Optimizing the Beneficial Health Effects of Exercise for Diabetes: Focus on the Liver!
2016年2月27日 更新者：Bram Brouwers
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.
調査の概要
研究の種類
介入
入学 (実際)
81
段階
- 適用できない
連絡先と場所
このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。
研究場所
-
-
Limburg
-
Maastricht、Limburg、オランダ、6200MD
- Maastricht University
-
-
参加基準
研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。
適格基準
就学可能な年齢
40年～70年 (大人、高齢者)
健康ボランティアの受け入れ
はい
受講資格のある性別
男
説明
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)
研究計画
このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：非ランダム化
- 介入モデル：単一グループの割り当て
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
実験的：Healthy control
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.
|
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.
|
|
実験的：Non-alcoholic fatty liver disease
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
|
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.
|
|
実験的：Type 2 diabetes patients
This group will exist of patients that suffer from type 2 diabetes
|
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.
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Proton Magnetic resonance spectroscopy to measure the reduction in liver fat content after a training intervention
時間枠：16 weeks
|
16 weeks
|
|
|
Magnetic resonance spectroscopy to measure the ATP and Pi concentrations in the liver
時間枠：16 weeks
|
16 weeks
|
|
|
13C-methionine breath test to measure hepatic mitochondrial function
時間枠：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.
|
16 weeks
|
|
Euglycemic-hyperinsulinemic clamp for measurement of insulin sensitivity and metabolic flexibility
時間枠：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.
|
16 weeks
|
|
Blood sampling to determine the concentration of cardiovascular risk factors in the blood before and after exercise
時間枠：16 weeks
|
16 weeks
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Peripheral arterial tonometry to measure endothelial function, as a marker for cardiovascular risk.
時間枠：16 weeks
|
16 weeks
|
|
|
Echography of the heart to measure diastolic dysfunction
時間枠：16 weeks
|
16 weeks
|
|
|
Fat biopsy to measure adipose tissue inflammatory markers and adipocyte size before and after training intervention
時間枠：16 weeks
|
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
|
16 weeks
|
|
Muscle biopsy to measure muscle mitochondrial density, muscle mitochondrial function and muscle lipid metabolism
時間枠：16 weeks
|
. 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.
|
16 weeks
|
協力者と研究者
ここでは、この調査に関係する人々や組織を見つけることができます。
スポンサー
捜査官
- スタディディレクター：Patrick Schrauwen, PhD、Maastricht University
- 主任研究者：Bram MW Brouwers, M.S.、Maastricht University
出版物と役立つリンク
研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。
一般刊行物
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
研究記録日
これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。
主要日程の研究
研究開始
2011年3月1日
一次修了 (実際)
2015年11月1日
研究の完了 (実際)
2015年11月1日
試験登録日
最初に提出
2011年3月16日
QC基準を満たした最初の提出物
2011年3月16日
最初の投稿 (見積もり)
2011年3月17日
学習記録の更新
投稿された最後の更新 (見積もり)
2016年3月1日
QC基準を満たした最後の更新が送信されました
2016年2月27日
最終確認日
2016年2月1日
詳しくは
この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。