The central goal therefore, is to identify mechanisms contributing to an improved mitochondrial fat oxidative capacity after physical activity and consequently identify the mechanisms which are responsible for the development of clinically overt…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
DAG levels, ATGL protein content, insulin sensitivity, lipid accumulation and
mitochondrial functioning in cardiac muscle and skeletal muscle.
Secondary outcome
Plasma free fatty acids, basal glucose level, body composition, VO2max.
Background summary
A key feature in the pathogenesis of type 2 diabetes mellitus is a decreased
ability of insulin to stimulate glucose uptake in peripheral tissues, i.e.
insulin resistance. Skeletal muscle plays a major role in the development of
(whole body) insulin resistance. However the mechanism behind the development
of skeletal muscle insulin resistance is still poorly understood. Nevertheless,
there is compelling evidence that the accumulation of fat in non-adipose
tissues is involved and that intracellular fatty acid metabolites of this IMCL,
such as diacylglycerol (DAG), long-chain fatty acyl CoA (LCFACoA) and ceramide,
can cause insulin-resistance. This is probably due to the fact, that patients
suffering from type 2 diabetes are characterized by a decreased fat oxidative
capacity and that DAG may accumulate if lipase activity results in hydrolysis
of primarily triacylglycerols (TAG) and not diacylglycerols. Recently, the main
triacylglycerol lipase responsible for hydrolysis of TAG to DAG,
AdiposeTriGlycerideLipase (ATGL), was identified. Increased ATGL
expression/activity in type 2 diabetes potentially contributes to chronically
elevated DAG levels and the development of type 2 diabetes. Next to ATGL, other
lipases and lipid-coating proteins are involved in regulating intramuscular
triglyceride lipolysis. In addition, it is well known that type 2 diabetic
patients have an increased risk for cardiovascular diseases, including
heart-failure. Therefore it is tempting to suggest that type 2 diabetes
mellitus is, next to increased skeletal muscle fat accumulation, also
characterized by increased cardiac fat accumulation and mitochondrial
dysfunction.
Study objective
The central goal therefore, is to identify mechanisms contributing to an
improved mitochondrial fat oxidative capacity after physical activity and
consequently identify the mechanisms which are responsible for the development
of clinically overt type 2 diabetes. The first aim of the study is to
investigate whether proteins, involved in muscular lipid handling, are altered
in persons with type 2 diabetes, compared to healthy control subjects, and
whether this leads to elevated fatty acid metabolite levels. Since several
investigations show a reduction in the incidence of diabetes after the
performance of physical exercise in persons of high risk, our second aim is to
examine whether lipid content in cardiac and skeletal muscle of type 2 diabetes
patients is increased and whether this is associated with impaired oxidative
capacity compared to healthy control subjects. Finally, the effect of a 12-week
physical activity training program on fatty acid metabolism in skeletal muscle
and on lipid accumulation and oxidative capacity in cardiac and skeletal muscle
in type 2 diabetic patients compared to healthy controls will be examined.
Study design
The subjects will be invited for screeningstests. These tests include a medical
examination, physical investigation, ECG, Oral Glucose Tolerance Test (OGTT),
control of laboratory parameters. In addition, the followings tests will be
done, before and after the training program: body composition, muscle- and fat
biopts, maximal cycling test, fat accumulation and mitochondrial functioning of
the heart muscle and the skeletal muscle, and a hyperinsulinemic-euglycemic
clamp.
Study burden and risks
Blood samples, infusions and muscle biopts might cause bruisings; participation
of the trainings program can possibly cause muscle stiffness or muscle pain.
universiteitssingel 50
6200 MD Maastricht
Nederland
universiteitssingel 50
6200 MD Maastricht
Nederland
Listed location countries
Age
Inclusion criteria
All subjects:
- Male sex
- Age 50-65 years
- BMI 27-35 kg/m2
- Stable dietary habits and physical activity levels;For diabetic patients only:
- Must be on sulphonylurea- or metformin therapy for at least six months with a
constant dose for at least two months, or on dietary treatment for at least six
months
- Well-controlled diabetes: fasting plasma glucose concentration must be <10.0
mmol/l at the time of screening.;For healthy controls only:
- normoglycemic according to WHO criteria
- no family history of diabetes
Exclusion criteria
- Female sex
- Unstable body weight (weight gain or loss > 3 kg in the past three months)
- Participation in an intensive weight-loss program or vigorous exercise program
during the last year before the start of the study
- Active cardiovascular disease
- liver disease of liver dysfunction (ALAT>2.5 x increased)
- renal dysfunction
- systolic blood pressure >160 mmHg or diastolic blood pressure > 100 mmHg
- haemoglobin < 7.5 mmol/l (anaemia)
- use of medications know to interfere with glucose homeostasis (i.e.
corticosteroids)
- abuse of drugs and/or alcohol
- participation in another biomedical study within 1 month before the first
screening visit
- severe diabetes which requires application of insulin or patients with diabetes-
related complications
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 | NL11297.068.06 |