Overweight/obese otherwise healthy volunteers will be recruited from the Old Order Amish
population in Lancaster County, PA. In order to assess pharmacodynamic responses,
research participants will undergo two frequently sampled intravenous glucose tolerance
tests (FSIGT). The first FSIGT will be conducted at baseline prior to administration of
drug. The second FSIGT will be conducted after six weeks of treatment with semaglutide
(0.25 mg/wk X 4 wks; 0.5 mg/sk X 2 wks). The proposal proposes two specific aims:
Specific Aim #1. To identify genetic variants associated with effects of a GLP1R
agonist to enhance glucose-stimulated first phase insulin secretion in the two
FSIGTs (before and after administration of drug).
Specific Aim #2. To identify genetic variants associated with the effect of a GLP1R
agonist to accelerate the rate of glucose disappearance as assessed in the two
FSIGTs (before and after administration of drug).
After being determined to be eligible and after having given informed consent,
participants will undergo two frequently samples intravenous glucose tolerance tests
conducted at two clinic visits as described below:
Visit #1 - Research participants 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 participant, one
for glucose infusion and the other for frequent blood sampling. NSS (normal saline
solution) will be used to maintain patency of IV. 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 180 ml (36 tsp.) of blood will be drawn. Upon completion of the
FSIVGTT, the participant will be instructed in the self-administration of subcutaneous
(s.c.) injection of semaglutide. The first dose of semaglutide .25mg will be administered
at this time. The participant will be provided with a post-fasting meal.
Home self-administration of weekly semaglutide: The participant will self-administer s.c.
semaglutide weekly for 5 weeks (.25 mg for weeks 2,3,4 and .5 mg for weeks 5,6) A
research nurse may observe the participant self-administering the first home dose and
will make additional home visits as needed to ensure successful self-injection. The
participant will use the study provided scale to obtain and record daily weights in the
morning before breakfast throughout the medication weeks.
Visit #2 - This visit will be scheduled within 1 week of the final (6th) dose of
semaglutide +/- 5 days. The FSIVGTT will be conducted exactly as during the previous
clinic visit.
Genotyping will be conducted using a high-density array with comprehensive coverage of
DNA sequence variants. The project will leverage a global imputation panel generated from
whole genome sequence data on ~ 100K subjects including 1,025 Amish individuals obtained
through the NHLBI-sponsored Trans-Omics for Precision Medicine (TOPMed) program.