Abnormalities in the Effects of Insulin and Exercise on Glucose- and Lipid Metabolism in Obesity and Type 2 Diabetes
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|ClinicalTrials.gov Identifier: NCT03500016|
Recruitment Status : Recruiting
First Posted : April 17, 2018
Last Update Posted : April 19, 2018
Type 2 diabetes are characterized by insulin resistance in skeletal muscle. Insulin resistance plays a major role for the increased risk of heart disease seen in type 2 diabetes. No specific treatment of insulin resistance is currently available, except from increased physical activity and weight-loss.
Insulin resistance is characterized by abnormalities in the use of glucose and fat in the muscle, and is associated with abnormal function and content of mitochondria (the power houses of our cells) as well as increased levels of fat within the muscle.
The investigators believe that abnormalities in the use of glucose and fat in muscle cells in response to insulin and exercise can explain why insulin resistance is associated with abnormal function and content of mitochondria and an increased amount of fat in skeletal muscle of patients with type 2 diabetes and individuals with obesity. The major purpose of our project is, therefore, to investigate the effect of insulin in physiological concentrations and the effect of both acute exercise and 8 weeks of exercise-training on
- insulin sensitivity and energy metabolism,
- insulin signaling,
- mitochondrial dynamics and mitophagy,
- regulators of storage of fat into lipid droplets and their interaction with mitochondria in skeletal muscle
- acetylation and phosphorylation of enzymes (proteins) in major metabolic and signaling pathways, as well as
- transcriptional and signalling networks regulating mitochondrial biogenesis and substrate metabolism.
The effects of insulin in physiological concentrations and novel exercise-interventions combining biking and rowing will be studied in a comprehensive study of obese patients with type 2 diabetes compared with weight-matched obese and lean healthy controls.
The effects of insulin and exercise on whole-body metabolism will be evaluated by measurement of maximal oxygen consumption, and well-known methods to determine insulin-stimulated glucose utilization and use of glucose and fat. Skeletal muscle and fat tissue samples obtained under these conditions will be used for assessment of tissue-levels of specific sets of genes and enzymes known to be involved in insulin action, quality and size of mitochondria, and storage of fat into lipid droplets and their interaction with mitochondria. This project is expected to provide important and novel insight into the causal relationship between insulin resistance, accumulation of fat and abnormal content and function of mitochondria in skeletal muscle in type 2 diabetes.
The investigators ultimately expect that our findings will help us to identify novel molecules or enzymatic pathways, which can be used to develop drugs that can enhance or mimic the effects of insulin and exercise, and hence be used in the prevention and treatment of type 2 diabetes and heart disease.
|Condition or disease||Intervention/treatment||Phase|
|Type2 Diabetes Insulin Resistance||Other: Acute exercise||Not Applicable|
Show Detailed Description
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||45 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||Metabolic and Molecular Abnormalities in Response to Insulin and Exercise in Obesity and Type 2 Diabetes|
|Actual Study Start Date :||February 26, 2018|
|Estimated Primary Completion Date :||November 12, 2020|
|Estimated Study Completion Date :||November 12, 2020|
Experimental: Acute exercise and exercise training
Euglycemic-hyperinsulinemic clamp before and after 8 weeks supervised exercise training. Before exercise training the participants will also do an "acute exercise" on 1 hour with muscle biopsies taken before and after exercise and then again 4 hours into recovery.
Other: Acute exercise
See under arm description.
Other Name: Exercise training
- Insulin sensitivity [ Time Frame: 26.02.2018-12.11.2020 ]Determined by euglycemic-hyperinsulinemic clamp before and after 8-weeks exercise training
- Mitichondrial respiration [ Time Frame: 26.02.2018-12.11.2010 ]Measurements of mitochondrial respiration in permeabilized muscle fiber using a high-resolution respirometer
- Gene expression changes in muscle and fat biopsies [ Time Frame: 26.02.2018-12.11.2020 ]TaqMan gene expression assays for all relevant genes
- Protein abundance and phosphorylation of all enzymes of interest [ Time Frame: 26.02.2018-12.11.2020 ]Protein abundance and phosphorylation of all enzymes of interest will be studied in human skeletal muscle and fat biopsies by Western blotting and quantified by densitometry in arbitrary units.
- Lipid droplet function, morphology, and interaction with mitochondria [ Time Frame: 26.02.2018-12.11.2020 ]Studies of genes and enzymes involved in the regulation of lipid droplets and their morphology and interaction with mitochondria in muscle biopsies determined by gene expression, Westen blotting and transmission electron microscopy (immunogold-labelling), all measured in arbitrary units
- mRNA levels and protein content and/or phosphorylation of regulators of adipose tissue expandability, mitochondrial dynamics and mitophagy, LD function, and transcriptional and signaling networks regulated by exercise [ Time Frame: 26.02.2018-12.11.2020 ]Determined by quantitative real-time PCR and Western blotting
- Maximal oxygen consumption [ Time Frame: 26.02.2018-12.11.2020 ]Determined before and after 8-weeks exercise training by a graded maximal test on a cycle ergometer using indirect calorimetry.
- Whole body composition (lean body mass, total, and regional fat mass) [ Time Frame: 26.02.2018-12.11.2020 ]Determined before and after 8-weeks exercise training by a DXA-scan.
- HbA1c [ Time Frame: 26.02.2018-12.11.2020 ]Determined by blood tests before and after 8-weeks exercise training
- Lipid profile [ Time Frame: 26.02.2018-12.11.2020 ]Determined by blood tests before and after 8-weeks exercise training
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03500016
|Contact: Maria H Petersen, MD||+0045 firstname.lastname@example.org|
|Contact: Kurt Højlund, Professor, DMSc, PhD, MDemail@example.com|
|Department of Endocrinology, Odense University Hospital||Recruiting|
|Odense, Denmark, 5000|
|Contact: Maria H Petersen, MD +0045 51427331 firstname.lastname@example.org|
|Contact: Kurt Højlund, Professor, DMSc, PhD, MD email@example.com|
|Principal Investigator: Kurt Højlund, Professor, DMSc, PhD, MF|
|Principal Investigator: Maria H Petersen, MD|
|Principal Investigator:||Kurt Højlund, Professor, DMSc, PhD, MD||Department of Endocrinology, Odense University Hospital|