A Study to Examine Changes in GIP Plasma Levels Following Gastric Bypass Surgery in Obese Patients

This is a pilot study to collect the relevant information for planning a larger and more
definitive investigation. A total of thirty subjects will be evaluated in this study to be
conducted at the Boston Medical Center. The study population will consist of obese patients
who meet the criteria and have been scheduled by their surgeon for GBS. We plan to enroll a
total of 30 subjects scheduled for GBS. Patients will be assigned according to standard
surgical care to either open or laparoscopic surgery. We plan to enroll 20 subjects who
undergo laparoscopic GBS (LAP) and 10 subjects who undergo open GBS (OPEN). All potential
subjects will have undergone baseline screening as a part of their routine medical
evaluation performed by Dr. Apovian or Dr. McDonnell in the Nutrition Center at BMC. This
standard testing includes medical history, physical examination, complete blood count, serum
electrolytes, BUN, creatinine, fasting blood glucose and glycosylated hemoglobin. If
patients are identified as having type 2 diabetes or glucose intolerance, they will be
provided informed consent. If consented subjects meet all the inclusion and exclusion
criteria, each will undergo a baseline oral glucose tolerance test (OGTT) approximately one
week before surgery. Plasma concentrations of insulin, GIP, glucagon, and GLP-1 will also be
measured along with glucose levels and other peptides (CCK, ghrelin, c-peptide) at the same
intervals, using commercially available assay kits. Post-operatively, subjects in the LAP
group will undergo 2 OGTTs, while subjects in the OPEN group will undergo 2 OGTTs and one
glucose tolerance test through the gastrostomy tube (GGTT). The results of the postoperative
OGTTs will be compared with baseline OGTTs. In a separate analysis, the results of the GGTTs
will be compared with the baseline and postoperative OGTTs.

Inclusion criteria Patients 21-64 y ears of age with obesity (defined as a body mass index,
BMI, > or = 30) and type 2 diabetes or impaired glucose tolerance, who have been selected
and scheduled for gastric bypass surgery.

Exclusion criteria Substance abuse, consumption of more than two alcoholic drinks per day,
use of more than 20 units of insulin (any brand or type) per day, and having a fasting blood
glucose >180mg/dl on screening bloodwork.

F2. Procedure

All subjects will undergo a total of 3 OGTTs, 1 before surgery and 2 after. The OPEN group
will also have a glucose tolerance test via a gastrostomy tube (GGTT) placed in the duodenum
(per routine surgical procedure) as described below. The OGTT consists of a 12-hour
overnight fast followed by drinking a 225 ml of solution containing 75 grams of a glucose
(Glucola), over 30 minutes. 30 minutes is the average time a patient requires in order to
drink a 225ml Glucola drink after gastric bypass surgery. In order to be able to make a
valid comparison of the three OGTTs, each OGTT will require that the subject drink over 30
minutes. Blood samples are obtained from an intravenous catheter at various time intervals:
5 minutes and immediately before drinking the Glucola, and 5, 10, 15, 30, 60, 90, 120, and
180 minutes afterwards. Blood levels of glucose, insulin, glucose-dependent insulinotropic
polypeptide (GIP), glucagon, and Glucagon-Like Peptide (GLP-1), CCK, ghrelin and c-peptide
will be determined from the samples obtained. In addition, at hour 2 during the OGTT (when
glucose peaks) we will obtain a real-time glucose level with a drop of blood from the
indwelling line. The GGTT follows that same protocol as the OGTT, but the Glucola is
administered via a gastrostomy tube, placed per routine surgical procedure in patients
undergoing open GBS. Approximately 1 week before surgery, all subjects will undergo an OGTT
in the GCRC. Between day 6 and 10 after their surgery, when subjects are tolerating their
standard 240cc liquid meals 3-4 times daily, subjects will undergo the third OGTT. Although
most subjects are discharged on day 3 or 4 after surgery, and will be asked to return to the
GCRC, those subjects who remain in the hospital through day 5 will have the option to remain
in the hospital for an additional time (1-2 days) or to go home and return to the GCRC
within 5 days (no later than POD 10) The additional hospital days will be paid for by the
GCRC. After surgery, subjects in LAP group will have one OGTT. Subjects in the OPEN group
will have a GGTT on one day and an OGTT on the following day. Subjects will be weighed
before surgery and every day during the first week after surgery and before each glucose
tolerance test. All subjects will undergo a final OGTT approximately 3 -4 weeks after
surgery. This will take place in the GCRC on the same day as a routine follow up visit to
their surgeon.

Patients will be contacted by telephone for assessment approximately 24 hours before and
after each GTT.

There are 2 primary outcomes: 1) Change in plasma GIP response to glucose after GBS and 2)
change in insulin sensitivity after GBS, as measured by an area-under-the-curve equation for
a standardized 180-minute oral glucose tolerance test. Secondary outcomes include 1) Change
in plasma GLP-1 response to glucose after GBS and 2) change in plasma glucagon response to
glucose after GBS, as measured by the equation used for the primary outcome.

We expect that our enrollment period will be 18 months to 24 months. The estimated duration
of the entire study is 28 months

Inclusion Criteria:

- Patients 21-64 years of age

- Obese (defined as a body mass index, BMI, > or = 30)

- Type 2 diabetes or impaired glucose tolerance

- Have been selected and scheduled for gastric bypass surgery.

Exclusion Criteria:

- Substance abuse

- Consumption of more than two alcoholic drinks per day

- Use of more than 20 units of insulin (any brand or type) per day

- Fasting blood glucose >180mg/dl on screening bloodwork.