Muscle OXPHOS and Nutrient Homeostasis

NCT02920671 | Completed

• 1 other identifier: 825558
• Study Type: observational
• Target: 45
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Mitochondrial Diseases; Obesity

Outcome Measures

Primary Outcomes (1)

• Glucose rate of disposal (glucose Rd) during OGTT*

  The primary outcome for the present study will be glucose rate of disposal (Rd) during the OGTT\*

  1 day

Secondary Outcomes (7)

• Exogenous rate of glucose appearance (exogenous glucose Ra) during OGTT*

  1 day

• Endogenous rate of glucose appearance (endogenous glucose Ra) during OGTT*

  1 day

• Endogenous rate of glycerol appearance (endogenous glycerol Ra) during OGTT*

  1 day

• Post-exercise exponential time constant for decline in CrCEST (skeletal muscle MRI)

  1 day

• Resting CrCEST (skeletal muscle MRI)

  1 day

Study Arms (3)

Mitochondrial Disease

Clinical history consistent with the diagnosis of mitochondrial disease, and molecular genetic diagnosis.

Other: Tracer-enhanced oral glucose tolerance test (OGTT*); Other: Muscle MRI; Other: Dual energy x-ray absorptiometry (DXA); Other: Questionnaires

Obese

BMI \> 30 kg/m2. These will be matched with subjects with mitochondrial disease by age, sex, estrogen status (women), and usual self-reported physical activity.

Other: Tracer-enhanced oral glucose tolerance test (OGTT*); Other: Muscle MRI; Other: Dual energy x-ray absorptiometry (DXA); Other: Questionnaires

Normal Weight & Overweight

BMI 18.5 - \< 30 kg/m2. These will be matched with subjects with mitochondrial disease by age, sex, estrogen status (women), and usual self-reported physical activity.

Other: Tracer-enhanced oral glucose tolerance test (OGTT*); Other: Muscle MRI; Other: Dual energy x-ray absorptiometry (DXA); Other: Questionnaires

Interventions

Tracer-enhanced oral glucose tolerance test (OGTT*) OTHER

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.

Mitochondrial Disease; Normal Weight & Overweight; Obese

Muscle MRI OTHER

Non-invasive muscle MRI will be performed to evaluated metabolic capacity.

Mitochondrial Disease; Normal Weight & Overweight; Obese

Dual energy x-ray absorptiometry (DXA) OTHER

DXA will be performed to evaluate body composition.

Mitochondrial Disease; Normal Weight & Overweight; Obese

Questionnaires OTHER

Questionnaires will be used to evaluate participants' health and habits.

Mitochondrial Disease; Normal Weight & Overweight; Obese

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

This study will enroll three groups of individuals (mitochondrial disease, obese, normal weight).

You may qualify if:

• Indvidiuals who meet all of the following criteria are eligible for participation in the study:
• Male and female patients age 18 to 65 years of age.
• Ability to provide written informed consent.
• Cognitively and medically stable and able to comply with the procedures of the study protocol.
• For individuals with mitochondrial disease:
• Clinical history consistent with the diagnosis of mitochondrial disease, and molecular genetic diagnosis. To ensure consistency with other trials performed in mitochondrial disease, investigators will also ensure that participants meet the same set of previously published criteria. These include clinical features consistent with primary mitochondrial disease and molecular genetic proof of a pathogenic mutation in mtDNA or nDNA in a gene known to be associated with dysfunction of complexes I-V of the respiratory chain. Specifically, eligible participants must have defined mtDNA or nDNA mutations affecting subunits or assembly of these complexes that are associated with known clinical/pathological features, such as chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), mitochondrial encephalopathy and ragged red fibers (MERRF), neuropathy, ataxia and retinitis pigmentosa (NARP) or Leigh syndrome (45). Investigators will explicitly include individuals with Friedreich's Ataxia (46), a mutation in the mitochondrial protein frataxin, and those with mutations in respiratory chain complex II protein, succinate dehydrogenase (SDH).
• For normal weight participants:
• BMI \< 25 kg/m2. These will be matched with subjects with mitochondrial disease by age, sex, estrogen status (women), and usual self-reported physical activity (as either sedentary or not, i.e., for sedentary, less than 30 minutes of moderate physical activity 5 days per week, or vigorous physical activity for 20 minutes 3 days per week).
• For obese participants:
• BMI \> 30 kg/m2. These will be matched with subjects with mitochondrial disease by age, sex, estrogen status (women), and usual self-reported physical activity (as either sedentary or not, i.e., for sedentary, less than 30 minutes of moderate physical activity 5 days per week, or vigorous physical activity for 20 minutes 3 days per week).

You may not qualify if:

• For all study groups (i.e., mitochondrial disease, normal weight, obese):
• Diabetes (HgbA1c \> 6.4%) and/or taking insulin or other anti-diabetic drug therapy within the 4 weeks prior to enrollment.
• Use of any lipid-lowering medication (excluding nutritional supplements) within the 4 weeks prior to enrollment.
• Any contraindication to MRI study (e.g., implanted non-compatible device, pacemaker, known claustrophobia).
• Kidney disease. Estimated glomerular filtration rate \< 60 ml/min/1.73 m2 (calculated using the subject's measure serum creatinine and the Modification of Diet in Renal Disease \[MDRD\] study estimation formula).
• Liver disease. Persistent elevation of liver function tests at the time of study entry. Persistent SGOT (AST), SGPT (ALT), Alk Phos or total bilirubin, with values \> 3 times normal upper limits, will exclude a subject from study participation.
• Severe co-existing cardiac disease, characterized by any one of these self-reported conditions:
• recent myocardial infarction (within the past 6 months).
• evidence of ischemia on functional cardiac exam within the last year
• left ventricular ejection fraction \< 30%.
• Acute or chronic pancreatitis.
• Receiving treatment for a medical condition requiring chronic use of systemic (oral or parenteral steroids, except for the use of \< 5 mg prednisone daily, or an equivalent dose of hydrocortisone, for physiological replacement only.
• Anemia (baseline hemoglobin concentration \< 11 g/dl in women and \<12 g/dl in men), lymphopenia, (\< 1,000/µL), neutropenia (\< 1,500/µL), or thrombocytopenia (platelets \< 100,000/µL).
• Any known coagulopathy (including Factor V deficiency) or medical condition requiring long-term anticoagulant therapy (e.g., warfarin) (low-dose aspirin treatment is allowed) or patients with an INR \> 1.5.
• For female participants: Positive pregnancy test.

Sponsors & Collaborators

• University of Pennsylvania: lead

Study Sites (2)

University of Pennsylvania

Philadelphia, Pennsylvania, 19004, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (1)

• Tamaroff J, Nguyen S, Wilson NE, Stefanovski D, Xiao R, Scattergood T, Capiola C, Schur GM, Dunn J, Dedio A, Wade K, Shah H, Sharma R, Mootha VK, Kelly A, Lin KY, Lynch DR, Reddy R, Rickels MR, McCormack SE. Insulin Sensitivity and Insulin Secretion in Adults With Friedreich's Ataxia: The Role of Skeletal Muscle. J Clin Endocrinol Metab. 2025 Jan 21;110(2):317-333. doi: 10.1210/clinem/dgae545.

  PMID: 39109797 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

Blood will be collected as part of this protocol. Results from screening laboratory studies will be entered into the secure database, and copies will be sent to the participant, as well as his/her physician if s/he wishes. De-identified, specimens coded with the participant's ID number will be stored in anticipation of future studies. DNA/RNA will be extracted and stored pending future analyses to be specified (e.g., whole exome or mitochondrial DNA sequencing, gene expression studies). No results of genetic analyses will be included in the electronic medical record. Participants will not be informed of results.

MeSH Terms

Conditions

Mitochondrial Diseases; Obesity

Interventions

Glucose Tolerance Test; Absorptiometry, Photon; Surveys and Questionnaires

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Blood Chemical Analysis; Clinical Chemistry Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Endocrine; Investigative Techniques; Radiography; Diagnostic Imaging; Densitometry; Photometry; Chemistry Techniques, Analytical; Data Collection; Epidemiologic Methods; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Study Officials

• Shana McCormack, MD, MTR

  University of Pennsylvania & Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 27, 2016
• First Posted: September 30, 2016
• Study Start: February 14, 2017
• Primary Completion: March 30, 2019
• Study Completion: August 28, 2024
• Last Updated: September 3, 2024

Record last verified: 2024-08

Locations

US (2)