Conditions: Type 2 Diabetes
Keywords: GLP1 insulin glucose exenatide GLP1 receptor agonist insulin secretion glucagon receptor GIP receptor
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 63
Healthy volunteers: yes

Brief summary:
Healthy volunteers were recruited from the Old Order Amish population in Lancaster County, Pennsylvania. After providing informed consent, research participants were screened for eligibility. The clinical trial was designed as a randomized crossover study in which participants underwent two frequently sampled intravenous glucose tolerance tests - one after receiving a subcutaneous injection of saline and one after receiving a subcutaneous injection of rapid-acting exenatide (BYETTA). The study sought to determine whether genetic variants are associated with the magnitude of the effect of exenatide. However, because the study fell far short of its recruitment targets, it was under-powered to evaluate genetic association. Thus, the data analysis focused on testing the hypothesis that the order of testing (whether the placebo FSIGT was conducted before the exenatide-stimulated FSIGT or whether the FSIGTs were conducted in the reverse order) does not alter the magnitude impact of exenatide on responses to a frequently sampled iv glucose tolerance test.

Detailed description:
Healthy volunteers were recruited from the Old Order Amish population in Lancaster County, Pennsylvania. After providing informed consent, research participants were screened for eligibility. The clinical trial was designed as a randomized crossover study in which participants underwent two frequently sampled intravenous glucose tolerance tests (FSIGT) - one after receiving a subcutaneous injection of saline and one after receiving a subcutaneous injection of rapid-acting exenatide (BYETTA). Based on data obtained from the FSIGT, participants' response to exenatide was assessed -- specifically, the effect of exenatide to enhance insulin secretion and accelerate metabolism of glucose. The study sought to determine whether genetic variants are associated with the magnitude of the effect of exenatide. However, because the study fell far short of its recruitment targets, it was under-powered to evaluate genetic association. Thus, the data analysis focused on testing the hypothesis that the order of testing (whether the placebo FSIGT was conducted before the exenatide-stimulated FSIGT or whether the FSIGTs were conducted in the reverse order) does not alter the magnitude impact of exenatide on responses to a frequently sampled iv glucose tolerance test.

Arms:
arm 1: Participants were randomized to receive exenatide 15 min before the first frequently sampled iv glucose tolerance test and saline 15 min before the second frequently sampled iv glucose tolerance test arm 2: Participants were randomized to receive saline15 min before the first frequently sampled iv glucose tolerance test and exenatide15 min before the second frequently sampled iv glucose tolerance test

Interventions: intervention 1: Exenatide Injection (before the first FSIGT) intervention 2: Exenatide injection before the second FSIGT)
Intervention descriptions: intervention 1: Nurses administered exenatide (5 mcg) subcutaneously 15 minutes prior to conducting the first frequently sampled intravenous glucose tolerance test.

In this crossover study, participants will also be "crossed over" to receive saline rather than exenatide: Nurses administered saline (0.2 mL) subcutaneously 15 minutes prior to conducting a frequently sampled intravenous glucose tolerance test. intervention 2: Nurses administered exenatide (5 mcg) subcutaneously 15 minutes prior to conducting the second frequently sampled intravenous glucose tolerance test.

Protocol document:
Prot_SAP_000.pdf: 
NCT05762744   
 


PHARMACOGENOMICS OF GLP1 RECEPTOR AGONISTS (HP-00067574):  
STUDY PROTOCOL 
I. SPECIFIC AIMS AND OBJECTIVES 
We hypothesize that genetic variants, GCGR and GIPR, are associated with an altered 
response to exenatide (a rapidly-acting, short-duration GLP1 agonist) and sitagliptin (a DPP4-
inhibitor). We will conduct our studies in the Old Order Amish – a population that is well suited 
for pharmacogenetic studies, as exemplified by a study identifying variability in the CYP2C19 
gene as a critical determinant of clopidogrel responsiveness (15). The 10-fold enrichment of the 
G40S in GCGR among the Amish greatly facilitates studies of the effects of this SNP. Indeed, a 
10-fold increase in the minor allele frequency translates into a ~100-fold increase in the 
prevalence of homozygotes. 
 
Specific Aim #1: To assess the impact of SNPs in GCGR (G40S) and GIPR (E354Q) on the 
response to exenatide. Just as homozygosity for either of the SNPs was associated with an 
impaired response to oral glucose, we hypothesize that homozygosity for either SNP will be 
associated with an impairment in the beta cell’s response to the incretin-like action of exenatide. 
Approach: Research subjects will undergo a randomized crossover study to assess the effect of 
exenatide upon insulin secretion. Subjects will be treated with either saline or exenatide (5 mcg, 
s.c.), prior to undergoing a frequently sampled intravenous glucose tolerance test to assess the 
pharmacodynamic impact of exenatide upon glucose-stimulated insulin secretion. Homozygotes 
for the common “wild type” alleles of both GCGR and GIPR will be compared to two study 
groups: homozygotes for two variant alleles (S40-GCGR homozygotes or Q354-GIPR 
homozygotes). 
 
Specific Aim #2: To assess the impact of SNPs in GCGR (G40S) and GIPR (E354Q) on the 
response to sitagliptin. We hypothesize that homozygosity for either SNP will be associated with 
an impairment in the beta cell’s response to the decreased degradation of incretins. Approach: 
Research subjects will undergo a crossover study to assess the effect of sitagliptin upon 
glucose-stimulated insulin secretion. Subjects will be treated with either placebo or sitagliptin 
(100 mg orally), prior to undergoing an oral glucose tolerance test to assess the 
pharmacodynamic impact of sitagliptin upon glucose-stimulated insulin secretion. Homozygotes 
for the common “wild type” alleles of both GCGR and GIPR will be compared to two study 
groups: homozygotes for two variant alleles (S40-GCGR homozygotes or Q354-GIPR 
homozygotes). 
 
Specific Aim #3: To assess the effect of the two SNPs (G40S in GCGR and E354Q in GIPR) on 
oral glucose tolerance tests. Our preliminary data suggesting an association of the two SNPs 
with delayed insulin secretion in an OGTT is based on a small number of homozygous research 
subjects. Accordingly, we propose to conduct a replication study to confirm whether this is a 
reproducible finding. In addition, we will measure hormone levels (glucagon, GIP, GLP1) to 
investigate mechanisms to compensate for the loss-of-function variants in cognate receptors for 
glucagon and GIP (GCGR and GIPR). 
II. RESEARCH DESIGN: OVERVIEW 
Eighty non-diabetic subjects [25 homozygous for p.G40S (GCGR), 25 homozygous for 
p.E354Q(GIPR) and 30 age/sex matched controls] will be enrolled. Following screening and 


baseline blood collection, participants will receive two 3 hour intravenous glucose tolerance 
tests (IVGTT) separated by a 5 day to 4 week wash-out period. Before each IVGTT, a 
subcutaneous injection of either 5 micrograms of exenatide or placebo (saline) will be 
administered. The participant will receive both in a random crossover fashion. After a 1-4 week 
washout, the participant will return for two 3 hour oral glucose tolerance tests separated by 1-4 
weeks, measuring glucose and insulin levels. Before each OGTT sitagliptin (100 mg) or placebo 
will be administered. The participant will receive both in a random crossover fashion. 
III. RESEARCH DESIGN: OVERVIEW 
Glucagon-like peptide 1 (GLP1) analogs and dipeptidyl peptidase-4 (DPP4) inhibitors are an 
important classes of anti-diabetic drugs, which combine substantial glucose-lowering activity 
with clinically meaningful weight loss (in the case of GLP1 analogs). In recently published 
Guidelines (1,2), the ADA and EASD reviewed 12 classes of drugs for treatment of type 2 
diabetes, and advocated “a patient-centered approach.” However, there is a shortage of 
scientific data to guide the selection of the best drug for each individual patient. We propose to 
address a portion of this knowledge gap by conducting a pharmacogenetic study to investigate 
contributions of genetic variation in determining an individual patient’s response to GLP1 
analogs and DPP4 inhibitors. In the present application, we propose studies of the effects of 
specific genetic variants in two candidate genes associated with abnormalities in beta cell 
function: GIPR and GCGR. 
IV. LITERATURE REVIEW 
 
GLP1 is a member of the secretin family of peptides, a family that also includes glucagon and 
gastric inhibitory peptide (GIP). GLP1, GIP, and glucagon have complex physiological 
interactions, which contribute importantly to metabolic regulation. Whereas secretion of GLP1 
and GIP is promoted by oral glucose (3), glucagon secretion is stimulated by hypoglycemia. 
Both GLP1 and GIP function as incretins, thereby potentiating the effect of glucose to promote 
insulin secretion by pancreatic beta cells (3). While glucagon also promotes insulin secretion 
(4), glucagon is best known for its functions as a counter-regulatory hormone that opposes 
many of the actions of insulin (5,6). GLP1 decreases plasma levels of glucagon by inhibiting 
glucagon secretion (3). Recent work has explored pharmacodynamic interactions among the 
GLP1, GIP, and glucagon agonist mechanisms by investigating the pharmacology of novel 
peptides possessing dual agonist (GLP1 plus either GIP or glucagon) or triple agonist activities 
(GLP1 + GIP + glucagon) (7-9). These unimolecular dual and triple agonists have superior 
metabolic activity to improve glycemic control, promote weight loss, and reverse hepatic 
steatosis. These observations raise the possibility that the actions of endogenous GIP and 
glucagon could affect the response to exogenously administered GLP1 analogs (e.g., 
exenatide) or DPP4 inhibitors (e.g. sitagliptin). 
Functionally significant, nonsynonymous SNPs have previously been identified in GCGR and 
GIPR, the genes encoding receptors for glucagon and GIP, respectively. The G40S substitution 
in GCGR (rs1801483) decreases the affinity of glucagon binding (10,11), thereby causing 
glucagon resistance (12). The E354Q substitution in GIPR (rs1800437) enhances the receptor’s 
sensitivity to agonist-induced desensitization (13), which could lead to GIP resistance in vivo. 
Both SNPs have minor allele frequencies of 0.12 in the Old Order Amish population. The G40S 
SNP in GCGR is ~10-fold enriched relative to the general European-American population 
whereas E354Q in GIPR is ~2-fold under-represented relative to the general European-


American population. We have obtained preliminary data from the Amish Family Diabetes Study 
(14) demonstrating that homozygosity for either SNP is associated with impaired insulin 
secretion in an oral glucose tolerance test – suggesting that these genetic variants compromise 
beta cell function. Please refer to the following sections of the American Diabetes Association 
Grant Application and the Diabetes Research Center Pilot & Feasibility grant application: 
• Specific Aims 
• Section A. Significance 
• Section B. Innovation 
• Research Approach: Section 1. Scientific Rationale and Background 
 
REFERENCES 
 
1. Inzucchi, S. E., Bergenstal, R. M., Buse, J. B., Diamant, M., Ferrannini, E., Nauck, M., Peters, 
A. L., Tsapas, A., Wender, R., Matthews, D. R., American Diabetes, A., European Association for 
the Study of, D.: Management of hyperglycemia in type 2 diabetes: a patient-centered 
approach: position statement of the American Diabetes Association (ADA) and the European 
Association for the Study of Diabetes (EASD). Diabetes Care 35: 1364-1379, 2012. 
2. Inzucchi, S. E., Bergenstal, R. M., Buse, J. B., Diamant, M., Ferrannini, E., Nauck, M., Peters, 
A. L., Tsapas, A., Wender, R., Matthews, D. R.: Management of hyperglycemia in type 2 
diabetes, 2015: a patient-centered approach: update to a position statement of the American 
Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 
38: 140-149, 2015. 
3. Campbell, J. E., Drucker, D. J.: Pharmacology, physiology, and mechanisms of incretin 
hormone action. Cell Metab 17: 819-837, 2013. 
4. Samols, E., Marri, G., Marks, V.: Promotion of Insulin Secretion by Glucagon. Lancet 2: 415-
416, 1965. 
5. Drucker, D. J.: Biologic actions and therapeutic potential of the proglucagon-derived peptides. 
Nat Clin Pract Endocrinol Metab 1: 22-31, 2005. 
6. Habegger, K. M., Heppner, K. M., Geary, N., Bartness, T. J., DiMarchi, R., Tschop, M. H.: The 
metabolic actions of glucagon revisited. Nat Rev Endocrinol 6: 689-697, 2010. 
7. Day, J. W., Ottaway, N., Patterson, J. T., Gelfanov, V., Smiley, D., Gidda, J., Findeisen, H., 
Bruemmer, D., Drucker, D. J., Chaudhary, N., Holland, J., Hembree, J., Abplanalp, W., Grant, E., 
Ruehl, J., Wilson, H., Kirchner, H., Lockie, S. H., Hofmann, S., Woods, S. C., Nogueiras, R., 
Pfluger, P. T., Perez-Tilve, D., DiMarchi, R., Tschop, M. H.: A new glucagon and GLP-1 co-
agonist eliminates obesity in rodents. Nat Chem Biol 5: 749-757, 2009. 
8. Finan, B., Ma, T., Ottaway, N., Muller, T. D., Habegger, K. M., Heppner, K. M., Kirchner, H., 
Holland, J., Hembree, J., Raver, C., Lockie, S. H., Smiley, D. L., Gelfanov, V., Yang, B., 
Hofmann, S., Bruemmer, D., Drucker, D. J., Pfluger, P. T., Perez-Tilve, D., Gidda, J., Vignati, L., 
Zhang, L., Hauptman, J. B., Lau, M., Brecheisen, M., Uhles, S., Riboulet, W., Hainaut, E., 
Sebokova, E., Conde-Knape, K., Konkar, A., DiMarchi, R. D., Tschop, M. H.: Unimolecular dual 
incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med 5: 
209ra151, 2013. 
9. Finan, B., Yang, B., Ottaway, N., Smiley, D. L., Ma, T., Clemmensen, C., Chabenne, J., 
Zhang, L., Habegger, K. M., Fischer, K., Campbell, J. E., Sandoval, D., Seeley, R. J., Bleicher, 
K., Uhles, S., Riboulet, W., Funk, J., Hertel, C., Belli, S., Sebokova, E., Conde-Knape, K., 
Konkar, A., Drucker, D. J., Gelfanov, V., Pfluger, P. T., Muller, T. D., Perez-Tilve, D., DiMarchi, R. 
D., Tschop, M. H.: A rationally designed monomeric peptide triagonist corrects obesity and 


diabetes in rodents. Nat Med 21: 27-36, 2015. 
10. Hansen, L. H., Abrahamsen, N., Hager, J., Jelinek, L., Kindsvogel, W., Froguel, P., 
Nishimura, E.: The Gly40Ser mutation in the human glucagon receptor gene associated with 
NIDDM results in a receptor with reduced sensitivity to glucagon. Diabetes 45: 725-730, 1996. 
11. Mukund, S., Shang, Y., Clarke, H. J., Madjidi, A., Corn, J. E., Kates, L., Kolumam, G., 
Chiang, V., Luis, E., Murray, J., Zhang, Y., Hotzel, I., Koth, C. M., Allan, B. B.: Inhibitory 
mechanism of an allosteric antibody targeting the glucagon receptor. J Biol Chem 288: 36168-
36178, 2013. 
12. Tonolo, G., Melis, M. G., Ciccarese, M., Secchi, G., Atzeni, M. M., Maioli, M., Pala, G., 
Massidda, A., Manai, M., Pilosu, R. M., Li, L. S., Luthman, H., Maioli, M.: Physiological and 
genetic characterization of the Gly40Ser mutation in the glucagon receptor gene in the 
Sardinian population. The Sardinian Diabetes Genetic Study Group. Diabetologia 40: 89-94, 
1997. 
13. Mohammad, S., Patel, R. T., Bruno, J., Panhwar, M. S., Wen, J., McGraw, T. E.: A naturally 
occurring GIP receptor variant undergoes enhanced agonist-induced desensitization, which 
impairs GIP control of adipose insulin sensitivity. Mol Cell Biol 34: 3618-3629, 2014. 
14. Hsueh, W. C., Mitchell, B. D., Aburomia, R., Pollin, T., Sakul, H., Gelder Ehm, M., Michelsen, 
B. K., Wagner, M. J., St Jean, P. L., Knowler, W. C., Burns, D. K., Bell, C. J., Shuldiner, A. R.: 
Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family 
Diabetes Study. Diabetes Care 23: 595-601, 2000 
V. STUDY PROCEDURES 
Recruitment and Screening Visit: 
As part of the consent process for Amish Research Clinic studies, participants are asked if we 
may re-contact them for future studies. Participants who have agreed to re-contact and who 
have genetic information available from past studies will be asked to participate, based on 
genotype. Potential participants will be visited in their homes by a field team consisting of a 
registered nurse and an Amish liaison. This mechanism is culturally appropriate since the Amish 
do not have phones in their homes and prefer face-to-face contact to letters. Subjects will be 
asked if they are interested in hearing about another research study. If the subject agrees, the 
study will be explained and eligibility criteria will be reviewed. Informed consent and HIPAA 
authorization will be obtained. Following informed consent, vital signs, height, weight, medical 
and family history will be obtained. Approximately 15 mL (3 teaspoons) of blood will be drawn for 
CBC, HbA1c, comprehensive metabolic panel, and thyroid function test (TSH) to evaluate 
eligibility. 
 
Female research participants will be informed that they may not participate in this study if they 
are pregnant. They will be informed that the risks of exenatide and sitagliptin to a pregnant 
woman and fetus are unknown. All female subjects will have an assessment of child-bearing 
potential. Pregnancy status will be determined by self-report at the screening visit. A urine 
pregnancy test will be performed at the clinic visit prior to drug administration, or within 1 week 
prior, on women who are not either surgically sterile via tubal ligation, bilateral oophorectomy or 
hysterectomy or post-menopausal for ≥1 year. 
 
Following review of screening information and lab results, eligibility will be confirmed and the 
Eligibility Checklist signed by the PI or designated co-investigators. Eligible participants will 
complete studies during the course of four visits to the Amish Research Clinic. Visits will be 


separated by a 5 day to 4 week washout period. FSIVGTT (Frequently sampled intravenous 
glucose tolerance test) visits will be consecutive and OGTT (Oral glucose tolerance test) visits 
will be consecutive, but either IVGTTs or OGTTs can occur first. If subjects would like participate 
in the study, but are unable to accommodate all four visits, they will have the option to do either 
both FSIVGTT visits or both OGTT visits. (Since the FSIVGTT and OGTT visits are independent 
of each other, integrity of results will not be altered if subjects only perform one and not the 
other) 
At the first visit only, fasting blood tests will be obtained to assess the lipid profile (LDL, HDL, 
and triglycerides), DNA, and for plasma and serum banking. Approximately 25 ml (5 tsp.) will be 
drawn in addition to the blood drawn for the glucose tolerance test at this visit. 
 
FSIVGTT #1 - Research subjects will be transported to the Amish Research clinic in the fasting 
state (minimum of 8 hour, maximum of 24 hour fast) where height, weight, waist and hip 
measurements, and vital signs will be measured. Women of child-bearing potential will undergo 
a urine pregnancy test. An FSIVGTT will be conducted as follows: IV (intravenous) access will 
be established in both arms of the research subjects, one for glucose infusion and the other for 
frequent blood sampling. NSS (normal saline solution) will be used to maintain patency of IV. 
The participants will be randomized to receive a subcutaneous (s.c.) injection of either saline or 
exenatide (5 mcg) 15 min prior to administration of IV glucose. Intravenous glucose (0.3 g/kg) 
will be infused over 2 min at time=0, and 31 blood samples will be obtained between -15 and 
+180 minutes. Approximately 120 ml (24 tsp.) of blood will be drawn. 
 
FSIVGTT #2 - The FSIVGTT will be conducted exactly as during the previous clinic visit. 
Research subjects will be “crossed over” to receive a s.c. injection of whichever agent they did 
not receive during the first clinic visit (i.e., saline or 5 mcg exenatide). 
 
OGTT #1 - Research subjects will be instructed to take a single dose of placebo at home at a 
specified time prior to being transported to the Amish Research clinic in the fasting state 
(minimum of 8 hour, maximum of 24 hour fast). At the clinic, height, weight, waist and hip 
measurements, and vital signs will be measured. A single venous access site will be used to 
collect blood samples. NSS may be infused KVO to maintain patency. The OGTT will begin 2 
hours after the placebo was taken. Plasma levels of glucose and insulin will be measured every 
30 minutes between 0-180 minutes after oral administration of 75 grams of glucose. In addition, 
plasma levels of glucagon, GIP, and total GLP1 will be measured at 0, 30, and 60 minutes. 
Approximately 80 ml (16 tsp.) of blood will be drawn. 
 
OGTT #2 - The OGTT will be conducted exactly as during the previous clinic visit except 
research subjects will take sitagliptin 100 mg by mouth 2 hours prior to the OGTT. An additional 
blood sample will be drawn for storage. 
 
Notification of results: Screening lab and lipid results will be reviewed with participants by study 
team professional at one of the clinic visits. A copy of lab results will be provided to the 
participants. 
VI. SAMPLE SIZE: POWER  CALCULATIONS 
The two co-primary end-points for the study are both derived from the FSIVGTTs: 
• Genotype-dependent effect of exenatide on insulin-AUC. Based on published dose-response 


data for liraglutide, insulin-AUC was 13.4 mU/L in placebo-treated individuals. In response to 
liraglutide (10-12.5 mcg/kg), insulin-AUC increased to approximately 30-36 mU/L with an S.D. of 
4-13 mU/L. A sample size of 24 per genotype group would provide 80% power (with alpha=0.05) 
to detect a decrease of delta insulin-AUC from 20 mU/L (in the control group) to 13.5 mU/L (in 
homozygotes for a genetic variant) assuming a standard deviation of 8 mU/L 
(http://www.stat.ubc.ca/~rollin/stats/ssize/n2.html). 
 
• Genotype-dependent effect of exenatide on the disappearance rate for glucose. Based on 
published dose-response data for liraglutide, Ksubscriptg was 1.00%/min in placebo-treated 
individuals. In response to liraglutide (10-12.5 mc/kg), Ksubscriptg increased to approximately 
1.58-2.39%/min with an S.D. of 0.14-0.23%/min. Thus, delta Ksubscriptg is estimated as ~1.0% 
(based on an assumption that mean Ksubscriptg would be ~1.0% off-treatment, and would 
increase to ~2.0% on drug). A sample size of 24 per genotype group would provide 80% power 
(with alpha=0.05) to detect a decrease of delta Ksubscriptg from 1.0%/min (in the control group) 
to 0.75%/min (in homozygotes for a genetic variant) assuming a standard deviation of 0.3%/min 
(http://www.stat.ubc.ca/~rollin/stats/ssize/n2.html). 
VII. DATA ANALYSIS 
Pre vs. post drug differences between insulin-AUC and disappearance rate for glucose will be 
calculated for each person and the differences between genotype groups will be tested. 
Specifically, data will be analyzed using a variance components method that accommodates 
participant level characteristics (eg. age, sex, renal function) and accounts for relatedness 
called the Mixed Model Analysis for Pedigrees (http://edn.som.umaryland.edu/mmap/index.php) 
program. 
 
 
 

ICF_001.pdf: 
Page 1 of 8
 RESEARCH CONSENT FORM
Protocol Title: 
Pharmacogenetics of Glucagon-Like Peptide 1 Receptor 
(GLP1R) Inhibitors
Study No.:  
HP-00067574
Principal Investigator:  
Simeon Taylor, M.D.   Phone: 410-706-7103
Sponsor: 
American Diabetes Association
We are asking you to take part in a research study. Your participation is voluntary.  Please read 
this consent form and ask any questions before you decide if you want to take part.
Background Information
Until recently, drugs have been made with the idea that each drug works pretty much the same in 
everybody. The field of pharmacogenetics has changed that "one size fits all" approach. 
Pharmacogenetics uses information about a person's genes to choose the drugs and drug doses 
that are likely to work best for that particular person.  Genes are pieces of DNA that have the 
instructions needed to make our bodies work.  DNA stores these instructions in the form of a 
code. This is the code that you inherit from your parents and that you pass on to your children.
This is a study to look at how two drugs called exenatide and sitagliptin work in different 
people. Exenatide and sitagliptin are  FDA approved drugs that are used to treat type 2 diabetes.  
Diabetes is a disease that causes a person to have high amounts of sugar in the blood.  Exenatide 
is in a class of drugs called glucagon-like peptide 1 receptor (GLP1R) analogs. Sitagliptin is in a 
class of drugs called dipeptidyl peptidase 4 (DPP4) inhibitors. GLP1R analogs and DPP4 
inhibitors work by stimulating the release of insulin to help lower blood sugar. 
You have been asked to be in this study because you have participated in an Amish Research 
Clinic study before and you carry a gene variation that may affect the way exenatide or 
sitagliptin works. 
What is the purpose of this study?
The purpose of this study is to see if a person’s genes affect how well exenatide and/or sitagliptin 
lower blood sugar in healthy people who do not have diabetes.  There will be up to 80 adult 
Amish participants in this study.
 
HP-00067574 UM IRB Approval Date 1/17/2019
Do Not Sign this Form after this Date 1/16/2020


Page 2 of 8 
What will happen if I join the study?
Screening Visit 
The screening visit will last about 1 hour.  We will ask you questions about your health and your 
family’s health. We will measure your height, weight, pulse and blood pressure.  We will draw 
about 3 teaspoons of blood from a vein in your arm. Your blood will be tested to make sure you 
do not have diabetes, significant kidney, liver, thyroid problems or low blood cell count.  If you 
meet the study requirements, you will have up to four study visits at the Amish Research Clinic 
spaced 5 days – 4 weeks apart.  You will be in the study for up to 16 weeks.  Your participation 
will include 3 or 4 of these study visits depending on your availability.   
Clinic Visits
For each visit, you will arrive at the clinic after a 12 hour fast. We will measure your height, 
weight, waist and hip circumference, pulse and blood pressure.  If you are female of child-
bearing potential, you will provide a urine sample at the visit or in the week prior to make sure 
you are not pregnant. At your first visit only, blood will be drawn for cholesterol testing, DNA, 
and samples to be stored for future research. About 5 teaspoons of blood will be drawn for these 
tests. 
Intravenous Glucose Tolerance Test (IVGTT)
At two of the visits, you will have an intravenous glucose tolerance test. This test is done to see 
how your body processes glucose (sugar). During this test you will rest comfortably on a cot. A 
small plastic tube (IV catheter) will be placed in a vein in each arm. 
Before the test, you will be given either exenatide OR salt water in an injection (a shot) under 
the skin on your arm or abdomen.  You will be given exenatide at one of the visits and the salt 
water at the other visit. The dose of exenatide is the same as the dose approved by the FDA for 
diabetic patients. 
You will be then be given glucose (sugar) through the IV tube in one arm vein. Blood samples 
will be drawn through the IV tube in your other arm at frequent intervals for three hours. We will 
then remove the IV tubes and you will be given lunch. About 24 teaspoons of blood will be 
drawn during this 3 hour test.     
Oral Glucose Tolerance Test (OGTT)
At the other two visits, you will have an oral glucose tolerance test. This test is done to see how 
your body processes glucose.  2 hours before the first test, you will take a “sugar” pill and 2 
hours before the second test you will take sitagliptin 100 mg.  The dose of sitagliptin is the same 
as the dose approved by the FDA for diabetic patients. You will take these at home before 
coming to the clinic. Other than taking the pill, you will continue your 12 hour fast. When you 
arrive at the clinic, an IV tube will be placed in a vein in one arm. You will be given a sugary 
beverage to drink.  Blood samples will be drawn through the IV tube in your arm every ½ hour 
for three hours. We will then remove the IV tube and you will be given lunch.  About 16 
HP-00067574 UM IRB Approval Date 1/17/2019
Do Not Sign this Form after this Date 1/16/2020


Page 3 of 8 
teaspoons of blood will be drawn during this 3 hour test.  At one of the visits we will also collect 
about 4 teaspoons of blood to store for future research.  
Future Use of Blood and Information
Your blood samples, genetic data and health information will be stored for future research use. 
Your samples will be stored with a code so that your name cannot be readily identified.  Your 
samples and information may be shared with other researchers. This may include researchers 
from University of Maryland as well as from other universities, the government, and drug- or 
health related companies. Researchers may study your genes and other substances using your 
samples. Researchers may do a wide range of genetic tests, from those on a single gene to whole 
genome sequencing, which looks at your entire genetic code.  Information from your stored 
samples, along with your health information, may be used by other researchers to help 
understand the cause of diseases and how to treat or prevent them.   Your samples will not be 
used to develop cell lines. Your samples will not be sold or given to third parties. Information 
that might identify you personally will NOT be provided to other researchers.  Results of 
research tests done with your samples will not be reported to you or put in your medical record.  
Any future research using your samples or health information will be reviewed and approved by 
an Institutional Review Board (IRB), which is a special Committee that oversees research studies 
to protect the rights and welfare of research participants. If at any time you wish to have your 
samples removed from the study and destroyed you may do so by contacting Dr. Simeon Taylor 
by phone at 410-706-7103 or by mail at 685 W. Baltimore Street, MSTF Room 357, Baltimore, 
MD 21201.
o
You can use the information and blood samples collected from me for future studies of 
drug response or other disorders or health conditions.     
Please mark and initial your choice:   YES ____      NO ____      Initials ________
In the future, we may want to ask you if you want to take part in other research studies. Once you 
hear the details of the study, you can decide then to take part or not take part.  
o
You can contact me in the future to ask me to take part in other studies.    
Please mark and initial your choice:   YES ____      NO ____      Initials ________
Sharing Data in Large Scientific Databases
To do more powerful research, it is helpful for researchers to share test results from studying 
human samples. They do this by putting it into one or more scientific databases, where it is 
stored indefinitely along with information from other studies. There are different kinds of 
databases. Some databases are open to the public and some are restricted. Anyone on the Internet 
can look at databases open to the public. Only researchers who apply and are approved can use 
restricted databases. Databases may be maintained by the University of Maryland, the federal 
government (for example, National Institutes of Health), or by private companies. Some of your 
genetic and health information could be placed into one or more of these open or restricted 
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databases.  Your name and other information that could directly identify you (such as address or 
social security number) will never be placed into any scientific database. 
Are there any risks to me?
Exenatide: Common side effects of exenatide include nausea, vomiting, diarrhea, headache, 
dizziness, or redness or swelling at the injection site.  Very rarely, exenatide can cause severe 
allergic reaction with rash, itching or swelling, dizziness, trouble breathing. There is a risk of 
acute pancreatitis. If you experience symptoms of severe abdominal pain or nausea, seek 
immediate medical attention. The chance of having side effects is reduced because you will only 
take one dose of exenatide at the lowest recommended dose.  
Sitagliptin:  Common side effects of sitagliptin include upper respiratory infection or headache. 
Very rarely, sitagliptin can cause pancreatitis, serious allergic reactions, kidney injury, and 
severe joint pain. The chance of having side effects is reduced because you will only take one 
dose of sitagliptin.
Blood Drawing: Blood drawing can cause pain, swelling, or bruising at the needle puncture site.  
Occasionally, blood drawing can cause feeling faint or even fainting. Rarely irritation of the vein 
or infection may occur.  To lower these risks, only trained staff will draw your blood.  The total 
amount of blood drawn for the entire study will be about 92 teaspoons (460 ml.).
Intravenous glucose tolerance test: In addition to the risks described above for blood drawing, IV 
administration of glucose may sometimes result in lightheadedness or tingling in the arm or 
shoulder.  Rarely, giving glucose solution can cause irritation of the vein or if it “leaks” out of 
the blood vessel, irritation of the surrounding tissue. We will instruct you to tell us if you feel 
any discomfort during the glucose infusion. There is a very slight chance that some people may 
have a drop in blood sugar towards the end of the test and feel symptoms such as sweating, 
weakness, and light-headedness. If this occurs, we will have you remain in bed until you are 
given a sugary drink or something to eat. 
Oral glucose tolerance test:  In addition to the risks described above for blood drawing, you may 
experience nausea after drinking the sugary beverage.  There is a very slight chance that some 
people may have a drop in blood sugar towards the end of the test and feel symptoms such as 
sweating, weakness, and light-headedness. If this occurs, we will have you remain in bed until 
you are given a sugary drink or something to eat.
Pregnancy: Because exenatide may be harmful to a pregnant woman and the unborn child, you 
should not become pregnant while you are in this study.  A urine pregnancy test will be done at 
or before each clinic visit if you are able to bear children. Women who are breast feeding cannot 
be in this study. 
Confidentiality: There is a small risk that your private medical or genetic information could be 
revealed or discovered by mistake.  If the information suggested something serious about your 
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health, it could be misused.  In the unlikely event this happens, this may cause you to experience 
feelings of anger, worry or embarrassment. The information could be used to try to make it 
harder for you to get or keep a job or health insurance. There are laws against using genetic 
information this way.  They may not give full protection for life, long-term care, or disability 
insurances. We believe that the chance these things will happen is very small, but we cannot 
promise that this will not happen. We will do our best to protect your study information. The 
steps we will take to keep your information private are described below under the section “How 
will you keep my information safe?”
We do not think that there will be further risks to your privacy and confidentiality by sharing 
your genetic information with large scientific databases.  However, we cannot predict how 
genetic information will be used in the future. There is a risk that someone could link the 
information in a scientific database back to you, because even without a name or other 
information, genetic information is unique to each person. We believe the chance that someone 
will figure out the sample is yours is very small.  
There may be risks in this study which are not yet known. You will be told of any significant 
new findings which develop during the study which may affect your willingness to participate in 
the study.
Will being in the study help me?
You may or may not benefit by taking part in this study.  A direct benefit cannot be guaranteed 
from your participation in this study.  Your blood pressure measurements, screening blood test 
results, and cholesterol results will be shared with you.  You may share your results with your 
doctor, who may make recommendations regarding your health. The knowledge gained from this 
study will improve our understanding of how genes affect people’s response to medications for 
the treatment of diabetes.  This may lead to the design of more effective medications and better 
patient care in the future.
What are my options?
This is not a treatment study. Your alternative is not to join the study.  If you choose not to join, 
your healthcare at University of Maryland, Baltimore will not be affected.  If you are an 
employee or student, your employment status or academic standing at UMB will not be affected 
by your participation or non-participation in this study.
Will it cost me anything to be in this study?
It will not cost you anything to take part in this study, including your transportation to and from 
the clinic.  
Will I get paid?
You will be paid $10 for the Screening Visit and $125 for each Clinic Visit completed for a total 
of up to $510. A check will be mailed to you about 4 weeks after completion of your study visits.  
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If you do not complete the study, you will be paid for the portion of the study that you complete. 
Your transportation costs to and from the clinic will be paid, or reimbursed to you.   
How will you keep my information safe?
Efforts will be made to limit access to your personal information, including research study and 
medical records to people who need to review this information. We cannot promise complete 
secrecy. Here are just a few of the steps we will take to protect your information:
We will remove your name and other identifiers from your study information and 
specimens, and replace them with a code number. We will keep the list that links the code 
number to your name separate from your study information.  Only a few of the study staff 
can see the list that links the code number to your name. 
We will store your information in locked cabinets and on password-protected computers. 
The data from the study may be published. However, you will not be identified by name.
Organizations that may inspect and copy your information from this study include the IRB, 
other representatives of the University of Maryland, the American Diabetes Association, 
the Food and Drug Administration and of the Office of Human Research Protections 
(OHRP). This is necessary to make sure the research findings are true. They also protect 
your safety and wellbeing.
Everyone using study information will work to keep your information confidential. Your 
personal information will not be given out unless required by law.  
What if I no longer want to be in the study?
Being in this study is voluntary. You can say no now, or leave the study at any time later.  There 
are no penalties, loss of benefits, or negative consequences if you choose not to take part or to 
leave the study. If you leave the study, data already collected will not be removed from the study 
database. If you decide to stop taking part, if you have questions, concerns, or complaints, or if 
you need to report a medical injury related to the research, please contact Dr. Simeon Taylor at 
410-706-7103. 
Can I be removed from the research?
The person in charge of the research study can remove you from the research study without your 
approval. Possible reasons for removal include if the doctor in charge decides that the research 
study is no longer in your best interest.  The study doctor will tell you about this and you will 
have the chance to ask questions if this were to happen.
UNIVERSITY STATEMENT CONCERNING RESEARCH RISKS 
The University of Maryland, Baltimore (UMB) is committed to providing participants in its 
research the rights due them under State and federal law. You give up none of your legal rights 
by signing this consent form or by participating in the research project. This research has been 
reviewed and approved by the Institutional Review Board (IRB). Please call the Institutional 
Review Board (IRB) if you have questions about your rights as a research subject.
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Participating in research may result in an injury, as explained above. If you suffer an injury 
directly related to your participation in this project, UMB and/or one of its affiliated institutions 
or health care groups will help you obtain medical treatment for the specific injury and provide 
referrals to other health care facilities, as appropriate. UMB and/or its affiliated institutions or 
health care groups will not provide you with financial compensation or reimbursement for the 
cost of care provided to treat a research-related injury or for other expenses arising from a 
research-related injury. The institution or group providing medical treatment will charge your 
insurance carrier, you, or any other party responsible for your treatment costs. If you incur 
uninsured medical costs, they are your responsibility. The study staff can give you more 
information about this if you have a study injury.
By signing this Consent Form, you are not giving up any legal rights. If this research project is 
conducted in a negligent manner and you are injured as a direct result, you may be able to 
recover the costs of care and other damages from the individuals or organizations responsible for 
your injury.
If you have questions, concerns, complaints, or believe you have been harmed through 
participation in this research study as a result of researcher negligence, you can contact members 
of the IRB or the Human Research Protections Office (HRPO) to ask questions, discuss 
problems or concerns, obtain information, or offer input about your rights as a research 
participant. The contact information for the IRB and the HRPO is:
University of Maryland Baltimore
Human Research Protections Office 
620 W. Lexington Street, Second Floor
Baltimore, MD 21201
410-706-5037
Signing this consent form indicates that you have read this consent form (or have had it read to 
you), that your questions have been answered to your satisfaction, and that you voluntarily agree 
to participate in this research study. You will receive a copy of this signed consent form.
If you agree to participate in this study, please sign your name below.
___________________________________
Participant’s Signature
___________________________________
Investigator or Designee Obtaining Consent 
Signature
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Date:______________________________
Date:______________________________
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