To provide insight in the physiological significance and underlying mechanisms involved in the relation between gut microbiota, energy balance and insulin sensitivity in overweight men with impaired glucose homeostasis
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Before and after treatment, insulin sensitivity (2 step hyperinsulinemic
euglycemic clamp) will be investigated (hepatic and peripheral)
Secondary outcome
Secondary parameters are: fasting and postprandial energy expenditure and
substrate metabolism (indirect calorimetry), in vivo fatty acid handling and
fatty acid partitioning in skeletal muscle, and gut permeability (multi-sugar
test). Furthermore, adipose tissue and skeletal muscle gene/protein expression
of markers of oxidative capacity and inflammation will be determined (i.e.
AMPK) in addition to inflammatory markers in plasma. Faecal and circulating
short- chain fatty acids, and faecal gut microbiota composition (HITChip /NTG
sequencing) will be assessed.
Background summary
The relation between gut microbiota and obesity originates from several animal
studies, showing that the change of gut microbiota can induce changes in both
insulin resistance and body composition.
In addition, recent human evidence suggested that the composition of the gut
microbiota differs in lean vs. obese, and between diabetic and non-diabetic
individuals.
The above mentioned animal studies have shown that the permeability of the gut,
parameters of inflammation (in adipose tissue and the circulation), energy
expenditure, and the uptake of fatty acids in skeletal musle, might play an
important role in the relation between obesity and gut microbiota. However, no
studies on underlying mechanisms in human have been performed yet.
Therefore, the aim of the current project is to investigate the effects of
changed gut microbiota composition (by use of broad or small-spectrum
antibiotics (amoxicillin and vancomycin respectively), on parameters of body
weight control and insulin sensitivity.
Study objective
To provide insight in the physiological significance and underlying mechanisms
involved in the relation between gut microbiota, energy balance and insulin
sensitivity in overweight men with impaired glucose homeostasis
Study design
Double-blind randomized placebo-controlled intervention study
Intervention
Subjects will be treated with vancomycin (500 mg 3 times per day), amoxicillin
(500mg, 3 times per day) or placebo for 7 days.
Study burden and risks
Additional to initial screening, participants will be asked to visit the
university 7 times within a period of approximately 10 weeks (total time
investment 36 hours)
-During visit 1 (approximately 7 hours) insulin sensitivity will be determined
using a 2 step hyperinsulinaemic-euglycemic clamp, combined with indirect
calorimetry, and an adipose tissue biopsy will be collected.
-During visit 2 (5 hours), gut permeability will be determined by a sugar test.
Subjects will also hand in collected faeces.
-During visit 3 (6 hours), subjects will undergo a mixed meal stable isotope
test combined with indirect calorimetry. At baseline and 4 hours after the meal
intake, a skeletal muscle biopsy will be collected.
These tests will be followed by antibiotics-treatment for 7 days. After a wash
out period of 36 hours, the measurements performed during visit 1, 2 and 3 will
be repeated in the same order (visit 4, 5, and 6). Pre- and post intervention,
subjects will collect feces for 2 days.
-During visit 7 (approximately 30 minutes), a blood sample will be taken for
calculation of the HOMA-IR index, an adipose tissue biopsy will be collected
and subjects will hand in collected feces.
During all visits, except for visit 7,blood will be collected via a catheter.
At visit 7, a single blood sample will be taken. Venapunctures can occasionally
cause local hematoma or bruise to occur. Some participants report pain during
venapuncture. The adipose tissue biopsy might cause local hematoma as well.
Some participants report pain which is experienced as muscle pain after the
muscle biopsy. More often the muscle feels stiff for a couple of days after the
biopsy. To minimize the risk for a hematoma, the biopsy place will be
compressed for approximately 5 minutes after biopsy. The place of incision will
leave a small scar (* 3 mm for adipose tissue biopsy and * 8 mm for skeletal
muscle biopsy). To promote good wound healing, the incision will be sealed with
sterile steri-strips and a waterproof band-aid. The muscle biopsy will, in
addition, be sealed with a compression bandage.
The use of antibiotics can cause more diluted and frequent stools and may, in
approximately 10% of the users, cause diarrhea. Furthermore side effects of
vancomycin might be temporary or permanent hearing loss, or kidney
insufficiency, although very rarely reported. Since vancomycin capsules are
generally not absorbed into the bloodstream, systemic side effects are very
unlikely to occur. Amoxicillin might cause allergic skin reactions,
interstitial nephritis or blood disturbances, also rarely reported.
The use of [U13C]-palmitate in the mixed meal test, is not considered as
harmfull, since palmitate, as part of triglycerides, is a naturally occuring
food substance present in almost all oils and dietary fats. D2-glucose in the 2
step hyperinsulinaemic-euglycemic clamp has been approved for human use as
well. All other study procedures (sugar test and indirect calorimetry) are
standard tests in human biology research, causing to no additional risks for
the selected group of subjects.
Universiteitssingel 50
Maastricht 6229 ER
NL
Universiteitssingel 50
Maastricht 6229 ER
NL
Listed location countries
Age
Inclusion criteria
BMI 25-35 kg/m2, insulin resistant (HOMA_IR > 2.2), caucasian, male, 35-70 years, impaired glucose tolerance (IGT: 2h plasma glucose during 75g OGTT 7.8-11.1 mmol/l) and/or impaired fasting glucose (plasma glucose >= 5.6), stable body weight for at least three months (±3 kg).
Exclusion criteria
Known allergic reaction to vancomycin, teicoplanine, amoxicillin and other β-lactam antibiotics (penicillins and cefalosporins) or related antibiotics. Diabetes mellitus, hearing disorders, cardiovascular disease, kidney disease, cancer, asthma or bronchitis, liver malfunction, major illness with a life expectancy < 5 years, diseases affecting glucose tolerance (e.g. pheochromocytoma, Cushing*s syndrome, acromegaly), use of antibiotics in the past 3 months, gastrointestinal disease, plans to lose weight and participation in organized sports activities for >3 hours per week.
The use of the following drugs: β-blockers, lipid lowering-drugs (e.g. PPAR γ or PPARα (fibrates) agonists), glucose-lowering agents (including all sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinediones, repaglinide, nateglinide and insulin), anti-oxidants or chronic corticosteroids treatment (> 7 consecutive days of treatment).
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL38547.068.11 |