NCT02920671

Muscle OXPHOS and Nutrient Homeostasis

Skeletal Muscle Oxidative Phosphorylation Capacity and Nutrient Homeostasis in Individuals With Primary (Genetic) and Secondary (Obesity-related) Mitochondrial Impairment as Compared to Healthy, Normal-weight Individuals

• Status: Completed
• Phase: —
• Study type: Observational
• Enrollment: 45 (actual)
• Sponsor: University of Pennsylvania · Academic / Other
• Sex: All
• Age: 18 Years – 65 Years
• Healthy volunteers: Accepted

Summary

Investigators are recruiting adults (men and women, ages 18 to 65 years, inclusive) with a confirmed genetic diagnosis of mitochondrial disease. Investigators are also recruiting both obese and normal-weight healthy volunteers (men and women, ages 18 to 65 years, inclusive) without a family history of mitochondrial disease to compare to affected individuals. The study involves non-invasive MRI methods and glucose tests to focus on the relationship between mitochondrial disease, obesity, and the risk of diabetes. All study visit procedures will be completed within 2 days, which includes an overnight stay at the Hospital of the University of Pennsylvania. There are no study medications or sedations, and participants will be continually monitored during minimally-invasive procedures (e.g., blood draws). All participants will be able to receive compensation. Furthermore, it may be possible to provide reimbursement for travel, lodging, and meals for individuals with mitochondrial disease. Investigators hope that this research will contribute to the current knowledge of mitochondrial disease and that it will improve diagnostic and treatment approaches.

Detailed description

Although obesity is a significant public health problem, why obesity leads to diabetes in some individuals but not others is poorly understood. Mitochondrial impairment, particularly in skeletal muscle with its high energy requirement, has been implicated in the pathogenesis of obesity-related insulin resistance. In addition, individuals with genetic disorders affecting mitochondrial function are at increased risk of diabetes. The proposed studies will investigate the association between skeletal muscle oxidative phosphorylation capacity (OXPHOS), which is a dimension of mitochondrial function, and glucose and lipid homeostasis in (i) individuals with genetic disorders of muscle mitochondrial function as compared to (ii) non-obese adults and (iii) otherwise healthy obese adults. During a single 2-day, 1-night study visit, investigators will use innovative, non-invasive magnetic resonance imaging-based methods of estimating skeletal muscle oxidative phosphorylation capacity, including post-exercise chemical exchange saturation transfer (CrCEST) recovery and 31-Phosphorus (31P) magnetic resonance spectroscopy (MRS) and muscle lipid content, including 1H magnetic resonance spectroscopy (MRS) and 3-point Dixon techniques, in conjunction with a tracer-enhanced oral glucose tolerance test (OGTT\*) to measure overall insulin sensitivity and the selective effect of insulin on glucose disposal (Rd). The percentage suppression of endogenous glucose production by the oral glucose load (% suppression of Ra of endogenous glucose) will also be assessed. Infusion of a glycerol tracer permits assessment of lipolysis in both the fasting state, and also after the oral glucose load, such that the percentage suppression of lipolysis by the oral glucose load can also be calculated (% suppression of Ra of glycerol). In addition, the insulin and c-peptide minimal models will also be used to model pancreatic β-cell responsiveness to the oral glucose load and hepatic insulin extraction.

Conditions

• Mitochondrial Diseases
• Obesity

Interventions

Type	Name	Description
OTHER	Tracer-enhanced oral glucose tolerance test (OGTT*)	Oral glucose tolerance test with stable isotope tracers will be administered. Resting energy expenditure and respiratory quotient will be evaluated during this test using indirect calorimetry.
OTHER	Muscle MRI	Non-invasive muscle MRI will be performed to evaluated metabolic capacity.
OTHER	Dual energy x-ray absorptiometry (DXA)	DXA will be performed to evaluate body composition.
OTHER	Questionnaires	Questionnaires will be used to evaluate participants' health and habits.

Timeline

• Start date: 2017-02-14
• Primary completion: 2019-03-30
• Completion: 2024-08-28
• First posted: 2016-09-30
• Last updated: 2024-09-03

Locations

2 sites across 1 country: United States