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Amino acids in type 2 diabetes


- candidate number15435
- NTR NumberNTR4181
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR20-sep-2013
- Secondary IDsBCAA_EP 
- Public TitleAmino acids in type 2 diabetes
- Scientific TitleThe fate of incomplete amino acid metabolism in type 2 diabetes
- ACRONYMBCAA-EP
- hypothesisWe hypothesize that patients with type 2 diabetes and first-degree realtives of patients with type 2 diabetes are characterized with a diminished branched-chain amino acid oxidative capacity
- Healt Condition(s) or Problem(s) studiedObesity, Diabetes Mellitus Type 2 (DM type II), Metabolic syndrome
- Inclusion criteriaIn order to be eligible to participate in this study, the participant must meet all of the following criteria:
- male or postmenopausal females
- 45-65 years
- BMI <35 and > 27 kg/m2
- stable dietary habits (no weight loss/gain >5kg in the last 3 months)
- stable physical activity levels for at least 6 months
- participants without T2DM should be normal glucose tolerant (OGTT with fasting plasma glucose <6.1 mmol/l and 2h glucose of <7.8 mmol/l
- FDR should be insulin resistant (glucose clearance rate below < 350 ml/kg/min) as determined using OGIS120

Patients with T2DM:
- non-insulin dependent patients diagnosed with T2DM for at least 1.5 years using sulphonylurea (i.e.glibenclamide, gliclazide, glimepiride en tolbutamide), and/or biguaniden (metformin) therapy for at least 6 months with a constant dose for at least 2 months
- patients should have a HbA1c < 8.5%
- patients will be included when having no active diabetes-related co-morbidities like cardiovascular diseases, diabetic foot, polyneuropathy, retinopathy
- subjects will be included only when the dependent medical doctor of this study approves participation after evaluating all data obtained during the screening (visit 1)
- 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
- mec approval receivedno
- multicenter trialno
- randomisedyes
- masking/blindingNone
- controlActive
- groupCrossover
- TypeSingle arm
- Studytypeintervention
- planned startdate 1-okt-2013
- planned closingdate15-okt-2015
- Target number of participants87
- InterventionsT2DM and FDR will undergo a dietary intervention including a diet low in BCAA or a control diet including normal levels of BCAA for 4 weeks in a randomized cross-over design, with in between a washout period of 2 months.
- Primary outcomeThe main study objectives are i) to determine whether T2DM is related to impaired BCAA metabolism (umol kg-1 min-1) in muscle, and ii) to evaluate the effect of lowering of BCAA on whole body and hepatic insulin sensitivity (umol kg-1 min-1) and endogenous glucose production (umol kg-1 min-1).
- Secondary outcomeSecondary study objectives are i) the effect of BCAA lowering on mitochondrial function (O2-flux pmol mg-1 s-1), and ii) fat accumulation in the liver (%).
- Timepointsn=112 days from start of the diet till end of the study, including 11 visits (including screening)
- Trial web siteN/A
- statusrecruitement status not public
- CONTACT FOR PUBLIC QUERIESDrs E. Phielix
- CONTACT for SCIENTIFIC QUERIESDrs E. Phielix
- Sponsor/Initiator Maastricht University Medical Center (MUMC+)
- Funding
(Source(s) of Monetary or Material Support)
NWO, European Foundation for the study of Diabetes (EFSD)
- PublicationsN/A
- Brief summaryRationale: Recent 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 aetiology 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 compromised mitochondrial function. Here, I propose the novel hypothesize that type 2 diabetes mellitus (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. Objective: 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 (FDR), 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. Study design: The study presented is an experimental study, including a cross-over dietary intervention. Study population: Twenty-nine male and female patients with T2DM, 29 FDR of patients with T2DM and 29 healthy, non-diabetic control participants will be enrolled into the study. Groups will be matched for age and BMI (age: 45-65 yrs; BMI: 27-35 kg/m2). Intervention: T2DM and FDR will undergo a dietary intervention including a diet low in BCAA or a control diet including normal levels of BCAA for 4 weeks in a randomized cross-over design, with in between a washout period of 2 months. Main study parameters/endpoints: The main study objectives are i) to determine whether T2DM is related to impaired BCAA metabolism (umol kg-1 min-1) in muscle, and ii) to evaluate the effect of lowering of BCAA on whole body and hepatic insulin sensitivity (umol kg-1 min-1) and endogenous glucose production (umol kg-1 min-1). Secondary study objectives are i) the effect of BCAA lowering on mitochondrial function (O2-flux pmol mg-1 s-1), and ii) fat accumulation in the liver (%). Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The risk on hematomas and inflammation upon taking muscle biopsies is low as sterile material and pressure bandage will be used. Participants will not have a direct benefit from the dietary intervention. The burden of the diet, the risks of the performed measurements and the physical discomfort are relatively low.
- Main changes (audit trail)primary outcome:
i) to determine whether T2DM and FDR have lower rate of leucine oxidation (umol kg-1 min-1) in muscle
ii) to evaluate whether lowering of BCAA will increase whole body and hepatic insulin sensitivity (umol kg-1 min-1) and decrease endogenous glucose production (umol kg-1 min-1)

secondary outcome:
i) whether lowering of BCAA will enhance mitochondrial function (O2-flux pmol mg-1 s-1)
ii) whether lowering of BCAA will decrease fat accumulation in the liver (%)
- RECORD20-sep-2013 - 23-dec-2013


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