Relative Sarcopenia and Cardiometabolic Risk in Young Adults With Obesity
Conditions: Overweight and Obesity, Insulin Resistance
Sponsor: Massachusetts General Hospital

Title: Relative Sarcopenia and Cardiometabolic Risk in Young Adults with Obesity 
 
NCT # 04195061 
 
Version date: June 14, 2021 

PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
1 
 
Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
 
Melanie Schorr Haines, MD 
 
PROTOCOL TITLE 
Relative Sarcopenia and Cardiometabolic Risk in Young Adults with Obesity 
 
FUNDING 
NIH (1 K23 DK115903-01) 
 
VERSION DATE 
6.14.21 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
 
SPECIFIC AIM 1: We hypothesize that obesity-related relative hormone deficiencies (growth 
hormone and adiponectin in both sexes and testosterone in men) will predict higher type 2 
diabetes (DM) risk over 3 or more years in 100 young adults with overweight/obesity (baseline 
visit completed as part of other studies; subjects will be recruited for a single follow-up study 
visit). This relationship will be mediated by relative sarcopenia (i.e. lower appendicular lean 
mass relative to body mass index (BMI)) and impaired muscle quality. 
Aim 1A: Obesity-related relative hormone deficiencies will predict higher DM risk (1° 
endpoint: ARIC DM risk score) over 3 or more years, independent of BMI, central adiposity, 
age and lifestyle factors.   
Aim 1B: These hormone deficiencies will be associated with relative sarcopenia and 
impaired muscle quality (1° endpoint: intramyocellular lipid (IMCL)). 
Aim 1C: Relative sarcopenia and impaired muscle quality at baseline will predict higher DM 
risk over 3 or more years (1° endpoint: ARIC DM risk score).  
Aim 1D: Relative sarcopenia and impaired muscle quality will mediate the relationship 
between obesity-related relative hormone deficiencies and higher DM risk over 3 or more (1° 
endpoint: ARIC DM risk score).   
Aim 1E: Associations in Aims 1A and 1B will be stronger in men than women and Whites 
than Blacks. 
 
EXERCISE SUB-STUDY 
SPECIFIC AIM 1: We hypothesize that compared to insulin-sensitive adults, insulin-resistant 
adults (1° exposure) will have an impaired skeletal muscle myokine profile in response to 
exercise, namely: 
Aim 1A: less reduction in serum myostatin levels from pre- to 3 hours post-exercise (1° 
endpoint) 
Aim 1B: less increase in serum irisin levels from pre- to 3 hours post-exercise 
Aim 1C: less increase in serum IL-6 levels from pre- to 3 hours post-exercise 
 
 
 
 

Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
2 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
 
Little is known about the impact of low muscle mass on future cardiometabolic risk, 
including type 2 diabetes (DM), especially in young adults with overweight/obesity. Skeletal 
muscle is responsible for 70-90% of post-prandial glucose disposal; therefore, lower 
appendicular lean mass (ALM) relative to BMI (i.e. relative sarcopenia) may be an under-
appreciated mechanism linking obesity to DM risk. Obesity-related relative hormone 
deficiencies, including growth hormone (GH) and testosterone (T), also may contribute to DM 
risk, in part mediated by impaired muscle mass and quality.   
Consistent with this hypothesis, relative sarcopenia is associated with greater DM 
prevalence in elderly adults with overweight/obesity; our preliminary data suggest that it is 
also associated with greater DM prevalence in young adults. Our data (NHANES, 1,507 
adults, 20-49y, BMI ≥25 kg/m2) demonstrate an association between relative sarcopenia and 
greater insulin resistance (IR) and DM prevalence; the association was stronger in men than 
women, and Whites than Blacks. To assess DM risk, we will use the Atherosclerosis Risk in 
Communities (ARIC) DM risk prediction model, which has excellent power to predict incident 
DM in Whites and Blacks in a large epidemiologic cohort.  
Obesity-related hormone deficiencies may also contribute to relative sarcopenia and 
impaired “muscle quality”, characterized by ectopic lipid deposition (intramyocellular lipid 
(IMCL) and mitochondrial dysfunction), which are associated with higher DM risk and can be 
assessed using MR spectroscopy. Obesity is complicated by relatively low GH and adiponectin 
in both sexes and T in men. Both GH and T are anabolic to muscle, and our preliminary data 
suggest that low GH, T and adiponectin are associated with impaired muscle quality. Whether 
these hormone deficiencies predict higher DM risk in young adults with overweight/obesity and 
whether this is mediated by hormone effects on muscle mass and quality are unknown. 
Our overarching hypothesis is that relative sarcopenia and impaired muscle quality contribute to 
higher DM risk in young adults with overweight/obesity; and that obesity-related hormone 
deficiencies contribute to relative sarcopenia and impaired muscle quality and lead to higher 
DM risk. 
It is known that regular exercise plays an important role in the prevention and treatment 
of DM, but the mechanisms responsible for exercise’s beneficial effect on insulin sensitivity 
are incompletely understood. The myokines myostatin, irisin, and IL-6 may be important 
mediators of the relationship between exercise and insulin sensitivity because their synthesis and 
secretion from skeletal muscle are regulated by exercise, and lower myostatin, higher irisin, and 
higher IL-6 levels (acutely) are associated with higher insulin sensitivity in preclinical models. It 
is known that insulin sensitivity fails to improve with supervised exercise training in 20-42% 
adults with DM, but to what extent production and release of myokines from skeletal muscle in 
response to exercise is impaired in adults with insulin resistance is not known. 
Since adults who are insulin resistant (vs insulin sensitive) may not improve their insulin 
sensitivity in response to exercise, our overarching hypothesis for the exercise sub-study is that 
adults who are insulin resistant (vs insulin sensitive) will have impaired myokine profiles in 
response to exercise. If this is true, then therapeutic manipulation of myokine pathways could be 
a potential therapeutic target for the prevention and treatment of DM. 
 
 
RESEARCH DESIGN AND METHODS 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be enrolled 
by researchers study-wide and by Partners researchers.  Provide a brief summary of the 
eligibility criteria (for example, age range, gender, medical condition).  Include any local site 

Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
3 
restrictions, for example, “Enrollment at Partners will be limited to adults although the sponsor’s 
protocol is open to both children and adults.”
 
Over the five years of this proposal, we expect to telephone screen 150 patients in order to enroll 
100  (50 women and 50 men) total men and women for an evaluable population of 100 subjects. 
The study is powered for 100 subjects.  
 
Eligibility: 
 
Subjects will undergo a pre-study telephone screen to determine eligibility for the study.  
 
Inclusion criteria: 
- Ages 18-70 and previously enrolled in protocol 2004P000013 or protocol 
2012P002276, which had overweight or obesity as inclusion criteria. They may also have 
participated in protocol 2009P002820 and had a baseline BMI of 25 kg/m2 or more 
 
Exclusion criteria: 
 
- For women: pregnancy, nursing 
 
- Routine MRI exclusion criteria including the presence of pacemaker or cerebral   
 
 
aneurysm clips 
 
- Use of testosterone, growth hormone, or glucocorticoid medications 
 
- History of HIV/AIDS, metastatic cancer or bariatric surgery 
 
- For the Oral Glucose Tolerance Test (OGTT), the use of insulin therapy (Subjects 
taking insulin may complete all other study procedures) 
 
Exercise sub-study 
We expect to enroll 30 (15 women and 15 men) total men and women in the exercise sub-study 
for an evaluable population of 30 subjects. The sub-study is powered for 30 subjects. Eligibility 
criteria for the sub-study are the same as for the main study, with the additional eligibility criteria 
to be determined at a pre-study telephone screen. Participants who completed the main study 
prior to the addition of the exercise sub-study in December 2019 may be invited back to 
complete the exercise sub-study and repeat the main study if they remain eligible for both.  
 
Additional exercise sub-study inclusion criteria: 
-Ability to walk up 3 flights of stairs and 3 city blocks (to ensure ability to complete 
exercise testing) 
 
Additional exercise sub-study exclusion criteria: 
- 
Unstable heart or lung disease 
- 
Exercise >150 minutes/week (to exclude those who are very fit) 
- 
Participation in college sports (to exclude those who are very fit) 
 
 
Briefly describe study procedures.  Include any local site restrictions, for example, “Subjects 
enrolled at Partners will not participate in the pharmacokinetic portion of the study.”  Describe 
study endpoints.
 
Study Visit (n= 100, 50 women and 50 men) 

Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
4 
The study visit will be broken up into 2 days, and the following assessments will occur within a 
30-day period of each other: 
- 
Medical history (may be over the phone) and physical exam (optional), including 
height, weight, waist/hip circumference 
- 
Blood draw to determine levels of hormones and other chemicals  
- 
Urine pregnancy test for women (may be mailed to the subject’s home and completed 
remotely) 
- 
Dual-energy x-ray absorptiometry (DXA) scan 
- 
Measurement of resting energy expenditure (optional) 
- 
X-ray prior to the MRI if subjects reports the possibility of metal in body 
- 
MRI (magnetic resonance imaging)/ MRS (magnetic resonance spectroscopy)  
- 
Single slice CT of the abdomen at the level of the liver and L4 and single slice CT of 
the mid-thigh  
- 
Functional strength testing (optional) 
- 
Growth hormone releasing hormone (GHRH) - arginine stimulation test 
- 
Oral glucose tolerance test (OGTT) 
- 
Questionnaires about exercise and eating habits (in person or over the phone or by 
Enterprise Zoom in accordance with MGB requirements) 
 
Study Endpoints 
Aim 1A: 
Primary Endpoint: ARIC DM risk score at year 3 or more 
Secondary Endpoint: incident DM, HOMA-IR at year 3 or more 
Aim 1B: 
Primary Endpoint: baseline IMCL 
Secondary Endpoint: baseline mitochondrial function (tau), ALM adjusted for BMI 
Aim 1C: 
Primary Endpoint: ARIC DM risk score at year 3 or more 
Secondary Endpoint: incident DM, HOMA-IR at year 3 or more 
Aim 1D: 
Primary Endpoint: ARIC DM risk score at year 3 or more 
Secondary Endpoint: incident DM, HOMA-IR at year 3 or more 
 
Exercise Sub-Study Visit (n=30, 15 women and 15 men) 
 The sub-study visit will take 4 hours to complete, and the following assessments will occur: 
- 
Urine pregnancy test for women (if not already completed that day as part of main 
study visit) 
- 
Vital signs 
- 
Blood draw to determine levels of hormones and other chemicals 
- 
Cardiopulmonary exercise test (CPET) to assess exercise capacity and overall fitness 
- 
Blood draws at 0, 1, 2, and 3 hours after CPET 
 
Exercise Sub-Study Endpoints 
Aim 1A: change in serum myostatin levels from pre- to 3-hours post-exercise 
Aim 1B: change in serum irisin levels from pre- to 3-hours post-exercise 
Aim 1C: change in serum IL-6 levels from pre- to 3-hours post-exercise 
 
For those subjects who are not eligible or are not interested in participating in the study, we will 
ask for their verbal permission over the phone to ask them questions about their medical history 

Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
5 
as it relates to these study endpoints (e.g. incident DM, use of DM medications, parental history 
of DM), as well as permission to view their EMR for these study endpoints (e.g. HbA1c, lipid 
panel, blood pressure).  
 
 
Dual-energy x-ray absorptiometry (DXA): DXA (Hologic Horizon, Hologic, Inc., Waltham, 
MA) will be used to measure body composition (i.e. ALM and trunk fat) as well as BMD of the 
AP and lateral spine (L1-L4), distal radius, total hip, femoral neck and total body, which will be 
used to generate preliminary data investigating the relationship between muscle mass/quality and 
BMD.  
 
Computed Tomography (CT): Low-dose cross-sectional CT scan of the abdomen at the level of 
the liver and L4 and cross-sectional CT scan of the right mid-thigh will be performed for 
assessment of liver fat, abdominal (visceral and subcutaneous) fat, thigh fat and thigh muscle 
area.  
 
MR spectroscopy: Proton MR Spectroscopy of the right and left hepatic lobe (for intrahepatic 
lipid (IHL) content) and of the tibialis anterior and soleus muscles (for IMCL content) will be 
performed with a 3.0 Tesla MR scanner (Siemens Trio, Siemens Medical Systems, Erlangen, 
Germany) as previously described by our group.  
 
Functional strength testing: Functional strength of the hand and forearm will be determined. 
Additionally, functional strength of the lower and upper extremities will also be determined.  
 
Resting energy expenditure: Resting energy expenditure will be measured using the VMAX 
Encore 29 metabolic cart (Viasys Healthcare, Carefusion, San Diego, CA).  
 
CPET:  Fasting CPET studies will be performed in the Cardiovascular Performance Program 
(CPP) exercise lab at MGH. Subjects will undergo CPET on an upright cycle ergometer with 
continual measurement of metabolic gas exchange via a commercially available metabolic cart 
(Ultima CardiO2, Medgraphics, St. Paul, MN), as well as heart rate (HR) and blood pressure (BP). 
Exercise will proceed according to a maximal effort clinical protocol. Exercise testing will end 
when the subject indicates they have reached exhaustion or if any contraindication to exercise is 
present, i.e. abnormal BP (>220/120), ventricular arrhythmia, decreased oxygen saturation (>15% 
from baseline), development of chest discomfort, lightheadedness, or excessive shortness of breath 
or at the discretion of subject and/or physician for safety. A trained exercise physiologist is present 
in the room with the subject at all times, and a physician is immediately available on the floor. The 
highest VO2 will be recorded as VO2max when the following criteria are met: (1) plateau of VO2 
despite increasing work load, (2) final respiratory exchange ratio (RER) >1.1, and (3) HR >85% 
of age-predicted maximum HR. Total exercise time, work, VO2max, VO2AT [the VO2 at 
anaerobic threshold (AT)], RER, baseline HR, HRAT (HR at AT), and peak HR will be recorded.  
 
Endocrine testing:  
 
- CBC, CMP, TSH, HbA1c 
- Fasting lipid profile (total, HDL and LDL cholesterol, triglycerides) 
- Fasting GHRH-arginine stimulation test 
 
-75-g oral glucose tolerance test (OGTT) 
 
- IGF-1  
 
- Total and free testosterone  

Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
6 
 
- Adiponectin  
 
- Pre- and post-exercise myostatin, irisin, and IL-6 
 
In the event that a portion of the study visit cannot be completed at the time of the scheduled 
visit, the subject will be asked to return for another day to complete all study procedures for that 
visit. 
 
Information on Planning for Potential Study Disruptions due to COVID-19  
 
• MRI screening may be done by MRI staff over the phone prior to arrival at Yawkey 6. 
Subjects will be asked the same questions as they normally would. Their responses will 
be documented then uploaded to the subject's chart in EPIC.  
• Several visit procedures are now optional. These include the strength testing, the 
metabolic cart, the physical exam, and waist/hip circumference measurements. 
• The medical history may be done over the phone. 
• The urine pregnancy test may be mailed to a subject’s home and completed there. The 
result will be photographed and sent to study staff. 
• Questionnaires about diet and eating habits will be completed in person or over the phone 
or by Enterprise Zoom in accordance with MGB requirements 
 
 
 
 
 
For studies involving treatment or diagnosis, provide information about standard of care at 
Partners (e.g., BWH, MGH) and indicate how the study procedures differ from standard care.  
Provide information on available alternative treatments, procedures, or methods of diagnosis.
 
Understanding the contribution of relative sarcopenia and impaired muscle quality to the 
development and progression of cardiometabolic disease in young adults with 
overweight/obesity may help identify new prevention and treatment targets in order to reduce 
long-term morbidity and mortality. We will share DM and bone density testing results with study 
participants and their physicians (with participants’ permission). If a significant abnormality is 
identified on CPET, we will inform that participant and their physician (with participant’s 
permission).  
 
 
Describe how risks to subjects are minimized, for example, by using procedures which are 
consistent with sound research design and which do not unnecessarily expose subjects to risk or 
by using procedures already being performed on the subject for diagnostic or treatment purposes.
 
A number of procedures will be instituted to protect against potential risk involved in this 
protocol. We will follow PHRC blood drawing guidelines. All premenopausal women will have 
pregnancy tests prior to receiving radiation. A DXA scan and 3 single-slice CT scans will be 
performed once at the study visit. The amount of radiation from these DXA and CT scans is 
about the amount of natural background radiation from the earth and the sky one receives in 1.3 
months. All subjects will be screened for the presence of metallic implants prior to undergoing 

Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
7 
MR Spectroscopy. Some subjects report claustrophobia during MR scans. If a patient expresses 
any discomfort during the scan, the procedure will be aborted and not repeated without his/her 
full consent.  
 
A physician will be available at all times during the study by pager to answer any questions a 
patient might have.  The physician will arrange to immediately see every patient with a concern.  
All efforts will be made to protect the confidentiality rights of the study subjects who will be 
referred to by code numbers only.  Confidentiality of the patients will always be of paramount 
importance to study investigators.  No data on patients will be shared with persons other than 
those directly involved in the study, except at the documented request of the patient.  Samples 
that are sent to laboratories outside of MGH or Quest Diagnostics will be labeled with a non-
identifying numeric code.    
 
All adverse events will be reported to the IRB in a timely manner according to the guidelines 
provided by Partner’s Human Subjects Research Committee.  
 
 
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective criteria for 
removing a subject from the study, for example, objective criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events.  The inclusion of objective drop criteria is 
especially important in studies designed with placebo control groups.
 
Safety Assessments 
 
- Urine pregnancy test for all premenopausal women prior to radiation 
 
- Screening for metal implants for all potential subjects prior to MR 
 
FORESEEABLE RISKS AND DISCOMFORTS 
Provide a brief description of any foreseeable risks and discomforts to subjects.  Include those 
related to drugs/devices/procedures being studied and/or administered/performed solely for 
research purposes.  In addition, include psychosocial risks, and risks related to privacy and 
confidentiality.  When applicable, describe risks to a developing fetus or nursing infant.
 
Subjects will have a single total body DXA scan and three single-slice CT scans. Subjects will be 
exposed to a total of 0.35 mSv of radiation from the radiology studies as outlined below. This 
amount of radiation is about the amount of natural background radiation from the earth and the 
sky one receives in 1.3 months  
 
1) Single DXA scan for body composition and BMD 0.070 mSv 
2) Single slice CT of abdomen and thigh for body composition 0.180 mSv 
3) Single slice CT of the liver for fat analysis 0.100 mSv 
 
Blood drawing may result in bruising or infection at the venipuncture site.   
 
MR Spectroscopy will be performed using FDA approved devices and pulse sequences. There 
are no known foreseeable risks associated with exposure to MRI, provided there are no metallic 
implants (i.e., vascular clamps or pacemakers). All potential subjects will be screened for the 
presence of such prior to the exam. Some subjects do report some claustrophobia during the 
scan. If a patient expresses any discomfort during the scan, the procedure will be aborted and not 

Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
8 
repeated without his/her full consent. Subjects will be required to lie in a magnet for about 1 hr. 
The 3.0T MR device is FDA-approved for clinical use. No serious or lasting side effects 
associated with the use of MRI have been reported. Rarely, subjects report sensations such as 
vertigo and a metallic taste when exposed to magnetic fields. Minor theoretical hazards arise 
from rapid gradient switching and RF transmission.  All parameters used for conventional and 
spectroscopic imaging fall within FDA limits for specific absorption rates (SAR) of RF 
transmission and rapid gradient switching (dB/dt). Experiments properly conducted in 
compliance with FDA, OSHA and standard safety practices of the MGH-NMR Center pose no 
significant risk to research subjects. MR examinations will be performed by a Radiological 
Technologist certified by the Commonwealth of Massachusetts. Any adverse events will be 
reported immediately to the MGH Human Research Committee. 
 
Regarding CPET, the electrocardiogram may produce some mild discomfort when the adhesive 
recording pads are applied or removed. CPET is a safe procedure, with the risk of death for 
patients between 2 and 5 per 100,000 exercise tests performed. The risk is likely much lower in 
those without known heart or lung disease. Throughout the test, participants will be closely 
monitored. If a participant develops chest pain, an abnormal fall or rise in blood pressure, 
shortness of breath and fall in oxygen saturation, loss of coordination, lightheadedness, or 
dizziness, the test will be stopped for safety concerns. 
 
 
EXPECTED BENEFITS 
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study.  Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.”  
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances. 
 
There is no expected benefit to participation in this study. It is possible that information learned 
from this study may help improve treatment strategies for people who are overweight or obese.  
 
EQUITABLE SELECTION OF SUBJECTS 
The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so.  Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research.
 
We are concentrating on recruiting both women and men in this protocol. We will make a 
considerable effort to recruit minorities. Our previously collected baseline data of 204 subjects 
included about 20% Black and 10% Asian subjects, as well as 15% Hispanic subjects. Our goal 
is to retain a similar percentage of Black, Asian, and Hispanic subjects at the 3 or more- year 
follow-up visit. Minors, pregnant women and adults with impaired decision making capacity will 
not be enrolled in the study.