1. to determine whether the oxidation of BCAA (leucine) is impaired in patients with T2DM and in humans at risk to develop T2DM (first degree relatives). 2. to investigate whether an altered leucine oxidation in muscle is associated with insulin…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Protein and amino acid metabolism disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study objectives are:
i) to determine whether T2DM and FDR have lower rate of leucine oxidation (umol
kg-1 min-1) in muscle
ii) to evaluate whether altered leucine oxidation is associated with whole body
and hepatic insulin sensitivity (umol kg-1 min-1)
Secondary outcome
The secondary study objectives are:
i) to evaluate whether altered leucine oxidation is associated with
mitochondrial function (pmol/mg/s)
ii) to evaluate whether altered leucine oxidation is associated with the amount
of liver fat (%)
Background summary
Recent high impact research identified clusters of circulating branched-chain
amino acids (BCAA), aromatic amino acids (AAA) and amino acid-derived
short-chain acylcarnitines in insulin resistant humans, as risk factors in the
development of type 2 diabetes. The elevated amino acid clusters may derive
from elevated amino acid supply or incomplete amino acid catabolism. These
findings shed new light in the etiology of diabetes, which for long time was
considered to be related only to disturbances in fat and glucose metabolism,
underlying the development of insulin resistance and mitochondrial dysfunction.
Here, I propose the novel hypothesize that type 2 diabetes (T2DM) is linked to
dysregulated amino acid metabolism, resulting in elevated clusters of BCAA, AAA
and acylcarnitines causing insulin resistance. Furthermore, I hypothesize that
impaired amino acid metabolism underlies impaired mitochondrial oxidative
capacity in T2DM via diminished delivery and flux of amino acid-derived
tricarboxylic acid cycle (TCA) intermediates. The experiments presented in this
project include metabolic profiling of amino acid metabolism-derived
intermediates in plasma and muscle of patients with T2DM and in first-degree
relatives, which has never been explored before. Another innovative element of
this study is to investigate whether sustained lowering of BCAA availability
via a dietary intervention will reverse possible detrimental effects of BCAA in
T2DM. The use of labelled glucose and amino acids, hyperinsulinemic-euglycemic
clamp and magnetic resonance spectroscopy are state-of-the-art methods applied
in this project. To conclude, this research project would reveal the fate of
dysregulated amino acid metabolism in T2DM, and could introduce a shift from
the recent 'lipotoxic view' towards a focus on amino acid metabolism, finally
leading to new strategies to treat diabetes.
Study objective
1. to determine whether the oxidation of BCAA (leucine) is impaired in patients
with T2DM and in humans at risk to develop T2DM (first degree relatives).
2. to investigate whether an altered leucine oxidation in muscle is associated
with insulin sensitivity, mitochondrial function and the amount of fat in the
liver.
Study design
Observational study in which 3 groups will be included: (1) healthy controls,
(2) patients with T2DM and (3) first degree relatives. The leucine oxidation
will be measured in all groups and the outcome will be related to other
metabolic parameters.
Intervention
A randomized, cross-over study in which patients with T2DM and first degree
relatives will undergo a 4 week dietary intervention with normal BCAA in the
diet or to a 4 week intervention with low BCAA levels in the diet. The two
periods will be seperated by a 2 months wash-out period.
Study burden and risks
The risks of the performed measurements for the participants are relatively
low. There is a very low risk of complications with the biopsies and with the
intravenous catheters. With taken the muscle biopsy a risk exits that a small
skin nerve get damaged causing a dull feeling, which will compeltely recover
wthin maximal 6-12 months. During the withdrawal of glucose lowering
medication, the patients with T2DM will be carefully monitored to prevent
hyperglycemia. Moreover, the experiments as scheduled in this research project
are performed at a regular basis at the Maastricht University and performed by
a very experienced researcher in the field already for many years. This
research project would reveal the fate of dysregulated amino acid metabolism in
T2DM, and could introduce a shift from the recent 'lipotoxic view' towards a
focus on amino acid metabolism, finally leading to new strategies to treat
diabetes. Therefore, the risk and burden for the participants is justified.
Universiteitssingel 50
Maastricht 6229 ER
NL
Universiteitssingel 50
Maastricht 6229 ER
NL
Listed location countries
Age
Inclusion criteria
Overall
* Male en postmenopausal females
* Age 45-70 years
* Body mass index (BMI) < 35 and > 27 kg/m2
* Stable dietary habits (no weight loss/gain >5 kg in the last 3 months)
* Stable physical activity levels for at least 6 months
* Control participants without type 2 diabetes should be normal glucose tolerant (OGTT with fasting plasma glucose <6.1 mmol/l (<110 mg/dl) and 2h glucose of <7.8 mmol/l (<140 mg/dl))
* FDR should have a at least 1 family member with type 2 diabetes (father, mother, sister or brother);Type 2 diabetic patients
* Non-insulin dependent type 2 diabetic patients, diagnosed with type 2 diabetes for at least 2 years using sulphonylurea- or metformin therapy for at least six months with a constant dose for at least two months
* Type 2 diabetic patients should have a HbA1c level <8.5%
* Type 2 diabetic patients will be included when having no active diabetes-related co-morbidities like cardiovascular diseases, diabetic foot, polyneuropathy, retinopathy.
Exclusion criteria
- participants will be excluded when being diagnosed with active cardiovascular disease, diabetic foot, polyneuropathy, retinopathy
- participants will be excluded when having uncontrolled hypertension
- participants following a vegetarian diet or having an allergy against soya
- participants with contra-indication for MRI
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 | NL41586.068.12 |
| Other | TC=4181 |