Clinical trial NCT01317576: 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
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes Mellitus, Type 2
Non-alcoholic Fatty Liver Disease
Obesity
Keywords: Magnetic Resonance Spectroscopy
Exercise
Lead sponsor: Maastricht University Medical Center
Sponsor class: OTHER
Collaborators: name: Dutch Diabetes Research Foundation
First posted: 2011-03-17
Enrollment: 81
Sex: MALE
Minimum age (years): 40
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. 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.
2. 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.
3. 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
4. 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:

1. 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
2. For diabetics:

   * Severe diabetes which requires application of insulin or patients with diabetes-related complications
3. For controls:

   * Liver disease or liver dysfunction (ALAT \> 2.5 x increased)

Primary outcomes:
measure: Proton Magnetic resonance spectroscopy to measure the reduction in liver fat content after a training intervention
timeFrame: 16 weeks
measure: Magnetic resonance spectroscopy to measure the ATP and Pi concentrations in the liver
timeFrame: 16 weeks
measure: 13C-methionine breath test to measure hepatic mitochondrial function
timeFrame: 16 weeks
measure: Euglycemic-hyperinsulinemic clamp for measurement of insulin sensitivity and metabolic flexibility
timeFrame: 16 weeks
measure: Blood sampling to determine the concentration of cardiovascular risk factors in the blood before and after exercise
timeFrame: 16 weeks
Secondary outcomes:
measure: Peripheral arterial tonometry to measure endothelial function, as a marker for cardiovascular risk.
timeFrame: 16 weeks
measure: Echography of the heart to measure diastolic dysfunction
timeFrame: 16 weeks
measure: Fat biopsy to measure adipose tissue inflammatory markers and adipocyte size before and after training intervention
timeFrame: 16 weeks
measure: Muscle biopsy to measure muscle mitochondrial density, muscle mitochondrial function and muscle lipid metabolism
timeFrame: 16 weeks
Other outcomes:
Locations:
city: Maastricht
country: Netherlands
facility: Maastricht University
state: Limburg
Study officials:
affiliation: Maastricht University
name: Patrick Schrauwen, PhD
role: STUDY_DIRECTOR
affiliation: Maastricht University
name: Bram MW Brouwers, M.S.
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
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.