9. Subjects were involved in previous research that included PET/CT scanning;
10. Participants who do not want to be informed about unexpected medical
findings; *
11. Participants who do not want that their treating physician to be informed;
12. Inability to participate and/or complete the required measurements;
13. Participation in organised or structured physical exercise (>2h per week);
14. Allergic or hypersensitive to iodine-containing contrast medium.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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In other registers
| Register | ID |
|---|---|
| CCMO | NL87584.068.24 |