Clinical trial NCT05210504
Conditions: Diabetes Mellitus, Type 2
Keywords: lysine
Sponsor: Vanderbilt University Medical Center
Start date: 2022-03-09; Completion date: 2023-01-27
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study aims to assess the effect and breakdown of lysine administration, specifically examining whether it leads to increased plasma 2-AAA in healthy humans.

Detailed description:
The purpose of this study is to investigate a novel biomarker, α-aminoadipic acid (2-AAA), which may influence the risk of diabetes. 2-AAA has been identified as a novel predictor of diabetes development in humans, identifying at-risk individuals before any detectable glucose abnormalities. 2-AAA is a naturally occurring metabolite in the body, and it has no known adverse effects at normal physiological levels. 2-AAA is generated in the body from the breakdown of lysine. Lysine is one of the twenty essential amino acids, meaning that it is essential for human function, but that our body cannot manufacture it. Thus, it is acquired from dietary sources (such as meat, eggs, soybeans and legumes), with a recommended daily intake of 30 mg/kg/day. Amino acids are the building blocks of proteins, which are what allow our cells, organs and body to maintain structure and function. The investigators are interested in whether 2-AAA is increased in the body after consumption of lysine.

Arms: arm 1: participants will be administered 5g oral lysine
Interventions: intervention 1: L-Lysine intervention 2: Normal Saline
Intervention descriptions: intervention 1: 5g L-lysine in 50ml water, administered orally intervention 2: Normal (0.9%) Saline

Protocol documents:
Prot_SAP_001.pdf: 
Sponsor: NIH, 9000 Rockville Pike, Bethesda, MD 200892 
Protocol Version #1.1 
 
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Determinants of alpha-aminoadipic acid (2-AAA) and relationship to diabetes: 
 
Study 3 
 
 
 
Principal Investigator 
 
Jane F. Ferguson, PhD 
 
Division of Cardiovascular Medicine 
Vanderbilt University Medical Center 
 
2220 Pierce Ave, PRB 354 
Nashville TN 37232 
 
 
Co-Investigator 
 
Jonathan D. Mosley, MD PhD 
 
Division of Clinical Pharmacology 
Vanderbilt University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sponsor: NIH, 9000 Rockville Pike, Bethesda, MD 200892 
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Table of Contents 
 
 
Contents 
1.0 Background ............................................................................................................... 3 
2.0 Rationale and Specific Aim ...................................................................................... 4 
3.0 Animal Studies and Previous Human Studies .......................................................... 4 
4.0 Inclusion/Exclusion Criteria ..................................................................................... 7 
5.0 Enrollment................................................................................................................. 7 
6.0 Study Procedures ...................................................................................................... 7 
7.0 Risks .......................................................................................................................... 8 
8.0 Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others ...................................................................................................... 9 
9.0 Study Withdrawal/Discontinuation ........................................................................... 9 
10.0 Statistical Considerations ........................................................................................ 9 
11.0 Privacy/Confidentiality Issues ................................................................................ 9 
12.0 Follow-up and Record Retention .......................................................................... 10 
13.0 References ............................................................................................................. 10 
 
             


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1.0 Background 
 
Diabetes is a major global health concern, associated with significantly increased 
mortality and high incidence of co-morbidities1. Given the high rate of cardiovascular and 
other diseases in individuals with diabetes, diabetes-related mortality may be under-
estimated and is estimated to be the third largest cause of death in the US2. Treatment 
efficacy and successful disease management varies between patients. This is in part 
attributable to the fact that diabetes is a heterogeneous disease, with multiple underlying 
causes. In a small proportion of cases of monogenic diabetes, the defects have been 
identified by genetic testing, sometimes leading to vastly improved treatment 
strategies3,4. However, the vast majority of cases of diabetes are polygenic and 
multifactorial. Despite some understanding of disease pathophysiology, and a variety of 
treatment options, the underlying causes of diabetes are unknown in most cases. A 
broader understanding of the variety of paths that lead to diabetes could identify 
alternative therapeutic targets. This may be crucial to preventing or managing disease in 
specific subsets of patients. Large-scale metabolomics studies have successfully 
identified novel candidates for diabetes, including a novel diabetes biomarker, α-
aminoadipic acid (2-AAA), which predicts the development of diabetes in humans5. In 
matched diabetes cases and controls from the Framingham Heart Study (FHS), higher 
plasma 2-AAA (at baseline) was associated with future diabetes, independent of fasting 
glucose and other known risk markers (age, sex, BMI, family history, diet)5.  
 
Source of 2-AAA: 2-AAA is generated from the catabolism of the amino acid lysine 
through the saccharopine (mitochondrial) and/or the pipecolic acid (peroxisomal) 
pathways6,7 (Figure 1). Both pathways converge in the generation of 2-aminoadipate-6-
semialdehyde, which is then further metabolized to 2-AAA in the cytosol8. 2-AAA is 
subsequently metabolized to 2-oxoadipate (α-
ketoadipic acid), and further to acetyl-coA, 
entering the TCA cycle. Lysine is an essential 
amino acid which is acquired from dietary 
sources, with a recommended daily intake of 
30mg/kg/day9. A portion of lysine in humans 
may be derived from the microbiome, with 
bacteria and fungi capable of de novo 
synthesis, in addition to modulation of 
bioavailability of dietary sources10.  
 
Genetics: Variation in genes encoding 
enzymes in the lysine degradation pathway 
(indicated in boxes in Figure 1) may influence 
2-AAA levels and downstream function. The 
strongest evidence thus far exists for DHTKD1, 
variation in which has been associated with 2-
Ketoadipic, 2-Aminoadipic and 2-Oxoadipic 
Aciduria8,11, and Charcot-Marie-Tooth 
Disease12. DHTKD1 expression correlates with 
ATP production in mitochondria in vitro, and 
siRNA knockdown of DHTKD1 leads to 
impaired mitochondrial biogenesis and 
increased reactive oxygen species production, resulting in apoptosis and reduced cell 
Figure 1. Multicompartmental model of L-lysine 
degradation (Adapted from Danhauser et al. 2012) 


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growth13. Variation in mouse Dhtkd1 has been found to associate with expression of the 
gene (eQTL) and levels of protein (pQTL) in liver, as well as with serum 2-AAA levels14. 
Liver Dhtkd1 expression correlated significantly with serum 2-AAA in these mice. 
Further, liver 2-AAA was negatively associated with liver mass, fasting glucose and 
serum cholesterol while higher liver 2-AAA was associated with higher insulin sensitivity.  
 
 
2.0 Rationale and Specific Aim 
 
Diabetes is a significant contributor to mortality and morbidity. The lysine-derived 
metabolite α-aminoadipic acid (2-AAA) has been identified as a novel predictor of 
diabetes development in humans, potentially identifying at-risk individuals before 
development of other known risk markers. Little is known about the function of 2-AAA. 
Our preliminary investigation of human clinical, human genetic, animal and cell 
experimental data has revealed multiple lines of evidence supporting 2-AAA and its 
pathway as biologically relevant to diabetes pathophysiology. However, it is not yet clear 
whether 2-AAA is itself causal in diabetes development, or is a biomarker for altered 
metabolic processes, and many questions remain as to mechanisms of action. The 
determinants of variation in 2-AAA levels between individuals are not known. The aim of 
the first phase of this study (2-AAA Screening study) was to measure plasma 2-AAA 
levels from healthy individuals from the general population, to identify subjects with 
extremely high or low 2-AAA (defined as top and bottom ~25% of distribution). The aim 
of the second phase of the study was to invite individuals with high or low 2-AAA (N=80) 
to participate in a dietary lysine modification study, to assess the effect of controlled 
lysine intake on plasma and urine 2-AAA. In this third phase of the study, we will invite a 
subset of individuals (N=20) from phase 2 to participate in a lysine metabolism study. 
We hypothesize that individuals differ in their rate of metabolism or excretion of lysine to 
2-AAA. This will be assessed by the rate of conversion of 13C lysine to 13C 2-AAA in 
plasma, and the rate of excretion of 13C lysine and 13C 2-AAA in urine. We expect that 
individuals with high plasma 2-AAA have an increased rate of metabolism of lysine to 2-
AAA, and a reduced rate of urinary excretion compared with low-2-AAA individuals. 
 
 
Specific Aim: To determine whether acute lysine administration leads to variability 
in increased plasma 2-AAA in humans. Catabolism of lysine leads to generation of 2-
AAA. To address the hypothesis that acute lysine ingestion leads to differences in the 
increased circulating and excreted 2-AAA in humans in vivo, we will administer isotope-
labeled lysine (5g orally) to healthy volunteers (N=20) and measure the level of 2-AAA in 
plasma and urine at baseline and serially post-ingestion. Carbon-13 is a stable naturally 
occurring heavy isotope of carbon. Inclusion of a 13C label on lysine allows for 
subsequent differentiation between endogenous and exogenous lysine and 2-AAA for 
calculation of clearance and excretion of the lysine bolus. 
 
 
3.0 Animal Studies and Previous Human Studies 
 
2-AAA has been identified as a marker of oxidative stress in C. elegans, and in 
endothelial cells in response to hyperglycemia15, highlighting a potential mitochondrial 
phenotype, and relationship between 2-AAA and reactive oxygen species (ROS)16,17. In 
animal models, administration of 2-AAA resulted in increased insulin levels and lower 
fasting plasma glucose, but no change in peripheral insulin sensitivity as measured by 


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insulin tolerance test5. In vitro 2-AAA treatment has been shown to enhance insulin 
secretion in pancreatic β cells and islets. 2-AAA is thought to have important functions in 
the brain18, as well as in other organs, including liver and pancreas.  
 
High baseline plasma 2-AAA in healthy individuals was associated with increased future 
risk of diabetes (12-year follow-up) in FHS participants and validation samples 
(N~2,000)5. Insulin sensitizing therapy leads to reduction in 2-AAA, but not other putative 
diabetes-biomarkers, including branched-chain amino acids (BCAAs)19. Increased 2-
AAA is found in skin in the setting of diabetes, as well as in chronic renal failure and 
sepsis, and increases with age20. Further, decreased urine 2-AAA has been reported in 
diabetes patients compared with non-diabetic14, highlighting a likely complex feedback 
relationship between 2-AAA levels and early diabetes development vs. the setting of 
established disease.  Treatment of overweight/obese adults with impaired fasting 
glucose or untreated diabetes with pioglitazone (45 mg/day) and metformin (1000 mg 
twice/day) led to a significant reduction in plasma 2-AAA and lysine, concurrent with an 
increase in insulin sensitivity19. Acute insulin infusion (7 hrs) in these subjects also led to 
a decrease in both lysine and 2-AAA19,21. The epilepsy drug vigabatrin, which acts 
through GABA transaminase inhibition, leads to increased 2-AAA in plasma and urine, to 
levels similar to those seen in alpha-aminoadipic aciduria22. Apart from diabetes, 2-AAA 
has been found to be elevated in the setting of other cardiometabolic or inflammatory 
diseases including atherosclerosis23, chronic renal failure and sepsis20, non-alcoholic 
fatty liver disease (NAFLD)24 and polycystic ovary syndrome (PCOS)25. There is likely 
some reciprocal regulation between insulin and 2-AAA: insulin infusion in humans leads 
to decreased 2-AAA19,21,26, while insulin deprivation and hyperglycemia in the setting of 
type 1 diabetes leads to increased 2-AAA27. 
 
Human clinical: We tested our ability to use lysine to 
modulate 2-AAA in 
the acute setting 
(human pilot 
study, N=10, 
NCT02756117). 
The rationale to 
use lysine as a 
probe to increase 
2-AAA was based 
in our hypothesis 
that exogenous 
lysine is a 
contributor to 2-
AAA levels, and 
that individuals 
with altered 2-AAA 
have alterations in 
the lysine-2-AAA 
metabolic 
pathway. We 
demonstrated that 
acute oral lysine 
(10g) resulted in 
an increase in plasma lysine (P<0.001, Fig.2A) and 
Figure 3. The effect of an oral lysine 
bolus (10g) on plasma insulin (A); and 
glucose (B) in 10 healthy subjects. 
Closed shapes denote male, open 
shapes denote female subjects. 
A 
 
 
 
 
 
 
 
 
B 
 
 
 
 
Figure 2. The effect of an oral lysine 
bolus (10g) on plasma lysine (A); and 
2-AAA (B) in 10 healthy subjects. 
Closed shapes denote male, open 
shapes denote female subjects. 
A 
 
 
 
 
 
 
 
 
B 
 
 
 


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2-AAA (P<0.0001, Fig.2B). There was an 
increase in plasma insulin (P<0.0001, 
Fig.3A) with no change in glucose 
(Fig.3B). Amino acids are known to 
stimulate insulin secretion, so the effect on 
insulin is not necessarily attributable to 2-
AAA. There were no changes in other 
amino acids. We detected a significant 
increase in urinary lysine and 2-AAA, and 
importantly, observed variation in the 
fractions excreted as lysine (Fig.4A), or as 
the 2-AAA metabolite (Fig.4B). We thus 
confirmed the hypothesis that plasma 2-AAA is modulated in part by oral lysine intake. 
However, we demonstrated that there is considerable inter-individual variability in the 2-
AAA response to lysine (Fig.2B), supporting the premise that factors other than diet (e.g. 
genetics) contribute to modulation of 2-AAA.  
Human lysine tracer 
study: The stable 
isotope tracer 13C-lysine 
replaces 12C with 13C on 
the lysine molecule. 
Previous studies have 
used isotope labeled 
lysine to calculate amino 
acid flux28,29. We invited 
two subjects from the 
pilot study to return for a 
labeled lysine challenge 
to distinguish between 
endogenous and 
exogenous metabolism 
(NCT03063476). We 
administered 5g of 
stable isotope-labeled 
lysine (U-13C lysine, 
Cambridge Isotope 
Laboratories) as an oral bolus, with repeated 
sampling of blood and urine over 6 hours for 
measurement of 12C and 13C lysine and 2-AAA. 
We observed the expected increase in 13C 
isotope-labeled lysine and 2-AAA in plasma in 
both subjects (Figure 5). Interestingly, we also 
observed a marked increase in endogenous 
(unlabeled) lysine and 2-AAA in Subject 02, not 
observed in Subject 01, suggesting secretion of 
stored intracellular lysine and 2-AAA into the 
circulation, potentially as a result of catabolism 
of lysine from endogenous proteins26.  
Figure 4. Estimates of urinary lysine fraction 
excreted (Fe) and 2-AAA fraction metabolized 
(Fm) over 4 hours post lysine bolus. 
A 
 
 
B 
Figure 6. Estimates of urinary lysine 
fraction excreted (Fe) and 2-AAA fraction 
metabolized (Fm) over 6 hours post 13C 
lysine bolus. Closed shapes denote male, 
open shapes denote female subject. 
Figure 5. The effect of an oral isotope-labeled 13C lysine bolus (5g) 
on plasma lysine and 2-AAA in 2 healthy subjects.  


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The rate of urinary clearance of 13C lysine and excretion of metabolized 13C 2-AAA also 
differed between the 2 subjects (Figure 6). Subject 01 excreted a greater proportion of 
the lysine and 2-AAA, with concurrently lower plasma levels of both. While the goal of 
this pilot study was to demonstrate feasibility, and was not powered to detect 
differences, these data further highlight inter-individual differences in the metabolic 
response to an identical lysine load. We hypothesize that there are genetic differences, 
between individuals with high or low 2-AAA, which control the rate of lysine and 2-AAA 
metabolism.  
 
 
4.0 Inclusion/Exclusion Criteria 
 
Inclusion Criteria:  
• 
Prior participant in 2-AAA study. 
Exclusion Criteria:  
• 
Newly diagnosed disease, including cardiovascular, renal, liver disease, bleeding 
disorder, or Diabetes mellitus. 
• 
Individuals who are pregnant or lactating. 
• 
Inability to provide electronic informed consent. 
• 
Inability to fast for 8 hours. 
 
5.0 Enrollment 
 
Our goal is to obtain study visit data for 20 individuals. To allow for expected drop-outs, 
we will enroll up to 30 participants who meet the inclusion and exclusion criteria. We will 
identify potential participants based on their participation in the previous phases of the 
study. We will contact eligible participants directly, by email or phone, and invite them to 
participate. 
 
6.0 Study Procedures 
 
Screening 
 
Potential participants will be identified based on their participation in the previous phases 
of the study. Informed consent will be obtained electronically. Inclusion/exclusion criteria 
will be reviewed to confirm that the individual meets study eligibility requirements. 
Individuals who meet the inclusion criteria, and do not meet any of the exclusion criteria 
will be invited to participate in the study.  
 
Study Visit 
Participants will be requested to arrive at the Vanderbilt Clinical Research Center on the 
morning of the study visit (~8:00 AM) in a fasting state (at least 8 hours, with no food or 
drink, excluding water). After informed consent has been reviewed and documented, 
inclusion/exclusion criteria will be reviewed to confirm that the subject meets study 
eligibility requirements. The participant’s medical history and medications will be 
discussed and documented by study personnel to assess for any changes that may 
potentially exclude the subject from participating. Study personnel will collect the 


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participant’s vital signs, height, weight, waist and hip circumference prior to study 
interventions. All participants will be asked to provide a urine sample for baseline 2-AAA 
measurement and will undergo a urine pregnancy test (if the woman is of child-bearing 
potential).  
 
Following the baseline urine sample, an intravenous line will be inserted into a superficial 
peripheral vein to perform blood draws. Participants will be asked to remain in a seated 
position for the duration of the study, but will be permitted to walk for brief periods 
throughout the study (e.g. to use the restroom). A baseline blood draw will be taken 
(time = 0 hr) for measurement of baseline plasma 2-AAA levels and related biomarkers. 
Immediately following the baseline blood draw, subjects will be given an oral bolus of 13C 
L-lysine (5g) (Cambridge Isotope Laboratories, Tewksbury, MA) in 50ml water. This is an 
amount of lysine equivalent to that which is found in a 5oz serving of beef. A similar dose 
of lysine has previously been shown to alter the response to glucose17. Blood samples 
will be taken at time = 30 minutes 1, 2, 3, 4, 5 and 6 hrs post-lysine administration. 
Normal (0.9%) Saline (NS) will be infused at a rate of 10 ml/hr to flush the canula prior to 
each blood draw, and a 3-5ml blood discard will be performed prior to each collection of 
samples. Each blood draw (including baseline) will collect about 20cc of blood, for a total 
collection of 160cc, or approximately 11 tablespoons of blood. Blood will be collected 
into one tube for serum (5ml) and 2 tubes for plasma (4ml each). Urine samples will be 
collected throughout the visit, in 2-hour increments (0-2, 2-4 hrs and 4-6 post-lysine). 
Peak post-prandial plasma 2-AAA levels are expected to be observed ~3hours post-
lysine27. Plasma and serum will be prepared from blood samples, and both plasma and 
urine aliquots will be frozen at -80°C and stored prior to analysis. 2-AAA and other 
metabolites and biomarkers (e.g. lysine, creatinine) will be measured at Vanderbilt core 
facilities (e.g. Mass Spectrometry core).  
 
Compensation 
Participants will receive $150 following successful completion of the study visit.  
 
Biomarkers 
Blood and urine samples will be coded for subject confidentiality. Plasma, serum and 
urine aliquots will be frozen at -80°C and stored for subsequent measurements. 
Peripheral blood mononuclear cells (PBMCs) may be isolated from blood for analysis.  
2-AAA and other relevant metabolites and biomarkers will be measured at Vanderbilt 
core facilities (e.g. Mass Spectrometry core, Hormone Assay core). For possible future 
investigations, excess blood, cell, and urine samples will be frozen and stored in Dr. 
Ferguson’s laboratory.  
 
 
 
7.0 Risks 
 
Venous Blood draw: This is a routine procedure that is considered standard of care in 
clinical medicine. At the study visit, subjects will undergo venous blood draws. All blood 
draws will be performed by trained personnel using universal precautions to protect both 
the subject and personnel. The risks to subjects are minimal, but may include pain, 
bruising, allergic reaction, infection or bleeding at the needle stick site. A small number 
of individuals may experience dizziness, lightheadedness or fainting. These usually 
resolve without any specific medical therapy over the course of minutes to days. 
 


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Lysine Administration: Lysine is expected to be well-tolerated by all participants. Lysine 
is used as a dietary supplement, available over the counter, with no known long-term 
risks. There are no additional risks associated with the use of stable isotope tracer 13C 
lysine. The proposed dose of lysine may cause mild gastrointestinal upset in some 
participants. This is expected to be minor and transient. 
 
Private Health Information: This information will be collected during the course of the 
study. However, only key study personnel will have access to this information, which will 
be stored in a HIPAA compliant, password protected REDCap database. No protected 
health information will be shared with employers, insurers, or non-research personnel.  
 
8.0 Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
 
Adverse events will be reported to the IRB per Vanderbilt University IRB policy. 
 
 
9.0 Study Withdrawal/Discontinuation 
 
Subjects may withdraw from the study at any time and should notify study personnel if 
they wish to withdraw from the study. Subjects may request their biological samples to 
be destroyed at any time. However, any data or biological samples that have already 
been used for research cannot be destroyed. Subjects may be discontinued from the 
study at the discretion of the investigator (possible reasons listed below). Subjects will 
receive financial compensation for completion of the visit. 
 
Possible reasons for withdrawal/discontinuation from study include, but are not limited 
to: 
• 
Noncompliance with treatment or procedures 
• 
Decision by participant/participant withdraws consent 
• 
Significant adverse event deemed by investigator to preclude continued 
participation 
 
 
10.0 Statistical Considerations 
 
Based on our preliminary study, we expect that some individuals will have modest 
increases in 13C 2-AAA post-lysine, estimated at 0.075µM at peak. We expect that other 
individuals will have greater response, estimated at 0.13µM peak 13C 2-AAA. Assuming 
a SD of 0.04µM, we would require a total of 16 individuals to detect significant 
differences in response by group, at α=0.05 and 80% power. We aim to recruit 20 
individuals to allow for adequate power in the event of attrition or lower than expected 
separation between groups. 
 
 
11.0 Privacy/Confidentiality Issues 
 
Strict confidentiality will be maintained to the fullest extent by the research team, 
including keeping all data in a secure location. All specimens will be coded anonymously 


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to remain confidential and identifiers will be kept in a separate, secure location.   
Samples may be shared with third parties outside of Vanderbilt for future testing but will 
remain anonymous to the recipient.  Participants may contact the principal investigator at 
any time to request that samples be destroyed.  
 
12.0 Follow-up and Record Retention 
 
Anticipated study duration is 5 years. Research data will be maintained by the PI after 
study closure. After study closure, research data will be maintained for a minimum of 6 
years and possibly indefinitely. Data will be stored on the Vanderbilt University computer 
network in a password-protected database. Only members of the study team will have 
access. Pertinent paper documentation will be kept in locked office and only study 
personnel will have access. Only personnel directly involved with the study will have 
access to source data and the electronic database. Data will be de-identified to protect 
study participants’ identities. 
 
13.0 References 
 
1.  
CDC. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in 
the United States, 2014. Atlanta, GA: US Department of Health and Human 
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2.  
Stokes A et al. Deaths Attributable to Diabetes in the United States: Comparison of 
Data Sources and Estimation Approaches. PLoS ONE. 2017;12:e0170219.  
3.  
Carmody D et al. GCK-MODY in the US National Monogenic Diabetes Registry: 
frequently misdiagnosed and unnecessarily treated. Acta Diabetol. 2016;53:703–8.  
4.  
Naylor RN et al. Cost-effectiveness of MODY genetic testing: translating genomic 
advances into practical health applications. Diabetes Care. 2014;37:202–9.  
5.  
Wang TJ et al. 2-Aminoadipic acid is a biomarker for diabetes risk. The Journal of 
Clinical Investigation. 2013;123:4309–17.  
6.  
Chang YF. Pipecolic acid pathway: the major lysine metabolic route in the rat brain. 
Biochemical and biophysical research communications. 1976;69:174–80.  
7.  
Posset R et al. Understanding cerebral L-lysine metabolism: the role of L-
pipecolate metabolism in Gcdh-deficient mice as a model for glutaric aciduria type 
I. Journal of inherited metabolic disease. 2015;38:265–72.  
8.  
Danhauser K et al. DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic 
aciduria. American journal of human genetics. 2012;91:1082–7.  
9.  
Joint WHOFAOUNUEC. Protein and amino acid requirements in human nutrition. 
World Health Organ Tech Rep Ser. 2007;1–265, back cover.  
10.  Neis EP et al. The role of microbial amino acid metabolism in host metabolism. 
Nutrients. 2015;7:2930–46.  
11.  Stiles AR et al. New Cases of DHTKD1 Mutations in Patients with 2-Ketoadipic 
Aciduria. JIMD Rep. 2015; 
12.  Xu WY et al. A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth 
disease type 2 in a large Chinese pedigree. American journal of human genetics. 
2012;91:1088–94.  
13.  Xu W et al. DHTKD1 is essential for mitochondrial biogenesis and function 
maintenance. FEBS letters. 2013;587:3587–92.  
14.  Wu Y et al. Multilayered genetic and omics dissection of mitochondrial activity in a 
mouse reference population. Cell. 2014;158:1415–30.  


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15.  Yuan W et al. Amine metabolomics of hyperglycemic endothelial cells using 
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16.  Zeitoun-Ghandour S et al. C. elegans metallothioneins: response to and defence 
against ROS toxicity. Molecular bioSystems. 2011;7:2397–406.  
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aminoadipic acid and lysine nitrile in vivo. Free radical biology & medicine. 
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18.  Wu HQ et al. L-alpha-aminoadipic acid as a regulator of kynurenic acid production 
in the hippocampus: a microdialysis study in freely moving rats. Eur J Pharmacol. 
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19.  Irving BA et al. Effect of insulin sensitizer therapy on amino acids and their 
metabolites. Metabolism. 2015;64:720–8.  
20.  Sell DR et al. Aging, diabetes, and renal failure catalyze the oxidation of lysyl 
residues to 2-aminoadipic acid in human skin collagen: evidence for metal-
catalyzed oxidation mediated by alpha-dicarbonyls. Annals of the New York 
Academy of Sciences. 2008;1126:205–9.  
21.  Barazzoni R et al. Insulin fails to enhance mTOR phosphorylation, mitochondrial 
protein synthesis, and ATP production in human skeletal muscle without amino acid 
replacement. American journal of physiology. 2012;303:E1117-25.  
22.  Vallat C et al. Treatment with vigabatrin may mimic alpha-aminoadipic aciduria. 
Epilepsia. 1996;37:803–5.  
23.  Saremi A et al. Advanced Glycation End Products, Oxidation Products, and the 
Extent of Atherosclerosis During the VA Diabetes Trial and Follow-up Study. 
Diabetes Care. 2017;40:591–598.  
24.  Feldman A et al. Clinical and Metabolic Characterization of Lean Caucasian 
Subjects With Non-alcoholic Fatty Liver. Am J Gastroenterol. 2017;112:102–110.  
25.  Chang AY et al. Combining a nontargeted and targeted metabolomics approach to 
identify metabolic pathways significantly altered in polycystic ovary syndrome. 
Metabolism. 2017;71:52–63.  
26.  Robinson MM et al. High insulin combined with essential amino acids stimulates 
skeletal muscle mitochondrial protein synthesis while decreasing insulin sensitivity 
in healthy humans. J Clin Endocrinol Metab. 2014;99:E2574-83.  
27.  Lanza IR et al. Quantitative metabolomics by H-NMR and LC-MS/MS confirms 
altered metabolic pathways in diabetes. PLoS ONE. 2010;5:e10538.  
28.  El-Khoury AE et al. Twenty-four-hour intravenous and oral tracer studies with L-[1-
13C]-2-aminoadipic acid and L-[1-13C]lysine as tracers at generous nitrogen and 
lysine intakes in healthy adults. The American journal of clinical nutrition. 
1998;68:827–39.  
29.  Metges CC et al. Availability of intestinal microbial lysine for whole body lysine 
homeostasis in human subjects. Am J Physiol. 1999;277:E597-607.  
 
 
 
 
 
 
 
 

ICF_000.pdf: 
Determinants of Alpha-aminoadipic Acid (2-AAA) and Relationship to Diabetes: 
Study 3 
 
 
 
 
ClinicalTrials.gov Identifier: NCT05210504 
 
 
 
 
 
 
 
ICD Last Update: January 5, 2022 
Most recent IRB approval date: February 7, 2022 
 
 
 
 


2 
VUMC Institutional Review Board 
Informed Consent Document for Research 
Study Title: 
Determinants of alpha-aminoadipic acid (2-AAA) and Relationship to Diabetes: Study 
3 Lysine Tracer 
1/5/2022 
Jane F. Ferguson, PhD 
Version Date: 
PI: 
Date of IRB Approval: 02/07/2022 
Date of Expiration: 02/01/2023 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
Key Information: 
The first section of this document contains some key points that the research team thought you 
would find important. The study is described in more detail after this section. If you do not 
understand something, please ask someone. 
Name of participant:  
_  Age:   
 
 
The following is given to you to tell you about this research study. Please read this form with care and 
ask any questions you may have about this study. Your questions will be answered. Also, you will be 
given a copy of this consent form. 
 
 
Key information about this study: 
 
1. What is the purpose of this study? 
 
We are studying a metabolite called α-aminoadipic acid (2-AAA). 2-AAA occurs naturally in the body. 
Different amounts of 2-AAA may alter the risk of developing diabetes. We are interested in whether 
acute lysine administration results in variability of increased plasma 2-AAA levels. 
 
 
2. 
What will happen and how long will you be in the study? 
 
You were selected as a candidate based on your participation in a previous phase of the study. We will 
ask you questions via email or over the phone to determine eligibility. 
 
If eligible, you will complete a single study visit. It will take you approximately 7 hours to complete the 
study. The single study visit will be conducted at the Clinical Research Center (CRC) at Vanderbilt 
University Medical Center. 
 
We will give you a drink containing lysine and take samples to measure the level of 2-AAA in your blood 
and urine before and after your lysine administration. You will be asked to provide a urine sample for 
baseline 2-AAA measurement and will undergo a urine pregnancy test (if you are of child-bearing 
potential). A light snack will be provided to you following the study visit. 


3 
VUMC Institutional Review Board 
Informed Consent Document for Research 
Study Title: 
Determinants of alpha-aminoadipic acid (2-AAA) and Relationship to Diabetes: Study 
3 Lysine Tracer 
1/5/2022 
Jane F. Ferguson, PhD 
Version Date: 
PI: 
Date of IRB Approval: 02/07/2022 
Date of Expiration: 02/01/2023 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
 
 
 
You are being asked to take part in this research study because you were selected as a candidate based 
on your participation in a previous phase of the study. 
 
You do not have to be in this research study. You may choose not to be in this study and get other 
treatments without changing your healthcare, services, or other rights. You can stop being in this study 
at any time. If we learn something new that may affect the risks or benefits of this study, you will be told 
so that you can decide whether you still want to be in this study. Your medical record will contain a note 
saying you are in a research study and may contain some research information about you. Anyone you 
authorize to receive your medical record will also get this information. 
 
 
3. Side effects and risks that you can expect if you take part in this study: 
 
Venous Blood Draw: This is a routine procedure that is considered standard of care in clinical medicine. 
All blood draws will be performed by trained personnel using universal precautions to protect both the 
study participant and personnel. The risks to study participants are minimal, but you may experience 
pain, an allergic reaction, bleeding or bruising where the intravenous (IV) needle is placed. Occasionally, 
a person feels faint or lightheaded when their blood is drawn. These usually resolve without any specific 
therapy over the course of minutes to days. Rarely an infection can develop; it can be treated. 
 
Lysine Ingestion: Lysine is used as a dietary supplement, available over the counter, with no known long- 
term risks. Lysine is expected to be well-tolerated by all study participants. There are no additional risks 
associated with the use of stable isotope tracer 13C lysine. The proposed dose of lysine may cause mild 
gastrointestinal upset in some study participants. This is expected to be minor and transient. 
 
Private Health Information: This information will be collected during the study. However, only key study 
personnel will have access to this information, which will be stored in a HIPAA compliant, password 
protected database. No protected health information will be shared with employers, insurers, or non- 
research personnel. 
Detailed Information: 
The rest of this document includes detailed information about this study (in addition to the 
information listed above). 


4 
VUMC Institutional Review Board 
Informed Consent Document for Research 
Study Title: 
Determinants of alpha-aminoadipic acid (2-AAA) and Relationship to Diabetes: Study 
3 Lysine Tracer 
1/5/2022 
Jane F. Ferguson, PhD 
Version Date: 
PI: 
Date of IRB Approval: 02/07/2022 
Date of Expiration: 02/01/2023 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
 
4. Good effects that might result from this study: 
You will not benefit from taking part in this study. The results of this research study may advance our 
understanding of a biomarker for Diabetes and help to guide the development of novel preventative and 
therapeutic strategies. This could benefit patients in the future. 
 
 
5. Procedures to be followed: 
 
Screening will be conducted by email, and/or via phone. We will email or call you about the study, 
review the inclusion/exclusion criteria, and send you the link for e-Consent. If you do not qualify for any 
reason, the study staff will tell you why. 
 
Study Visit: 
Upon arrival, the consent form will be reviewed to confirm that you still wish to participate. You will be 
asked to arrive fasting (≥ 8 hours). This means that you cannot eat or drink anything (with the exception 
of water) for at least 8 hours before your visit. We will review your medical history, medications, and 
inclusion/exclusion criteria, which will be documented by study personnel to assess for any changes that 
may potentially exclude you from participating. We will measure your blood pressure, height, and 
weight prior to study interventions. You will be asked to provide a urine sample for baseline 2-AAA 
measurement and will undergo a urine pregnancy test (if you are of child-bearing potential). 
 
Following the baseline urine sample, we will place a small tube in the vein of your arm to take blood. A 
baseline blood draw will be taken for measurement of baseline plasma 2-AAA levels and related 
biomarkers. Next, you will be given a drink containing L-Lysine in 50mL of water. This amount is 
equivalent to the lysine content in a 5 oz. serving of beef. Blood samples will be taken at time= 30 mins, 
1, 2, 3-, 4-, 5- and 6-hours post-lysine administration. Normal Saline (0.9%) will be infused in the vein of 
your arm to flush the canula prior to each blood draw, and a 3-5mL blood discard will be performed 
prior to each collection of samples. Each blood draw collection (including baseline) will collect about 
20cc of blood, for a total collection of 160cc, or approximately 11 tablespoons of blood. Urine samples 
will be collected throughout the visit, in 2-hour increments (0-2, 2-4 hrs. and 4-6 hrs. post-lysine). You 
will be asked to remain seated for the duration of the study but will be permitted to walk for bri ef 
periods throughout the study (e.g., to use the restroom). 
 
6. Payments for your time spent taking part in this study or expenses: 
Individuals that complete all the required study activities will be compensated with $150. This will come 
in the form of a check that will be mailed to your home; it typically takes about 4 weeks to arrive. We 


5 
VUMC Institutional Review Board 
Informed Consent Document for Research 
Study Title: 
Determinants of alpha-aminoadipic acid (2-AAA) and Relationship to Diabetes: Study 
3 Lysine Tracer 
1/5/2022 
Jane F. Ferguson, PhD 
Version Date: 
PI: 
Date of IRB Approval: 02/07/2022 
Date of Expiration: 02/01/2023 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
 
will need to collect your full social security number and address before you are compensated for taking 
part in this study, and any income you make from participating in clinical research could be taxable if 
you make $6700 or more in one year. You are not allowed to accept any money for taking part in this 
study if you are not eligible to receive money from a U.S. person or company or the U.S. government 
because of U.S. national security and/or foreign policy laws. You can still take part in the study; 
however, you will not be paid if you are a resident of a country restricted by the US. government's 
comprehensive territorial sanctions or if you are listed on the U.S. Treasury Department's Office of 
Foreign Assets Control's Specially Designated Nationals (SDN) list of prohibited individuals. You do not 
have to say why you choose not to be paid. 
 
7. 
Costs to you if you take part in this study: 
There is no cost to you for taking part in this study. 
 
8. Payments in case you are injured because of this research study: 
If it is determined by Vanderbilt and the Investigator with the National Institutes of Health (NIH) that an 
injury occurred as a direct result of the tests or treatments that are done for research, then you and/or 
your insurance will not have to pay for the cost of immediate medical care provided at Vanderbilt to 
treat the injury. 
 
There are no plans for Vanderbilt or the National Institutes of Health (NIH) to pay for any injury caused 
by the usual care you would normally receive for treating your illness or the costs of any additional care. 
There are no plans for Vanderbilt or the National Institutes of Health to give you money for the injury. 
 
9. Who to call for any questions or in case you are injured: 
If you should have any questions about this research study, or if you feel you have been hurt by being a 
part of this study, please feel free to contact Dr. Jane Ferguson at (615) 875-9896 or the Clinical 
Research Coordinator Stacy Desine at (615) 875-6520 or Holly M. Smith at (615) 936-1916. If you cannot 
reach the research staff, please contact the Cardiac Access Center at (615) 343-9188. 
 
For additional information about giving consent or your rights as a person in this study, to discuss 
problems, concerns, and questions, or to offer input, please feel free to call the VUMC Institutional 
Review Board Office at (615) 322-2918 or toll free at (866) 224-8273. 
 
10. Reasons why the study doctor may take you out of this study: 
The study investigator may remove you from the study if you experience complications during any of the 
discussed procedures. You will also be removed if you are not compliant with treatment or procedures. 


6 
VUMC Institutional Review Board 
Informed Consent Document for Research 
Study Title: 
Determinants of alpha-aminoadipic acid (2-AAA) and Relationship to Diabetes: Study 
3 Lysine Tracer 
1/5/2022 
Jane F. Ferguson, PhD 
Version Date: 
PI: 
Date of IRB Approval: 02/07/2022 
Date of Expiration: 02/01/2023 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
 
 
11. What will happen if you decide to stop being in this study? 
If you decide to stop being part of the study, you should tell the Principal Investigator. Deciding to not 
be part of the study will not change your regular medical care in any way. You may change your mind 
and cancel this authorization at any time. If you cancel, you must contact the Principal Investigator in 
writing to let her know. Her mailing address is: 
 
Dr. Jane Ferguson 
2220 Pierce Ave, PRB 354B 
Division of Cardiovascular Medicine 
Vanderbilt University Medical Center 
Nashville, TN 37232 
 
Your cancellation will not affect information already collected in the study, or information that has 
already been shared with others before you canceled your authorization. You will get a copy of this form 
after it is signed. 
 
12. Clinical Trials Registry: 
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. Law. This 
website will not include information that can identify you. At most, the website will include a summary 
of the results. You can search this Web site at any time. 
 
13. Confidentiality: 
Your study records and data will be stored in a secure database. The database will reside in a password 
protected secure website supported by Vanderbilt University. Only study personnel will have access to 
the database. 
 
Information in the database that will identify you will only be available to study personnel. 
Your biological samples will be stored with a study ID label. This label will not include any identifying 
information. Only key study staff will have access to your identifying information. 
 
All key study personnel at Vanderbilt University involved in the design or conduct of this study will 
receive the required education on the protection of human participants. This study will follow the 
relevant federal guidelines regarding HIPAA regulations on patient-related information. Only key study 
personnel will have access to identified information. 


7 
VUMC Institutional Review Board 
Informed Consent Document for Research 
Study Title: 
Determinants of alpha-aminoadipic acid (2-AAA) and Relationship to Diabetes: Study 
3 Lysine Tracer 
1/5/2022 
Jane F. Ferguson, PhD 
Version Date: 
PI: 
Date of IRB Approval: 02/07/2022 
Date of Expiration: 02/01/2023 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
 
Vanderbilt may share your information, without identifiers, to others or use it for other research 
projects not listed in this form. Vanderbilt, Dr. Ferguson, or her staff will comply with any and all laws 
regarding the privacy of such information. There are no plans to pay you for the use or transfer of this 
de-identified information. 
 
This study may have some support from the National Institutes of Health (NIH). If so, your study 
information is protected by a Certificate of Confidentiality. This Certificate allows us, in some cases, to 
refuse to give out your information even if requested using legalmeans. 
 
It does not protect information that we have to report by law, such as child abuse or some infectious 
diseases. The Certificate does not prevent us from disclosing your information if we learn of possible 
harm to yourself or others, or if you need medical help. 
 
Disclosures that you consent to in this document are not protected. This includes putting research data 
in the medical record or sharing research data for this study or future research. Disclosures that you 
make yourself are also not protected. 
 
14. Privacy: 
Any samples and information about you may be made available to others to use for research. To protect 
your privacy, we will not release your name. You will not receive any benefit as a result of the tests done 
on your samples. These tests may help us, or other researchers learn more about the causes, risks, 
treatments, or how to prevent this and other health problems. 
 
Your samples may be used to make new products or tests. These may have value and may be developed 
and owned by the study staff, Vanderbilt University, Vanderbilt University Medical Center, and/or others. 
If this happens, there are no plans to provide money to you. 
 
 
15. Study Results: 
In the event new information becomes available that may affect the risks and/or benefits associated with 
this study or your willingness to participate in it, you will be notified so you can make a decision whether 
or not to continue your participation in this study. 
 
Your study records and data will be stored in a secure database. The database will reside in a password 
protected secure website. Information in the database will only be available to study personnel. Your 
biological samples will be stored with a study ID label in a locked freezer. This label will not include any 
identifyinginformation. Onlykey study staff will have access to your identifying information. All key study 


8 
VUMC Institutional Review Board 
Informed Consent Document for Research 
Study Title: 
Determinants of alpha-aminoadipic acid (2-AAA) and Relationship to Diabetes: Study 
3 Lysine Tracer 
1/5/2022 
Jane F. Ferguson, PhD 
Version Date: 
PI: 
Date of IRB Approval: 02/07/2022 
Date of Expiration: 02/01/2023 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
 
personnel involved in the design or conduct of this study will receive the required education on the 
protection of human participants. 
 
If results of this study are reported in medical journals or at meetings, you will not be identified by name, 
by recognizable photograph, or by any other means without your specific consent. 
16. Authorization to Use/Disclose Protected Health Information 
What information is being collected, used, or shared? 
To do this research, we will need to collect, use, and share your private health information. By signing 
this document, you agree that your health care providers (including both Vanderbilt University Medical 
Center and others) may release your private health information to us, and that we may use any and all 
of your information that the study team believes it needs to conduct the study. Your private 
information may include things learned from the procedures described in this consent form, as well as 
information from your medical record (which may include information such as HIV status, drug, alcohol 
or STD treatment, genetic test results, or mental health treatment). 
 
Who will see, use, or share the information? 
The people who may request, receive, or use your private health information include the researchers 
and their staff. Additionally, we may share your information with other people at Vanderbilt, for 
example if needed for your clinical care or study oversight. By signing this form, you give permission to 
the research team to share your information with others outside of Vanderbilt University Medical 
Center. This may include the sponsor of the study and its agents or contractors, outside providers, study 
safety monitors, government agencies, other sites in the study, data managers and other agents and 
contractors used by the study team. We try to make sure that everyone who sees your information 
keeps it confidential, but we cannot guarantee that your information will not be shared with others. If 
your information is disclosed by your health care providers or the research team to others, federal and 
state confidentiality laws may no longer protect it. 
 
Do you have to sign this Authorization? 
You do not have to sign this Authorization, but if you do not, you may not join the study. 
 
How long will your information be used or shared? 
Your Authorization for the collection, use, and sharing of your information does not expire. Additionally, 
you agree that your information may be used for similar or related future research studies. 


9 
VUMC Institutional Review Board 
Informed Consent Document for Research 
Study Title: 
Determinants of alpha-aminoadipic acid (2-AAA) and Relationship to Diabetes: Study 
3 Lysine Tracer 
1/5/2022 
Jane F. Ferguson, PhD 
Version Date: 
PI: 
Date of IRB Approval: 02/07/2022 
Date of Expiration: 02/01/2023 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
 
What if you change your mind? 
If you decide to stop being part of the study, you should tell the Principal Investigator. Deciding to not be 
part of the study will not change your regular medical care in any way. You may change your mind and 
cancel this authorization at any time. If you cancel, you must contact the Principal Investigator in writing 
to let her know. Her mailing address is: 
 
Dr. Jane Ferguson 
2220 Pierce Ave, PRB 354B 
Division of Cardiovascular Medicine 
Vanderbilt University Medical Center 
Nashville, TN 37232 
 
Your cancellation will not affect information already collected in the study, or information that has 
already been shared with others before you cancelled your authorization. You will get a copy of this 
form after it is signed. 
 
STATEMENT BY PERSON AGREEING TO BE IN THIS STUDY 
 
I have read this consent form and the research study has been explained to me verbally. All my 
questions have been answered, and I freely and voluntarily choose to take part in this study. 
 
In-Person Consent: 
 
I confirm that I freely and voluntarily choose to take part in this study. 
 
 
 
Date 
Name of patient/volunteer 
 
Consent obtained by: 
 
 
 
Date 
Signature 
_ 
  
Printed Na me and Title 
Time 


10 
VUMC Institutional Review Board 
Informed Consent Document for Research 
Study Title: 
Determinants of alpha-aminoadipic acid (2-AAA) and Relationship to Diabetes: Study 
3 Lysine Tracer 
1/5/2022 
Jane F. Ferguson, PhD 
Version Date: 
PI: 
Date of IRB Approval: 02/07/2022 
Date of Expiration: 02/01/2023 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
 
 
Consent for Sample and Data Storage and Future Research: 
You are being asked to give blood and urine samples for research. What we learn about you from this 
sample will not be put in your health record. Your test results will not be shared with you or your doctor. 
No one else (like a relative, boss, or insurance company) will be given your test results. 
 
Multiple blood samples totaling 11 tablespoons will be drawn from a vein in your arm using a needle; urine 
will be obtained by self-collection throughout the study visit; The entire study visit will take about 7 hours of 
your time. 
 
Blood samples – The risks to study participants are minimal, but you may experience pain, an allergic 
reaction, bleeding or bruising where the intravenous (IV) needle is placed. Occasionally, a person feels 
faint or lightheaded when their blood is drawn. These usually resolve  without any specific therapy over 
the course of minutes to days. Rarely an infection can develop; it can be treated. You may feel bothered 
or pained from the needle stick. 
 
One risk of giving samples for this research may be the release of your name that could link you to the 
stored samples and/or the results of the tests run on your samples. 
 
To prevent this, these samples will be given a code. Only the study staff will know the code. The name 
that belongs to the code will be kept in a locked file or in a computer with a password. Only the PI, Jane 
F. Ferguson, and trained study personnel (including Stacy Desine, Holly M. Smith) will have access to 
your name. 
 
Your sample will be kept for an unknown length of time (maybe years) for future research. The sample will 
be destroyed when it is no longer needed. 
 
At any time, you may ask to have your sample destroyed. You should contact Dr. Jane Ferguson at 2220 
Pierce Ave, Room 354B, Nashville, TN 37232, or phone  615-875-9896  to have  your sample destroyed 
and no longer used for research. We will not be able to destroy research data that has already been 
gathered using your sample. Also, if your identity was removed from the samples, we will not be able to 
locate and destroy them. 
 
There will be no costs to you for any of the tests done on your samples. You will not be paid for the use of 
your samples. 
 
Please check Yes or No to the questions below: 
My blood/tissue sample may be used for research. 
Yes 
No 
 
My blood/tissue sample may be stored/shared for future research in diabetes. 


11 
VUMC Institutional Review Board 
Informed Consent Document for Research 
Study Title: 
Determinants of alpha-aminoadipic acid (2-AAA) and Relationship to Diabetes: Study 
3 Lysine Tracer 
1/5/2022 
Jane F. Ferguson, PhD 
Version Date: 
PI: 
Date of IRB Approval: 02/07/2022 
Date of Expiration: 02/01/2023 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
 
 
Yes 
No 
 
My blood/tissue sample may be stored/shared for future research for other health problems (such as 
cancer, heart disease, etc.). 
 
Yes 
No 
 
 
Signature:  
Date: