Diabetes Mellitus, Type 2NCT01317576
Optimizing the Beneficial Health Effects of Exercise for Diabetes: Focus on the Liver!
A study testing Exercise intervention in people with Diabetes Mellitus, Type 2 and Non-alcoholic Fatty Liver Disease, run by Bram Brouwers at 1 site in Netherlands.
Trial summary
Due to the western lifestyle, correlated with a high calorie intake and low physical activity, obesity is becoming a major health problem. All over the world obesity reaches epidemic proportions. Read more about this study
- Who is it for?
- Ages 40 to 70 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Diabetes Mellitus, Type 2, Non-alcoholic Fatty Liver Disease, Obesity
- What is being tested?
- Exercise intervention
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 81 participants
- Where
- 1 siteNetherlands
- Study dates
- Mar 2011to Nov 2015
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 70 years
- Men only
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- All subjects:
- Male sex
- Age 40-70 years
- BMI 27-35 kg/m2
- Stable dietary habits
- Sedentary: No participation in any kind of sports for at least 2 years.
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- For diabetic patients only:
- Must be on sulphonylurea or metformin therapy for at least 6 months with constant dose for at least 2 months, or on a dietary treatment for at least 6 months
- Well-controlled diabetes: fasting plasma glucose concentration ≥ 7.0 mmol/l and < 10.0 mmol/l at the time of screening.
- For subjects with non-alcoholic fatty liver disease:
- Liver fat content ≥ 5,56%, based on the formula of Kotronen et al. and confirmed with MRS.
- Fasting plasma glucose concentration must be < 7.0 mmol/l
- For control subjects:
- Liver fat content < 5,56%, based on the formula of Kotronen et al. and confirmed with MRS.
- Normoglycemic according to the WHO criteria (OGTT)
Who cannot join
- All subjects:
- Female sex
- Unstable body weight (weight gain or loss > 3 kg in the past three months)
- Participation in an intensive weight-loss program or in vigorous exercise program during the last year before the start of the study.
- Active cardiovascular disease. (This will be determined by questionnaires and by screening on medication. Furthermore, all subjects will undergo a physical examination by a medical doctor).
- Chronic renal dysfunction (creatinine > 2 increased (normal values: 64-104 µmol/l))
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- Use of Thiazolidines (glitazone/rosiglitazone/pioglitazone/troglitazone)
- Systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg
- Haemoglobin < 7.5 mmol/l (anaemia)
- Blood donor
- Use of medication known to interfere with glucose homeostasis (i.e. corticosteroids), except for diabetic patients.
- Use of anti-thrombotic medication
- Claustrophobia and contra-indications for MRI
- Abuse of alcohol(> 3 units (1unit = 10 gram ethanol) per day)
- Abuse of drugs
- Participation in another biomedical study within 1 month before the first screening visit
- For diabetics:
- Severe diabetes which requires application of insulin or patients with diabetes-related complications
- For controls:
- Liver disease or liver dysfunction (ALAT > 2.5 x increased)
Trial locations and contacts
1 site in 1 country.
About this study
Due to the western lifestyle, correlated with a high calorie intake and low physical activity, obesity is becoming a major health problem. All over the world obesity reaches epidemic proportions. Obesity is closely linked to type 2 diabetes, a multi-factorial disease that increases the presence of multiple health problems. Until now, exercise and dietary intervention seem to be the single most effective interventions to treat obesity and type 2 diabetes mellitus. In obesity and type 2 diabetes, not only fat accumulation in adipose tissue, but also fat accumulation in the peripheral tissues occurs. Fat accumulation in peripheral tissues has been associated with insulin resistance. Exercise seems to have a positive effect on the accumulation of fat in the peripheral tissue and on the insulin sensitivity in type 2 diabetic patients.
In this study we want to investigate if a prolonged exercise training program can lower the intrahepatic lipid content and can improve the metabolism of the liver in type 2 diabetic patients and patients with non-alcoholic fatty liver disease, and to examine if this leads to improvements in metabolic risk markers. To this end, we will include investigation of the effect of exercise on adipose tissue (inflammatory markers and adipocyte size) and skeletal muscle (ex vivo lipid metabolism) to incorporate the effect of exercise on liver, muscle and adipose tissue and to clarify the crosstalk between these tissues in the pathophysiology of type 2 diabetes.
- Being tested
- Exercise intervention
- Keywords
- Magnetic Resonance Spectroscopy, Exercise
- Medical subject headings
- Diabetes Mellitus, Type 2, Non-alcoholic Fatty Liver Disease, Obesity, Motor Activity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Exercise interventionBehavioural
Subjects will be training for 12 week, 3 times a week. Two times a week they will perform a 30 minutes bicycle training. Once a week they will perform a 30 minutes resistance training.
| Study group | Role | What they receive |
|---|---|---|
| Healthy control | Experimental | This group will exist of healthy obese that are matched for BMI and age with the type 2 diabetes group and non-alcoholic fatty liver disease group. Receives: Behavioral: Exercise intervention |
| Non-alcoholic fatty liver disease | Experimental | This group will exist of people that suffer from non-alcoholic fatty liver disease. They will be matched for BMI and age according to the Type 2 diabetes group Receives: Behavioral: Exercise intervention |
| Type 2 diabetes patients | Experimental | This group will exist of patients that suffer from type 2 diabetes Receives: Behavioral: Exercise intervention |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proton Magnetic resonance spectroscopy to measure the reduction in liver fat content after a training intervention
Measured: 16 weeks
Magnetic resonance spectroscopy to measure the ATP and Pi concentrations in the liver
Measured: 16 weeks
13C-methionine breath test to measure hepatic mitochondrial function
Subjects will drink a solution of 200ml H2O with 13C-Methionine. The following 2 hours, every 10 minutes a breath sample will be taken and analysed to measure the concentration of 13C in the exhaled breath.
Measured: 16 weeks
Euglycemic-hyperinsulinemic clamp for measurement of insulin sensitivity and metabolic flexibility
After taking fasting blood samples, a primed constant infusion of glucose is initiated. Plasma glucose levels are clamped at ~5 mmol/L by variable co-infusion of 20 % glucose. Every 5 minutes, blood is sampled for immediate determination of plasma glucose concentration. Glucose infusion rate is adjusted to obtain plasma glucose levels of ~5 mmol/L (euglycemia). A bolus of insulin is then infused. Before and during steady state, substrate oxidation is measured using an indirect calorimeter, which determines metabolic flexibility.
Measured: 16 weeks
Blood sampling to determine the concentration of cardiovascular risk factors in the blood before and after exercise
Measured: 16 weeks
Secondary outcomes (4)
Peripheral arterial tonometry to measure endothelial function, as a marker for cardiovascular risk.
Measured: 16 weeks
Echography of the heart to measure diastolic dysfunction
Measured: 16 weeks
Fat biopsy to measure adipose tissue inflammatory markers and adipocyte size before and after training intervention
A small amount of abdominal subcutaneous adipose tissue (~1g) will be collected under local anaesthesia (2% lidocain) using needle biopsy (with the needle connected to a vacuum syringe). Inflammatory markers in the adipose tissue (e.g. IL-6, IL-8, IL-1b, PAI-1, TNFa, CD68, CD163, CD11b, MCP-1, leptin, adiponectin mRNA expression) and adipocyte size will be analysed
Measured: 16 weeks
Muscle biopsy to measure muscle mitochondrial density, muscle mitochondrial function and muscle lipid metabolism
. After local anaesthesia (2.0% Xylocain without adrenaline), a 5-mm diameter side-cutting needle will be passed through a 7-mm skin incision, according to the protocol of the Medical Ethical committee of the Academic Hospital and University of Maastricht. The muscle biopsy will be used to measure ex vivo lipid metabolism, muscle mitochondrial density and muscle mitochondrial function.
Measured: 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Mar 2011 (estimated)
- Study startMar 2011
- Primary completionNov 2015
- Study completionNov 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus, Type 2Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 81 participants (actual)
Sponsor and investigators
- Lead sponsor
- Bram Brouwers
- Sponsor type
- University, hospital or other
- Collaborators
- Dutch Diabetes Research Foundation
- Responsible party
- Sponsor-investigator, Bram Brouwers, Maastricht University Medical Center
- Investigators
- Patrick Schrauwen, PhD, Study director, Maastricht UniversityBram MW Brouwers, M.S., Principal investigator, Maastricht University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01317576
- Sponsor's protocol ID
- MEC 11-3-002
- Status last verified
- Feb 2016
- First submitted
- 16 Mar 2011
- Last updated
- 1 Mar 2016
- Results posted
- No
Publications
Kotronen A, Peltonen M, Hakkarainen A, Sevastianova K, Bergholm R, Johansson LM, Lundbom N, Rissanen A, Ridderstrale M, Groop L, Orho-Melander M, Yki-Jarvinen H. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology. 2009 Sep;137(3):865-72. doi: 10.1053/j.gastro.2009.06.005. Epub 2009 Jun 12.
PubMed 19524579Meex RC, Schrauwen-Hinderling VB, Moonen-Kornips E, Schaart G, Mensink M, Phielix E, van de Weijer T, Sels JP, Schrauwen P, Hesselink MK. Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity. Diabetes. 2010 Mar;59(3):572-9. doi: 10.2337/db09-1322. Epub 2009 Dec 22.
PubMed 20028948Kelley DE, McKolanis TM, Hegazi RA, Kuller LH, Kalhan SC. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E906-16. doi: 10.1152/ajpendo.00117.2003.
PubMed 12959938Vanweert F, Boone SC, Brouwers B, Mook-Kanamori DO, de Mutsert R, Rosendaal FR, Lamb HJ, Schrauwen-Hinderling VB, Schrauwen P, Hesselink MKC, Phielix E. The effect of physical activity level and exercise training on the association between plasma branched-chain amino acids and intrahepatic lipid content in participants with obesity. Int J Obes (Lond). 2021 Jul;45(7):1510-1520. doi: 10.1038/s41366-021-00815-4. Epub 2021 May 2.
PubMed 33935282Mancilla R, Brouwers B, Schrauwen-Hinderling VB, Hesselink MKC, Hoeks J, Schrauwen P. Exercise training elicits superior metabolic effects when performed in the afternoon compared to morning in metabolically compromised humans. Physiol Rep. 2021 Jan;8(24):e14669. doi: 10.14814/phy2.14669.
PubMed 33356015Stinkens R, Brouwers B, Jocken JW, Blaak EE, Teunissen-Beekman KF, Hesselink MK, van Baak MA, Schrauwen P, Goossens GH. Exercise training-induced effects on the abdominal subcutaneous adipose tissue phenotype in humans with obesity. J Appl Physiol (1985). 2018 Nov 1;125(5):1585-1593. doi: 10.1152/japplphysiol.00496.2018. Epub 2018 Sep 13.
PubMed 30212302Brouwers B, Schrauwen-Hinderling VB, Jelenik T, Gemmink A, Havekes B, Bruls Y, Dahlmans D, Roden M, Hesselink MKC, Schrauwen P. Metabolic disturbances of non-alcoholic fatty liver resemble the alterations typical for type 2 diabetes. Clin Sci (Lond). 2017 Jul 7;131(15):1905-1917. doi: 10.1042/CS20170261. Print 2017 Aug 1.
PubMed 28620012
Study at a glance
From the registry record, last updated by the sponsor on 1 Mar 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Optimizing the Beneficial Health Effects of Exercise for Diabetes: Focus on the Liver!
- ClinicalTrials.gov ID
- NCT01317576
- Acronym / sponsor ID
- MEC 11-3-002
- Keywords
- Magnetic Resonance Spectroscopy, Exercise
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 81 participants (actual)
- Lead sponsor
- Bram BrouwersUniversity, hospital or other
- Collaborators
- Dutch Diabetes Research Foundation
- Study start
- Mar 2011
- Primary completion
- Nov 2015 (actual)
- Study completion
- Nov 2015 (actual)
- First posted
- 17 Mar 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Due to the western lifestyle, correlated with a high calorie intake and low physical activity, obesity is becoming a major health problem. All over the world obesity reaches epidemic proportions. Obesity is closely linked to type 2 diabetes, a multi-factorial disease that increases the presence of multiple health problems. Until now, exercise and dietary intervention seem to be the single most effective interventions to treat obesity and type 2 diabetes mellitus. In obesity and type 2 diabetes, not only fat accumulation in adipose tissue, but also fat accumulation in the peripheral tissues occurs. Fat accumulation in peripheral tissues has been associated with insulin resistance. Exercise seems to have a positive effect on the accumulation of fat in the peripheral tissue and on the insulin sensitivity in type 2 diabetic patients.
In this study we want to investigate if a prolonged exercise training program can lower the intrahepatic lipid content and can improve the metabolism of the liver in type 2 diabetic patients and patients with non-alcoholic fatty liver disease, and to examine if this leads to improvements in metabolic risk markers. To this end, we will include investigation of the effect of exercise on adipose tissue (inflammatory markers and adipocyte size) and skeletal muscle (ex vivo lipid metabolism) to incorporate the effect of exercise on liver, muscle and adipose tissue and to clarify the crosstalk between these tissues in the pathophysiology of type 2 diabetes.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Healthy control | Experimental | Behavioral: Exercise interventionThis group will exist of healthy obese that are matched for BMI and age with the type 2 diabetes group and non-alcoholic fatty liver disease group. |
| Non-alcoholic fatty liver disease | Experimental | Behavioral: Exercise interventionThis group will exist of people that suffer from non-alcoholic fatty liver disease. They will be matched for BMI and age according to the Type 2 diabetes group |
| Type 2 diabetes patients | Experimental | Behavioral: Exercise interventionThis group will exist of patients that suffer from type 2 diabetes |
Who may qualify
- Ages
- 40 to 70 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- All subjects:
- For diabetic patients only:
- For subjects with non-alcoholic fatty liver disease:
- For control subjects:
Key exclusion criteria (20 listed)
- All subjects:
- For diabetics:
- For controls:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Exercise interventionSubjects will be training for 12 week, 3 times a week. Two times a week they will perform a 30 minutes bicycle training. Once a week they will perform a 30 minutes resistance training. | Behavioural | Healthy control, Non-alcoholic fatty liver disease, Type 2 diabetes patients |
Primary outcome
Proton Magnetic resonance spectroscopy to measure the reduction in liver fat content after a training intervention
Time frame: 16 weeks
Magnetic resonance spectroscopy to measure the ATP and Pi concentrations in the liver
Time frame: 16 weeks
13C-methionine breath test to measure hepatic mitochondrial function
Time frame: 16 weeks
Subjects will drink a solution of 200ml H2O with 13C-Methionine. The following 2 hours, every 10 minutes a breath sample will be taken and analysed to measure the concentration of 13C in the exhaled breath.
Euglycemic-hyperinsulinemic clamp for measurement of insulin sensitivity and metabolic flexibility
Time frame: 16 weeks
After taking fasting blood samples, a primed constant infusion of glucose is initiated. Plasma glucose levels are clamped at ~5 mmol/L by variable co-infusion of 20 % glucose. Every 5 minutes, blood is sampled for immediate determination of plasma glucose concentration. Glucose infusion rate is adjusted to obtain plasma glucose levels of ~5 mmol/L (euglycemia). A bolus of insulin is then infused. Before and during steady state, substrate oxidation is measured using an indirect calorimeter, which determines metabolic flexibility.
Blood sampling to determine the concentration of cardiovascular risk factors in the blood before and after exercise
Time frame: 16 weeks
4 secondary outcomes
Peripheral arterial tonometry to measure endothelial function, as a marker for cardiovascular risk.
Time frame: 16 weeks
Echography of the heart to measure diastolic dysfunction
Time frame: 16 weeks
Fat biopsy to measure adipose tissue inflammatory markers and adipocyte size before and after training intervention
Time frame: 16 weeks
Muscle biopsy to measure muscle mitochondrial density, muscle mitochondrial function and muscle lipid metabolism
Time frame: 16 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Mar 2016.
- Background: PubMed 19524579Kotronen A, Peltonen M, Hakkarainen A, Sevastianova K, Bergholm R, Johansson LM, Lundbom N, Rissanen A, Ridderstrale M, Groop L, Orho-Melander M, Yki-Jarvinen H. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology. 2009 Sep;137(3):865-72. doi: 10.1053/j.gastro.2009.06.005. Epub 2009 Jun 12.
- Background: PubMed 20028948Meex RC, Schrauwen-Hinderling VB, Moonen-Kornips E, Schaart G, Mensink M, Phielix E, van de Weijer T, Sels JP, Schrauwen P, Hesselink MK. Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity. Diabetes. 2010 Mar;59(3):572-9. doi: 10.2337/db09-1322. Epub 2009 Dec 22.
- Background: PubMed 12959938Kelley DE, McKolanis TM, Hegazi RA, Kuller LH, Kalhan SC. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E906-16. doi: 10.1152/ajpendo.00117.2003.
- Derived from this study: PubMed 33935282Vanweert F, Boone SC, Brouwers B, Mook-Kanamori DO, de Mutsert R, Rosendaal FR, Lamb HJ, Schrauwen-Hinderling VB, Schrauwen P, Hesselink MKC, Phielix E. The effect of physical activity level and exercise training on the association between plasma branched-chain amino acids and intrahepatic lipid content in participants with obesity. Int J Obes (Lond). 2021 Jul;45(7):1510-1520. doi: 10.1038/s41366-021-00815-4. Epub 2021 May 2.
- Derived from this study: PubMed 33356015Mancilla R, Brouwers B, Schrauwen-Hinderling VB, Hesselink MKC, Hoeks J, Schrauwen P. Exercise training elicits superior metabolic effects when performed in the afternoon compared to morning in metabolically compromised humans. Physiol Rep. 2021 Jan;8(24):e14669. doi: 10.14814/phy2.14669.
- Derived from this study: PubMed 30212302Stinkens R, Brouwers B, Jocken JW, Blaak EE, Teunissen-Beekman KF, Hesselink MK, van Baak MA, Schrauwen P, Goossens GH. Exercise training-induced effects on the abdominal subcutaneous adipose tissue phenotype in humans with obesity. J Appl Physiol (1985). 2018 Nov 1;125(5):1585-1593. doi: 10.1152/japplphysiol.00496.2018. Epub 2018 Sep 13.
- Derived from this study: PubMed 28620012Brouwers B, Schrauwen-Hinderling VB, Jelenik T, Gemmink A, Havekes B, Bruls Y, Dahlmans D, Roden M, Hesselink MKC, Schrauwen P. Metabolic disturbances of non-alcoholic fatty liver resemble the alterations typical for type 2 diabetes. Clin Sci (Lond). 2017 Jul 7;131(15):1905-1917. doi: 10.1042/CS20170261. Print 2017 Aug 1.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Patrick Schrauwen, PhD study director
Maastricht University
Bram MW Brouwers, M.S. principal investigator
Maastricht University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Exercise intervention in people with Diabetes Mellitus, Type 2 and Non-alcoholic Fatty Liver Disease, run by Bram Brouwers at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Mar 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proton Magnetic resonance spectroscopy to measure the reduction in liver fat content after a training intervention (time frame: 16 weeks). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01317576, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Mar 2016.