RESIST! Blood-flow Restriction Resistance Training for Improving Insulin Sensitivity in Type 2 Diabetes

Study Overview
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Brief Summary
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The study aims to investigate the metabolic and cardiovascular effects of classical resistance training with high loads and blood-flow restricted training (BFRT) with low loads in individuals with type 2 diabetes over 12 weeks.

Detailed Description
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Type 2 diabetes (T2D) is characterized by an increasing insensitivity of muscle, fat and liver cells to the hormone insulin. About 9% of the global population is affected by this condition and mortality risk is twice as high in individuals with diabetes compared to similar-aged people without diabetes. Muscle is of particular importance for glucose homeostasis, since in healthy people it accounts for 80-90% of postprandial insulin-stimulated glucose disposal. After cellular uptake of glucose by the specialized glucose transporter 4 (GLUT4), glucose is phosphorylated and stored as glycogen. In individuals with obesity or T2D, the capacity for insulin to facilitate glucose uptake and glycogen synthesis is impaired. This reduced response of a given insulin concentration to exert its biological effect is termed insulin resistance. Subsequent diminished insulin secretion due to β-cell failure results in fasting hyperglycemia and overt diabetes. Importantly, muscle insulin resistance is the initial defect occurring in the development of T2D and precedes the clinical development of the disease by up to 20 years. Thus, the preservation of skeletal muscle function is essential for people with T2D who have an increased risk of sarcopenia. On the one hand high intensity resistance training (HIT) with 80 % one-repetition maximum (%1-RM) is a well-recognized strategy to improve muscle strength and glycemic control for individuals with T2D, on the other hand elderly or obese people may not be able to tolerate these high loads. Blood flow restriction training (BFRT) with low loads (20-30% 1-RM) has consistently demonstrated comparable effects to HIT and seems to be a promising alternative to increase muscle function. During the BFRT the muscle becomes hypoxic due to a brief occlusion of venous blood flow using a tourniquet while exercising. Consequently metabolites like lactate, growth hormone (GH) and insulin like growth factor (IGF-1) are released and result in muscle hypertrophy through activating the collagen synthesis and the recruitment of satellite cells. Furthermore cell swelling based on venous blood pooling, reactive hyperemia and metabolite accumulation has been shown to increase protein synthesis by activating the mammalian Target of Rapamycin Complex 1 (mTORC1) pathway. Also, BFRT increases the level of reactive oxygen species (ROS) which may lead to higher glucose uptake during exercise. Last but not least higher threshold motor units (fast twitch fibers) are recruited due to hypoxia and metabolite accumulation. Although there is a significant inverse relationship between muscle strength and the risk of cardiovascular mortality, cardiovascular adaptations to resistance training are under-explored and poorly understood. The study therefore aims to investigate the metabolic and cardiovascular effects of BFRT with low loads in individuals with T2D.

Official Title
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Metabolic Effects of a New Resistance Training in Individuals With Type 2 Diabetes

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Other: Blood-flow restriction resistance training
* Other: Classical resistance training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female, age between ≥ 30 and ≤ 69 years Individuals with type 2 diabetes BMI: 19-40 kg/m² Exclusion Criteria: Acute infections in the last 2 weeks Weight fluctuations (> 10% in the last 6 month) Therapy with Glitazone, Beta blocker, Insulin Malignant cancer Heart diseases (angina pectoris, myocardial infarction, acute myocarditis or pericarditis, cardiac wall aneurysms/ stenose, untreated hypotension or hypertension, aortic stenosis, stroke, cardiac insufficiency, NYHA-class ≥II, heart arrhythmia, disturbances of blood circulation in extremities, venous insufficiency, varicose veins) Diabetic neuropathy Respiratory disease (COPD, Gold grade ≥II) Serious heart, kidney or liver disease: - New York Heart Association-Classification (NYHA) stage ≥ II - creatinine ≥ 1.6 mg / dl - Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ two-fold upper reference value Anemia (Hb <12g / l), blood donation in the last 3 month Disease of the immune system (leucocytes <5000/μl) Application of immunomodulatory agents (Glucocorticoids, Antihistamine, Acetylsalicylic acid) Application of antithrombotic agents (Anticoagulant) Blood clotting disorders (abnormally levels of thrombocytes [<150.000, >450.000 ± 50 ], Partial thromboplastin time (PTT) [26-36 s ± 5 s], Quick [70-120% ± 10%]) or wound healing Thyroid disease (untreated hypothyroidism or hyperthyroidism, treatment with thiamazol) Epilepsy Application of drugs which can manipulate the thermoregulation (Antipsychotic) Rosacea Vitamine supplement (with the las 4 weeks) Cigarettes (or non-smokers <1 year) alcohol consumption (men> 30 g / d, women> 20 g / d), drug abuse Severe psychiatric illness or addiction Risk for/ or HIV or Hepatitis B or C Shift work or anormal circadian rhythm Muscle diseases, orthopedic restrictions Hypersensitivity to local anaesthetic Pregnancy, lactation Metallic and magnetic implants (for example, mechanical heart valves, joint prostheses, clip after vascular surgery, middle and inner ear implants or fresh dental implants) Claustrophobia Hypohidrosis Participation in another intervention study within the last 3 month

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blood-flow restriction resistance training<br>Resistance training with low loads (15-30% RM) in combination with a brief occlusion of venous blood flow using a tourniquet while exercising. | Other: Blood-flow restriction resistance training<br>* Training program: After 10 minutes of warm-up the participant performs three exercises with BFRT for the lower extremities. The intensity is about 15-30% of 1-RM.<br>|
| Experimental: Classical resistance training<br>Resistance training with high loads (60-80% RM). | Other: Classical resistance training<br>* Training program: After warm-up the participant performs three exercises for lower body. The intensity is about 60-80% of 1-RM.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in insulin sensitivity by blood-flow restriction or classical resistance training | By using hyperinsulinemic-euglycemic clamp technique, changes in the M-value (mg x kg-1 x min-1) will be measured. The m-value represent the glucose infusion rate at a defined level of hyperinsulinemia during a glucose clamp test. The hyperinsulinemic-euglycemic clamp technique will thus be implicated to assess changes in insulin sensitivity before and after 12 weeks of resistance training. | Before and after 12 weeks of training (intervention) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in skeletal muscle mass by blood-flow restriction or classical resistance training | Cross-sectional area (cm2) from quadriceps will be measured by MRI imaging technique to evaluate changes in muscle diameter (hypertrophy) before and after 12 weeks of resistance training. | Before and after 12 weeks of training (intervention) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin sensitivity, Blood flow restriction training, Muscle hypertrophy, Muscle Strength, Hypoxia