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Optimizing the Beneficial Health Effects of Exercise for Diabetes: Focus on the Liver!

Primary Purpose

Diabetes Mellitus, Type 2, Non-alcoholic Fatty Liver Disease, Obesity

Status

Completed

Phase

Not Applicable

Locations

Netherlands

Study Type

Interventional

Intervention

Exercise intervention

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 2 focused on measuring Magnetic Resonance Spectroscopy, Exercise

Eligibility Criteria

40 Years - 70 Years (Adult, Older Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria:

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.
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)

Exclusion Criteria:

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))
- 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)

Sites / Locations

Maastricht University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Healthy control

Non-alcoholic fatty liver disease

Type 2 diabetes patients

Arm Description

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.

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

This group will exist of patients that suffer from type 2 diabetes

Outcomes

Primary Outcome Measures

Proton Magnetic resonance spectroscopy to measure the reduction in liver fat content after a training intervention

Magnetic resonance spectroscopy to measure the ATP and Pi concentrations in the liver

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.

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.

Blood sampling to determine the concentration of cardiovascular risk factors in the blood before and after exercise

Secondary Outcome Measures

Peripheral arterial tonometry to measure endothelial function, as a marker for cardiovascular risk.

Echography of the heart to measure diastolic dysfunction

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

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.

Full Information

NCT ID

NCT01317576

First Posted

March 16, 2011

Last Updated

February 27, 2016

Sponsor

Bram Brouwers

Collaborators

Dutch Diabetes Research Foundation

1. Study Identification

Unique Protocol Identification Number

NCT01317576

Brief Title

Optimizing the Beneficial Health Effects of Exercise for Diabetes: Focus on the Liver!

Official Title

Optimizing the Beneficial Health Effects of Exercise for Diabetes: Focus on the Liver!

Study Type

Interventional

2. Study Status

Record Verification Date

February 2016

Overall Recruitment Status

Completed

Study Start Date

March 2011 (undefined)

Primary Completion Date

November 2015 (Actual)

Study Completion Date

November 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Bram Brouwers

Collaborators

Dutch Diabetes Research Foundation

4. Oversight

5. Study Description

Brief 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetes Mellitus, Type 2, Non-alcoholic Fatty Liver Disease, Obesity

Keywords

Magnetic Resonance Spectroscopy, Exercise

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

81 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Healthy control

Arm Type

Experimental

Arm Description

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.

Arm Title

Non-alcoholic fatty liver disease

Arm Type

Experimental

Arm Description

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

Arm Title

Type 2 diabetes patients

Arm Type

Experimental

Arm Description

This group will exist of patients that suffer from type 2 diabetes

Intervention Type

Behavioral

Intervention Name(s)

Exercise intervention

Intervention Description

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.

Primary Outcome Measure Information:

Title

Proton Magnetic resonance spectroscopy to measure the reduction in liver fat content after a training intervention

Time Frame

16 weeks

Title

Magnetic resonance spectroscopy to measure the ATP and Pi concentrations in the liver

Time Frame

16 weeks

Title

13C-methionine breath test to measure hepatic mitochondrial function

Description

Time Frame

16 weeks

Title

Euglycemic-hyperinsulinemic clamp for measurement of insulin sensitivity and metabolic flexibility

Description

Time Frame

16 weeks

Title

Blood sampling to determine the concentration of cardiovascular risk factors in the blood before and after exercise

Time Frame

16 weeks

Secondary Outcome Measure Information:

Title

Peripheral arterial tonometry to measure endothelial function, as a marker for cardiovascular risk.

Time Frame

16 weeks

Title

Echography of the heart to measure diastolic dysfunction

Time Frame

16 weeks

Title

Fat biopsy to measure adipose tissue inflammatory markers and adipocyte size before and after training intervention

Description

Time Frame

16 weeks

Title

Muscle biopsy to measure muscle mitochondrial density, muscle mitochondrial function and muscle lipid metabolism

Description

Time Frame

16 weeks

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

40 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. 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) Exclusion Criteria: 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)) 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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Patrick Schrauwen, PhD

Organizational Affiliation

Maastricht University

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Bram MW Brouwers, M.S.

Organizational Affiliation

Maastricht University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Maastricht University

City

Maastricht

State/Province

Limburg

ZIP/Postal Code

6200MD

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

19524579

Citation

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.

Results Reference

background

PubMed Identifier

20028948

Citation

Meex 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.

Results Reference

background

PubMed Identifier

12959938

Citation

Kelley 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.

Results Reference

background

PubMed Identifier

33935282

Citation

Vanweert 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.

Results Reference

derived

PubMed Identifier

33356015

Citation

Mancilla 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.

Results Reference

derived

PubMed Identifier

30212302

Citation

Stinkens 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.

Results Reference

derived

PubMed Identifier

28620012

Citation

Brouwers 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.

Results Reference

derived

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