Identifying Therapeutic Targets of Accelerated Sarcopenia
Phase: NA
Conditions: Sarcopenia, Diabetes Mellitus, Aging
Sponsor: The University of Texas Medical Branch, Galveston

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Accelerated Sarcopenia 
#15-0229 
 
Elena Volpi, MD, PhD 
 
National Institute of Health 
 
 
 
Version 7 
 
 February 4, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. Introduction and Purpose: 
 
Accelerated Sarcopenia. Sarcopenia is a complex geriatric syndrome characterized by the loss of 
skeletal muscle mass, strength and function with aging15. It is a major contributor to the cycle of frailty 
38 and increases the risk of falls, physical dependence, disability and mortality in older adults15,68,82.  
While the loss of muscle mass and function occurs gradually with healthy aging, diseases or other 
insults and injuries can accelerate sarcopenia and lead to catastrophic declines in mobility and 
independence74.  
Type 2 Diabetes Chronically Accelerates Sarcopenia. Chronic diseases are associated with 
acceleration of sarcopenia. Among these, Type 2 Diabetes Mellitus (T2DM) has been reported in 
longitudinal studies to hasten the loss of muscle mass and strength in older persons, even after 
adjustment for comorbidities, glucose control, disease length and other factors58,72-74. Insulin 
resistance may play a role in this process62. However, we do not know which specific mechanisms are 
involved in the acceleration of sarcopenia by T2DM.  
Knowledge Gap. Conditions that accelerate sarcopenia, such as T2DM, increase the risk of disability 
and dependency in older adults. However, the fundamental mechanisms by which sarcopenia 
accelerators induce loss of muscle mass and function are unknown.  As a consequence of this 
knowledge gap, and in the absence of specific therapeutic targets, it is not possible to develop 
innovative and effective strategies for prevention and treatment of accelerated sarcopenia in older 
patients.  
Significance. The proposed research is expected to spur a vertical advancement in our knowledge of 
the mechanisms that underlie accelerated sarcopenia in older adults. This work is significant because 
it will lead to the identification of novel, specific targets for the development of evidence-based 
interventions to prevent and treat accelerated sarcopenia and maintain independence in older adults 
at high risk of physical dependence.  
Benefit. Mobility disability and physical dependence are major concerns for older adults, and 
important contributors to rising healthcare costs in the geriatric population53.  In the year 2010, 26.9% 
of the U.S. adults 65 and older had diabetes11. A decline in muscle mass and muscle quality in this 
patient population is associated with reduced mobility90 and increased risk of functional disability91. 
Hospitalization and bed rest for any cause are major events that interact with chronic conditions, 
further reducing function and independence in older adults14,47. By identifying the fundamental 
mechanisms that accelerate sarcopenia in these disabling conditions, we will be able to develop novel 
treatments for maintenance of independence. Thus, our research has the potential to positively impact 
not only healthcare outcomes but also costs over the long term. 
 
2. Background: 
Low muscle mass is a basic component of sarcopenia15. The association between muscle 
mass and function is not linear in healthy older adults35. However, conditions that accelerate 
sarcopenia decrease muscle mass at the same rate as strength, or faster3. A major determinant of 
skeletal muscle mass is contractile protein content, which is regulated by the balance between protein 
synthesis and proteolysis99. Incorporation of dietary amino acids into newly synthesized proteins is a 
fundamental process for maintenance and growth of skeletal muscle, because it allows for 
replacement of the essential amino acids released by proteolysis and lost with oxidation or transport 
to other tissues92. The stimulatory effect of an amino acid/protein meal on skeletal muscle protein 
synthesis is large and rapid48,84, and driven by essential amino acids, particularly leucine, which 
directly stimulate muscle protein synthesis by activating translation initiation via the mTORC1 
pathway18,5. To activate mTORC1 signaling and protein synthesis, amino acids must first enter the 
muscle cell via amino acid transport. Amino acid transport is an active process that is emerging as a 
key regulator of skeletal muscle protein homeostasis and anabolism55. Amino acid transport is 
controlled by several factors 1,55. We have reported that dietary amino acid intake27,96, insulin 86 and 
resistance exercise26 can independently activate amino acid transporter expression and function in 
humans, and this effect is associated with increased muscle protein synthesis 19.     

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There is growing evidence from our group43,75,87 and others80 that healthy aging per se induces 
a mild but significant reduction in the response of muscle proteins to anabolic stimulation. This 
phenomenon has been termed “anabolic resistance” and may account for the slow loss of muscle 
mass with advancing age. It is characterized by a reduced anabolic response to low amino acid 
doses17,56,57,84,94 and insulin43. This is a true “resistance” because the maximal anabolic response to 
high doses of amino acids83,93,96 or insulin43 is preserved in healthy older adults and comparable to 
that observed in younger individuals.  
Our preliminary data suggest that a global, underlying mechanism of accelerated sarcopenia is 
an increase in anabolic resistance associated with a reduction in amino acid transport. With this 
application we will examine how amino acid transport is impacted by conditions accelerating 
sarcopenia and identify factors that control it.     
We propose that resistance exercise will improve the response of muscle protein anabolism to 
amino acids in T2DM by increasing mTORC1 signaling and amino acid transporter expression. 
Upstream regulatory pathways will be explored also in this aim to identify promising therapeutic 
targets for interventions. 
 
Innovation 
The research we propose is innovative, in our opinion, for at least three major reasons: 
1. Conceptual Innovation. Our proposed studies will explore for the first time the potential 
global role of amino acid transport in conditions that accelerate sarcopenia chronically and acutely. By 
using a well described and common model of accelerated sarcopenia, T2DM, this research may also 
rapidly yield practical innovation that could be rapidly translated in the clinical setting.     
2. Methodological Innovation. Innovation also stems from our novel integrative and 
interdisciplinary translational approach that combines state of the art and novel methodologies to 
determine amino acid transporter expression and function and their upstream regulation.  These 
methodologies include: a 3-pool model tracer methodology to measure amino acid trafficking across 
vascular and intracellular compartments20; molecular techniques to measure regulation of muscle 
protein synthesis and amino acid transport26,27; and near infrared spectroscopy (NIRS) to determine 
the role of endothelial function and microvascular muscle perfusion86,87.  Exercise is a well-established 
means to induce muscle growth. Resistance exercise also stimulates amino acid transport and 
transporter expression independent of changes in amino acid availability26. In this application, we will 
innovatively use exercise as a tool to modify the response of amino acid transport and transporter 
expression with the purpose of testing our hypotheses and identifying new therapeutic targets.  
3. Discovery of Novel Molecular Targets. Our secondary outcomes will include exploration 
of the role of novel regulatory proteins in relation to the changes in amino acid transport associated 
with T2DM. The basic assumption is that chronic and acute sarcopenia accelerators may reduce 
amino acid transport with different mechanisms. Thus, we will determine the potential role of newly 
identified amino acid sensing pathways such as the Sestrins-GATOR1/2 and the lysosomal 
vATPase/SLC38A9/Ragulator complex in the activation, or lack of thereof, of mTORC1 signaling and 
amino acid transporter expression and function.  
Our approach ― unique and substantially different from the status quo ― is expected to 
unravel the key underlying mechanisms responsible for accelerated sarcopenia due to T2DM. The 
knowledge generated by our studies is needed to develop future evidence-based clinical trials of 
interventions. 
 
 
3. Concise Summary of Project: 
Subjects. We will test our central hypothesis in community dwelling, independent older adults 
with non-insulin dependent T2DM. To account for screening failures and drop-outs/withdrawals we 
plan to enroll about 30 subjects in order to have 15 subjects completing the study. Since data 
previously gathered on healthy subjects will serve as controls for T2DM subjects, who are expected to 
be overweight or obese, we will limit inclusion to subjects with BMI 23-35 kg/m2.  Those who have a 
BMI ≥ 35 kg/m2 will be considered for inclusion on a case-to-case basis, depending on whether or not 

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thigh adiposity would impair muscle biopsy. Morbidly obese, frail or exercise trained subjects will be 
excluded, as these conditions can significantly impact muscle protein metabolism13,79,89, confounding 
the results. Subjects will be weight stable, as active weight loss in obese older adults can temporarily 
improve the response of muscle protein synthesis to anabolic stimuli88.  Subjects will be recruited from 
the UTMB Pepper Center Volunteer Registry, the Diabetes Clinic for Seniors directed by Dr. Volpi, 
and the UTMB Stark Diabetes Clinic. 
Screening:  After carefully explaining procedures and risks, informed consent will be obtained 
from all subjects.  Eligibility will be assessed with clinical history, physical exam, questionnaires, 
functional testing, and a number of laboratory tests including blood count, metabolic panel, 
hemoglobin A1c, uric acid levels, lipid profile, thyroid function, coagulation panel, urinalysis, urine 
toxicology drug screening, hepatitis B and C screening, HIV test, DEXA scan, and a stress test. An 
OGTT will also be performed, and may involve the use of tracer methodology (U-C13 glucose) to 
better describe glucose kinetics.  Habitual physical activity will be measured using both StepWatch 
Activity Monitors (SAM) and pedometers for approximately 1 week during the screening process. 
 
4. Study Design. Subjects will undergo a two acute experiments, one prior to and one immediately 
following the completion of 13 weeks’ (1 run-in week and 12 weeks progressive resistance exercise) 
training, in which we will test the effects of 7 g of EAA in older T2DM patients.  
1) Run-In: The day prior to the experiment we will: 
• 
Admit subjects to the ITS-CRC. 
• 
Draw safety labs (blood count, metabolic panel, coagulation panel, urinalysis) and other 
individualized clinical labs necessary to follow up on safety parameters. 
• 
Provide standardized meals 
• 
Hold vasodilators, monitor blood pressure, and manage hypertension with other medications if 
necessary 43,75,87. 
2) Metabolic Experiment. The experimental procedure is designed to measure skeletal muscle 
amino acid transporter expression and function, whole body and muscle amino acid kinetics, muscle 
protein synthesis and proteolysis.  The subjects will be studied in the post-absorptive state, after an 
overnight stay in the ITS-CRC. After admission, subjects will be given dinner at approximately18:00 
and a snack at approximately 21:00, after which they will be allowed only water ad libitum. At 
approximately 05:00 we will insert: an antecubital forearm venous catheter for systemic infusions; at 
approximately 07:00 we will insert a retrograde venous catheter in the opposite hand placed in a 
heating pad for arterialized blood draws; at approximately 09:00 we will attempt to place a pediatric 
central catheter in the femoral vein for blood draws.  Subsequently, we will start a primed-continuous 
infusion of L-[ring-13C6]-phenylalanine, L-[5,5,5-2H3]-leucine, and [1-13C]-glycine to measure muscle 
protein turnover as well as the amino acid transport rates through LAT1 (Phe, Leu), SNAT2 (Gly), and 
PAT1 (Gly)55,93.  To reduce risks we will use arterialized blood samples, rather than arterial blood, to 
measure arterial amino acid concentrations and enrichments. This method has been previously 
validated for amino acid and other metabolite concentrations8, and we have preliminary data 
indicating that it is also valid for amino acid enrichments.  After an approximately 4-hr baseline period, 
subjects will ingest the amino acid mixture, as a bolus.  The mixture will contain EAA in the pattern 
found in animal protein22 and will be enriched with L-[ring-13C6]-phenylalanine, L-[5,5,5-2H3]-leucine to 
maintain the isotopic steady state22 (labeled glycine will not be added because glycine is not included 
in the oral mixture).  Large vessel blood flow will be measured by Doppler86,87.  Microvascular nutritive 
flow is emerging as a potential regulator of muscle amino acid and protein metabolism85-87. Thus, 
whenever possible we will perform a Flow Mediated Dilation (FMD) test to detect endothelial function 
using Doppler Ultrasound and Near Infrared Spectroscopy.  Frequent blood samples will be collected 
during the last hour of the basal period and the first and third hour of the amino acid period to 
measure amino acid concentrations and enrichments, glucose, insulin, cytokines and endothelin-1. 
T2DM is characterized by hyperglycemia, hyperinsulinemia, inflammation and endothelial dysfunction, 
which may have an impact on muscle protein metabolism 69,86. Additional serum samples will also be 
collected and stored for future analyses (e.g. other hormonal assays, proteomics, metabolomics).  Up 
to two muscle biopsies will be taken in each period to measure pertinent parameters including amino 

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acid and protein kinetic parameters, cross-sectional area, cell signaling, novel regulatory pathways, 
and gene expression (see Analytical Methods).  A portion of the biopsies will be collected for 
immunohistochemistry. A third incision may be made should the need arise. At the end of the 
experiment catheters will be removed and subjects will be given a meal. 
 
3) Resistance Training: This experiment will involve measurement of the chronic effect of 
resistance exercise on the response of muscle amino acid transport and protein anabolism to 
approximately 7 g of EAA in older adults with T2DM.  Within one week after the first metabolic 
experiment, subjects will initiate progressive, supervised resistance exercise training, 3 times per 
week for 12 wks. Prior to initiating the 12-week program, a run-in week will be completed, for a total of 
13 weeks overall (Table 1).  During the intervention, we will monitor physical activity with SAMs in all 
subjects to determine if exercise reduces habitual physical activity. If possible, we will also use 
continuous glucose monitors to assess changes in blood glucose control throughout the intervention.  
At the end of the 12-week 
period, and approximately 48 
hours after the last  
bout of exercise, we will repeat 
oral glucose tolerance testing. 
The Metabolic Experiment will 
be repeated the following day, 
to measure the effect of 
training on amino acid 
transport and muscle protein 
anabolism. 
 
 
5. Sub-Study Procedures: 
 
Specimens obtained 
during the study will be stored 
in the principal investigator’s 
laboratory and may be used in 
future research. For example, 
from time to time, new 
laboratory tests and 
procedures are developed that 
could be used to better 
understand the human body 
during metabolism studies.   
 
The extra muscle tissue/blood 
left over after the initial 
research study tests are done 
will be stored and used in 
future research. The samples 
will be used to look at muscle 
growth related pathways.  DNA 
will not be stored and no genetic testing will be done. Any future research will not involve additional 
specimens being taken or require any extra involvement from subjects. We will not need to contact 
the subjects again. The specimens will be labeled with a code number and will not directly identify any 
of the subjects who partake in the study. 
 
 
6. Criteria for Inclusion of Subjects: 
• 
Age 60-85 yr 
• 
Body mass index: 23-35 kg/m2 
Table 1. Progressive resistance exercise training protocol. 
Resistance Exercise Training 
• 
5 min. warm up 
• 
3 times per week 
• 
Weights will be increased as necessary and 1RM will be 
formally determined every 6 weeks to progressively 
increase weight lifted. 
• 
If subjects are unable to complete the entire training 
session, leg exercises will be prioritized 
• 
Modifications to exercises, including substitution with free 
weight or band exercises, will be made as necessary to 
accommodate orthopedic limitations of subjects 
 
Free 
Weights 
Machine Run-
In 
Week 
Weeks 
1-4 
Weeks 
5-8 
Weeks 
9-12 
Bicep curl  X 
X 
2 x 
15 @ 
60% 
1-RM 
3 x 15 
@ 
60% 
1-RM 
3 x 12 
@ 
65% 
1-RM 
3 x 10 
@ 
70% 
1-RM 
Triceps 
Extension 
 
X 
Chest 
press 
 
X 
Lat 
pulldown 
 
X 
Shoulder 
press 
 
X 
Leg press  
X 
Leg 
extension 
 
X 
Leg curl 
 
X 
Seated 
calf raise 
 
X 
crunches 
- 
- 

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• 
Or BMI>35 if thigh adiposity does not impair muscle biopsy 
• 
Stable body weight for at least 3 months 
• 
T2DM  
• 
Able to provide informed consent 
 
7. Criteria for Exclusion of Subjects: 
• 
Insulin therapy that cannot be converted to non-insulin therapies  
• 
Significant diabetes complications  
• 
A1c > 8%. Those excluded based on A1c will be eligible for re-evaluation. 
• 
Impairment in Activities of Daily Living 
• 
Score <25 on the 30-item Mini Mental State Examination 
• 
Severe depression as determined by Geriatric Depression Scale >5 
• 
≥ 2 falls in the past 12 months 
• 
Weight loss ≥ 10% bodyweight in the past 12 months 
• 
Moderate or High activity level as indicated by the International Physical Activity Questionnaire 
Short Form 
• 
Significant Cardiac abnormalities considered exclusionary by the study physician (e.g., CHF, 
CAD)  
• 
Vascular disease  
• 
Use of anticoagulant therapy. (e.g., warfarin, heparin, Pradaxa) 
• 
Uncontrolled blood pressure: systolic >160 mmHg or diastolic > 100 mmHg 
• 
History of stroke with motor disability 
• 
Significant Chronic kidney disease 
• 
Anemia 
• 
Liver disease (AST/ALT 2.5 times above the normal limit) 
• 
Significant Respiratory disease (acute upper respiratory infection, chronic lung disease) 
• 
Active cancer or infection 
• 
Recent (within 3 months), chronic treatment with anabolic steroids, systemic corticosteroids or 
estrogen. 
• 
HIV or active hepatitis B or C 
• 
Alcohol (CAGE questionnaire) or drug abuse (urine screening) 
• 
Inability to perform OGTT (i.e., bad veins) 
• 
History of mastectomy with axillary lymph node dissection 
• 
Any other condition or event considered exclusionary by the PI and faculty physician 
 
8. Sources of Research Material: 
 
Participants will provide verbal and written data specifically for research purposes. The study 
physician will have access to UTMB EPIC for subjects Measurement equipment (DEXA, stress test, 
food diary, timers for functional tests) will capture numerical and qualitative data. The SAM device will 
collect data on steps.  Study data will also be securely stored on REDCAP. Only trained study staff 
will have access to study data. These data will be confidential. 
 
9. Recruitment Methods and Consenting Process: 
 
Subjects will be recruited through an institutional review-board approved advertisement that 
will be posted at UTMB, in local newspapers, and at social centers such as the library and recreation 
centers. We will also utilize university announcements, flyers, patient letters, and word of mouth.    
After responding to ads, subjects will be pre-screened and asked to come in for a screening visit at 
the ITS-CRC.  If they qualify, they will be offered an opportunity to participate in the study. This will 
happen on a "first come first served" basis. We will study a normal healthy population between the 
ages of 60-85 representative of the ethnic makeup of the United States. Prior to screening at the ITS-
CRC, subjects will be asked to provide informed consent. During the consenting process, each 
subject will have a private room. The door will be closed during the consenting process. We will take 

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all measures to ensure that subject privacy is maintained. The details of the experimental procedures, 
including risks and benefits, will be explained by a research team member at the time of initial 
screening at the ITS-CRC. At this time, the subject will be given ample time to read the consent form, 
ask questions and discuss any concerns. After the subject has been satisfied, the subject will be given 
an opportunity to sign the consent form.  At every study encounter, each subject will be asked if they 
are still willing to participate in the study. Each subject will be asked if they have any questions, 
concerns, complaints, or comments. If the subjects have any of those listed, they will be appropriately 
addressed by the PI.   
 
 
 
10. Potential Risks: 
 
 
Possible risks and discomforts a subject might be exposed to during the course of the study include: 
 
Psychological Stress: Some of the questions asked as part of the study may make the subject feel 
uncomfortable.   
 
Positive screening tests: One or more of the screening tests might be positive of for a medical 
condition. This information might be upsetting for the subject. The PI and study physician, Dr. Elena 
Volpi, will provide counselling to the subject in the event that a screening test is positive for a medical 
condition or a blood level is abnormal. The likelihood of this is low. 
 
Fasting: Risks of fasting include hypoglycemia, dizziness, nausea, and light headedness. Risk is low. 
 
Blood draws: The subjects will undergo blood draws during the course of the study. The total amount 
of blood drawn will be approximately 170 ml for each of the two metabolic study days. The risks are 
pain, bruising and infection. People with borderline anemia might become more anemic with the 
repeated blood draws. Fainting is also a risk as some people faint at the sight of needles and/or 
blood. The risk of this event is low. 
 
Anemia: Repeated blood draws or excessive sampling volume increases the risk of anemia. This is 
unlikely as the blood collected is less than a blood donation.  
 
Muscle biopsies: The risks of this procedure are pain, bleeding, bruising, infection, and a little scar at 
the site of the incision. The risks are low. The biopsy scar is in the shape and size of this "_" Some 
people may also faint at the sight of needles and/or blood. Up to 50% of subjects experience some 
soreness at the site of the biopsy up to 48 hours after it is done.  
 
Stable Isotopes Infusion: The only possible risks are sepsis (blood infection) and fever, but the risk of 
these is so small that the precise number is unknown. The isotopes are tested in order to assure their 
sterility (absence of microorganisms, such as bacteria, that may cause infections and fever). 
Antibiotics can treat these infections should they occur.  
 
DEXA Scan: Each DEXA scan will expose the subject to a small amount of radiation. Exposure to 
radiation can increase the risk of cancer and birth defects. The amount of radiation that a subject will 
be exposed to is so small that the exact risk is unknown. 
 
Femoral Venous Catheter: We will insert only a pediatric catheter in the femoral vein. The risks are 
the following: (A) Trauma to structures adjacent to the targeted vein (hematoma, nerve injury) is the 
most commonly recognized complication/error during the cannulation process (1.9-3.6% incidence 
during central venous cannulation are generally reported). Traumas rarely are serious, but the 
experience of the operator and the use of ultra-sound assistance can bring the risk to virtually 0%. (B) 
Complications related to the presence of the catheters, i.e., infection, thrombosis and 

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thromboembolism. For patients with central venous catheters (CVC), an infection rate of 1.4 per 1,000 
catheters is reported. However, most patients with CVC are immunosuppressed because of their 
underlying disease, and therefore have a higher risk of infections than our research volunteers. 
Infection in the immediate post-insertion period (3-5 days) is commonly due to infection of the 
subcutaneous track caused by intraoperative contamination and as such are more easily diagnosed 
and treated than the feared systemic infections more prone to appear later. Catheter-related 
thrombosis occurs in 3.7-10% of patients. This complication is more likely to occur in patients with 
specific thromboembolic risk. Factors that contribute to thrombosis in patients are hypercoagulability 
(malignant tumors), venous irritation caused by chemotherapeutic agents and hyperalimentation 
fluids.  The risk is moderate.  
 
Stress Test/Exercise:  Risks may include muscle tightness, soreness, fatigue and rarely a muscle 
strain or tear.  In older individuals, there is a small risk of myocardial infarction during maximal 
exercise tests.  This is generally assumed to be approximately 1 in 10,000. Stress testing with ECG 
monitoring will be done at screening in the older subjects under the supervision of a MD to exclude 
subjects with asymptomatic heart disease. The exercise training sessions will be performed at the 
UTMB Center for Recovery, Physical Activity & Nutrition under the supervision of a CPR trained and 
BCLS licensed physical therapist or certified trainer. The exercise facility is equipped with emergency 
defibrillators. Muscle soreness or cramps, the most likely side effects of stress and muscle 
performance testing, can be reduced or avoided with an adequate warm-up and ramped up exercise 
training, both of which are integrated into our research protocol. 
 
Strength Testing: The subject will experience soreness and tenderness in the muscles for 2 to 3 days 
following exercise. This is normal and is one of the ways in which the human body responds to 
exercise in order for the muscle to grow. A cardiovascular event such as a heart attack is a very rare 
potential risk.  
 
Weight Training: It is rare but also possible that subjects may experience a major injury to their back, 
ligaments, joints, muscles, or tendons during exercise. This is a potential risk with any physical 
activity. 
 
Near Infrared Spectrometry (NIRS): No additional protection is necessary. The effect of heat due to 
near infrared light absorption is low – less than 0.5°C. 
 
Confidentiality: There is a general risk of disclosure of personal sensitive data in a clinical 
investigation. The risk is minimal. 
 
 
11. Subject Safety and Data Monitoring: 
Data Safety and Monitoring Plan. The ultimate responsibility for data and safety monitoring 
rests with Dr. Volpi.  The risk level associated with this study is estimated to be moderate. 
Our data safety and monitoring plan will include: 
1. Review during of screening results and any other available data at the weekly investigators’ 
meeting. A signed eligibility form will be kept on file for each subject. 
2. A quarterly review of data safety and interim data analysis performed by the PI.  
3. An annual review performed by the UTMB IRB. 
4. Semi-annual patient safety review by a Medical Monitor, Mukaila Raji, MD, Chief of the Division of 
Geriatric Medicine, UTMB, will be initiated after completion of the first 10 subjects or after the 
occurrence of the first SAE whichever comes first. Minutes of the semi-annual Medical Monitor 
review will be kept on file and submitted to UTMB’s IRB in a Miscellaneous form within a two week 
period. 
Careful monitoring of the recruitment, enrollment, retention, adverse events, and study 
procedures will help protect the safety of study subjects, the quality of data, and the integrity of the 
study.  As part of the safety plan for this study, Dr. Volpi, who is ultimately responsible for the medical 

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management of the subjects, will review each subject’s records to ensure that appropriate 
mechanisms to protect the safety of study participants are being followed; that protocol requirements 
are being adhered to; and that data are accurate, complete, and secure.  Subject records include 
consent forms, case report forms, flow of data forms, laboratory specimen records, inclusion/exclusion 
forms, adverse event logs, and medical charts.   
Non-serious, anticipated adverse events (AE) include hematoma, pain, infection, syncope, and 
loss of subject confidentiality.  If an anticipated adverse event occurs, Dr. Volpi will be immediately 
notified and a note will be entered into the subject's CRC chart.  Dr. Volpi will be responsible for 
evaluating each AE and determining attribution as well as the impact of the AE on the risk/benefit 
ratio.   
All unanticipated, serious, fatal and/or life-threatening adverse events will be reported to the 
IRB within 24h of occurrence.  The IRB and the PI will be responsible for determining whether 
modifications to the protocol and consent form are required.  If a determination is made that 
participants are found to be exposed to excessive risks in relation to anticipated benefits, the study 
will be immediately suspended.  Studies will not resume until modifications are made that are deemed 
to result in an acceptable risk/benefit ratio by the PI and the IRB.  Aggregate reports of adverse 
events will be prepared as mandated and forwarded to the IRB and ITS-CRC for review. 
Plan for Adverse Event Reporting. The PI will be responsible for evaluating each adverse 
event and determining attribution as well as the impact on the risk/benefit ratio, using the following 
Grading and Attribution criteria: 
Mild – transient laboratory test alterations that do not suggest injury; discomfort noted but no 
disruption of daily activities; no therapy, or only symptomatic therapy required. 
Moderate – Laboratory test alterations indicating injury without long-term risk, discomfort 
sufficient to modify normal daily activity, specific therapy required (i.e., more than symptomatic). 
Serious – laboratory tests indicating a serious health threat or permanent injury, incapacity, 
inability to work, or to perform normal daily activity, hospitalization required or prolonged, emergency 
treatment required, life-threatening events, death. 
The attribution scale assesses the relation of the event to the study procedures. Dr. Volpi will 
judge whether an adverse event is: 1) not related; 2) possibly related; 3) probably related; or 4) 
definitely related to the study interventions. 
Data Safety and Monitoring Board. We will consult our IRB at the time of protocol 
submission to determine if we need to establish a DSMB. Should a DSMB be required, we will 
establish it including physician-investigators from the Texas Regional CTSA Consortium and other 
Claude D. Pepper Centers.  
 
 
12. Procedures to Maintain Confidentiality: 
 
All study data will be collected in REDCap by the research team. Paper data flow 
sheets or case report forms will be stored in locked file cabinets in a secure area of the PI’s 
recruitment office.  Interim data will be reviewed by the PI.  Any appearance of a Conflict of Interest by 
the research team will be avoided by the periodic monitoring by UTMB’s Conflict of Interest 
Committee.  The subjects’ right to confidentiality will be protected at all times and no subject will be 
identified by name in any publication that results from this research. 
 
 
13. Potential Benefits: 
 
The only potential benefits for the participation in this protocol are related to the knowledge of 
the results of the screening tests that will be released to the volunteer, and the availability of 
nutritional counseling at the conclusion of the study. T2DM patients who participate in progressive 
resistance exercise training may experience an improvement in their blood glucose control, strength 
and endurance with training. No other benefits are expected for the subjects.  The knowledge 
collected from the present studies may be of benefit to society, as these studies will help develop the 
scientific basis for designing treatments for reducing loss in muscle mass and function in older 
subjects with T2DM. 

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Importance of the Knowledge to be Gained. These studies will allow us to identify the biological 
mechanisms by T2DM accelerate sarcopenia in older individuals.  Since T2DM is quite common in 
older adults and increases the risk of physical dependence, the knowledge to be gained will be very 
important to develop interventions to maintain independence in older adults. 
 
 
 
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