To Determine Whether Estrogen Influences the Effects of Training on Glycemic Control and Insulin Sensitivity
Conditions
Keywords
exercise training, insulin sensitivity, glycemic control, estrogen
Brief summary
Previous research has found that males and females respond differently to exercise training, particularly with respect to improvements in blood sugar control and immune system health. This is crucial since insulin resistance, which can lead to type 2 diabetes and other health problems, affects millions of Canadians. People with insulin resistance often have higher inflammation. Exercise is known to improve insulin resistance and reduce inflammation, but females seem to benefit less from exercise compared to men. The investigators believe this difference might be due to estrogen, a hormone that helps regulate blood sugar (in non-exercising conditions) and reduce inflammation. Females have higher estrogen levels, which might explain their ability to regulate resting blood sugar control and also immune function at rest. Our research will investigate how estrogen influences the acute and chronic effects of exercise males. The investigators will study how estrogen influence's the body's response to exercise, particularly in terms of reducing inflammation and improving blood sugar levels as well as immune function. Overweight and obese males will undergo 2 weeks of high intensity interval training while taking either an estrogen supplement or placebo. Prior to and following training males will undergo an assessment of maximal fitness (VO2max test) and an oral glucose tolerance test. Prior to and following the acute exercise test blood samples will be taken to determine the acute effects of exercise on immune cell function and inflammation. Prior to and during the oral glucose tolerance test participants will have blood samples taken to determine glucose handling and insulin sensitivity. They will also have a muscle biopsy taken prior to and 1h into the oral glucose tolerance test to determine the effects of estrogen supplementation on insulin signaling, mitochondrial content and function, fat metabolism and fat storage in skeletal muscle.
Interventions
OTHEREXERCISE TRAINING WITH OR WITHOUT MEDICATION
2 weeks of high intensity interval training while either taking estrogen or placebo
Sponsors
University of Waterloo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
* Biological males (with no previous hormonal supplementation). * Between the ages of 18-35 years old * Non-smokers * Sedentary individuals (i.e., engaging in intentional moderate-to-vigorous physical activity \<2x/week) * Body mass index 27-32 kg/m2 * Body fat % \> 22%
Exclusion criteria
1. Any state that can impact the hormonal milieu (e.g., drug/hormonal supplementation related to health). 2. Usage of anti-inflammatory medications, \>1 glucose lowering medications, insulin, platelet inhibitors, anti-coagulant medications or simvastatin, beta-blockers, weight loss medications (Orlistat, Saxenda, Contrave, Ozempic) or any medications known to affect protein metabolism (i.e., corticosteroids). 3. Presence of cardiovascular, respiratory, metabolic, autoimmune or renal disease. 4. Presence of any condition that makes the participant unable to participate in physical activity as determined using the CSEP Get Active Questionnaire. 5. Presence of injury that restricts exercise performance. 6. VO2max \> 50th percentile for age. 7. Previous (within the last 2 months) or current use of ergogenic aids (i.e. creatine). 8. Previous or current use of weight loss medications, including liraglutide, semaglutide, orlistat, ozempic, etc. 9. History and/or diagnosis of blood clots or family history of blood clot disorders. 10. History of allergies or sensitivities to local anesthetic 11. Ophthalmic vascular disease 12. Classical migraines 13. History of thromboembolic disease 14. Consume 15 or more alcoholic drinks/week or 3 drinks per day 15. Bleeding disorders 16. Severe peripheral neuropathy 17. Muscular dystrophy 18. Prior bariatric surgery 19. Osteoporosis/osteopenia 20. Orthopaedic issues 21. Presence of GI disorders (i.e., Colitis, Crohns disease, Celiac disease) 22. Presence of liver disease or dysfunction (i.e., diagnosed NAFLD, NASH, cirrhosis, previous liver transplant) 23. History of cancer 24. Type 1 or 2 diabetes 25. Presence of renal disorders (creatinine \> 140) 26. Uncontrolled hypertension (\>140/90 mmHg) 27. History of allergies or sensitivities to estradiol or to any ingredient in the formulation or component of the container 28. History and/or diagnosis of blood clots or family history of blood clot disorders 29. Have an implantable electronic device 30. Medical psychiatric history of depression, bipolar, anxiety, suicidal ideation, etc. 31. Inherited clotting disorders 32. Chest pain or shortness of breath 33. Inflammatory disorders (e.g., inflammatory bowel disorder) 34. Significant weight loss in the 3-month period prior to the study (10% of total body weight) 35. Any kind of major surgery recently 36. Bleeding disorders 37. Active or history of thromboembolic disease (including confirmed venous thromboembolism) 38. Ophthalmic vascular disease 39. Classical migraines
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glucose AUC | Visit 3 (baseline) and Visit 11 (Day 16) | Glucose AUC determined from blood samples taken during a 2h oral glucose tolerance test |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin resistance/sensitivity | Visit 3 (baseline) and Visit 11 (Day 16) | at rest (HOMA-IR) and during a 2 h oral glucose tolerance test (Matsuda index) |
| Markers of insulin signaling | Visit 3 (baseline) and Visit 11 (Day 16) | Western blot of the following markers: AMPKα Thr172 \& total AMPKα; phosphorylated Akt Ser437 \& total Akt; phosphorylated TBC1D4 Thr642 \& total TBC1D4; phosphorylated TBC1D1 Ser237 \& total TBC1D; total GLUT4 in human skeletal muscle in the fasted and insulin stimulated state |
| Membrane bound GLUT4 | Visit 3 (baseline) and Visit 11 (Day 16) | GLUT4 content at the membrane in the fasted and insulin stimulated state (determined via immunofluorescence) |
| Peripheral blood mononuclear cells | Visit 2 (baseline) and Visit 10 (Day 14) | determination of immune cell response to acute exercise |
| Plasma cytokines from isolated PBMCs | Visit 2 (baseline) and Visit 10 (Day 14) | pro- and anti-inflammatory cytokine content will be determine using a cytokine array and commercially available kits |
| Mitochondrial content | Visit 3 (baseline) and Visit 11 (Day 16) | determined using electron microscopy |
| Mitochondrial respiration | Visit 3 (baseline) and Visit 11 (Day 16) | skeletal muscle mitochondrial respiration determined using high-resolution respirometry |
| intramyocellular lipid (IMCL) content | Visit 3 (baseline) and Visit 11 (Day 16) | total and subcellular location-specific content and storage characteristics |
| aerobic fitness (VO2max) | Visit 2 (baseline) and Visit 10 (Day 14) | VO2max determined during a graded exercise test |
| Sex hormone concentrations | Visit 3 (baseline) and Visit 11 (Day 16) | Serum estradiol measured using commercially available kits |
| Serum hormone concentrations | Visit 3 (baseline) and Visit 11 (Day 16) | Serum progesterone measured using commercially available kits |
| Neurotransmitter concentration | Visit 2 (baseline) and Visit 10 (day 14) | Serum epinephrine concentration measured using a commercially available kit prior to a maximal graded exercise test and immediately (t=0 min), 30 and 60 min after the graded exercise test. |
Countries
Canada
Contacts
CONTACTVito Pipitone, PhD Candidate
PRINCIPAL_INVESTIGATORMichaela Devries, PhD
University of Waterloo
Outcome results
None listed