Muscle OXPHOS and Nutrient Homeostasis



Status:Active, not recruiting
Conditions:Obesity Weight Loss, Gastrointestinal
Therapuetic Areas:Endocrinology, Gastroenterology
Healthy:No
Age Range:18 - 65
Updated:3/15/2019
Start Date:February 14, 2017
End Date:February 14, 2020

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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

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.

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.

Inclusion Criteria:

Indvidiuals who meet all of the following criteria are eligible for participation in the
study:

1. Male and female patients age 18 to 65 years of age.

2. Ability to provide written informed consent.

3. 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).

Exclusion Criteria:

For all study groups (i.e., mitochondrial disease, normal weight, obese):

1. Diabetes (HgbA1c > 6.4%) and/or taking insulin or other anti-diabetic drug therapy
within the 4 weeks prior to enrollment.

2. Use of any lipid-lowering medication (excluding nutritional supplements) within the 4
weeks prior to enrollment.

3. Any contraindication to MRI study (e.g., implanted non-compatible device, pacemaker,
known claustrophobia).

4. 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).

5. 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.

6. Severe co-existing cardiac disease, characterized by any one of these self-reported
conditions:

1. recent myocardial infarction (within the past 6 months).

2. evidence of ischemia on functional cardiac exam within the last year

3. left ventricular ejection fraction < 30%.

7. Acute or chronic pancreatitis.

8. 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.

9. 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).

10. 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.

11. For female participants: Positive pregnancy test.

12. Known active alcohol or substance abuse, including known tobacco use.

13. Use of any investigational agents within 4 weeks of enrollment.

14. Inability to fast comfortably for 10 hours (i.e., overnight).

15. Individuals who have a pacemaker, metal implants, claustrophobia, have worked around a
metal grinder or a construction site, or that have known medical conditions which can
be exacerbated by stress such as anxiety or panic attacks. Inability to lie flat in
the MRI scanner for 90 minutes is also an exclusion criterion.

In addition, specific exclusion criteria for undergoing MRI scanning include:

- ANY intra-luminal implant, filter, stent or valve replacement

- ANY type of life assist device, pump, or prosthetic

- ANY vascular clip or clamp

- ANY surgically placed clips or clamps or bands on visceral organs

- ANY intracranial implants of any type other than dental fillings

- ANY non-removable piercings, jewelry, or medicinal patch

- ANY personal history of intraocular injury or fragment in or around the orbit
that cannot be cleared through radiologic examination.

- ANY personal history of bullet, shrapnel, or stabbing wounds that cannot be
cleared through radiologic evaluation.

16. Any medical condition that, in the opinion of the investigator, will interfere with
the safe completion of the study.
We found this trial at
2
sites
3451 Walnut St
Philadelphia, Pennsylvania 19104
1 (215) 898-5000
Principal Investigator: Shana E McCormack, MD
Univ of Pennsylvania Penn has a long and proud tradition of intellectual rigor and pursuit...
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South 34th Street
Philadelphia, Pennsylvania 19104
 215-590-1000
Children's Hospital of Philadelphia Since its start in 1855 as the nation's first hospital devoted...
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