A Pilot Study Evaluating Exenatide for the Treatment of Postprandial Hyperinsulinemic Hypoglycemia Post-RYGB

Roux-en-Y gastric bypass surgery (RYGB) is one of the most common bariatric surgeries in the
United States and is generally highly effective for weight loss. Unfortunately, among the
potential complications is hyperinsulinemic hypoglycemia. Though the prevalence of this
disorder has not been fully characterized, it can be associated with debilitating symptoms
which severely impact quality of life and can be life-threatening. The underlying
pathophysiology of hyperinsulinemic hypoglycemia likely involves a mismatch in the amount of
insulin secreted in response to mealtime carbohydrate absorption. It has been observed that
the ingestion of a high carbohydrate load often leads to a modest rise in post-prandial
glucose levels followed by an inappropriately exaggerated insulin release among individuals
with this condition. Low carbohydrate diet sometimes provides full or partial relief of the
symptoms.

Standard medical management for RYGB associated postprandial hyperinsulinemic hypoglycemia
includes acarbose, which partially reduces carbohydrate absorption from the gut, and
diazoxide, which directly inhibits insulin release from pancreatic beta cells. However, the
medical options are not reliably effective, leading some individuals to reverse RYGB, which
also may not be effective, or even undergo partial pancreatectomy, risking additional
complications such as diabetes. Much more reliably effective treatments are needed for this
special population who develop this bariatric surgical complication.

Potential mechanisms contributing to the mismatched insulin secretion post RYGB include
decreased systemic and adipose tissue inflammation, and increased insulin receptor expression
in liver and skeletal muscle, and increases in adiponectin.

Inclusion Criteria:

1. must have undergone RYGB and subsequently developed post-prandial hypoglycemia
(defined as at least 3 episodes over a six-month period with documented capillary
blood sugars [<60 mg/dL with hypoglycemic symptoms). Subjects may also have had a
formal mixed meal tolerance test with post meal blood sugar <60 mg/dL.

2. Subjects who otherwise meet the study criteria above with hypoglycemia symptoms but
who do not have documented hypoglycemia by plasma measurement may undergo a screening
visit to document the requisite levels for consideration into the study.

Exclusion Criteria:

1. Chronic or acute diseases of the liver.

2. Chronic or acute diseases of the pancreas (including type 1 diabetes or pancreatitis
or a history of pancreatitis). Subjects may have a diagnosis of type 2 diabetes but
must no longer require diabetes medication.

3. Chronic or acute diseases of the kidneys.

4. Known malignancies and must not have a family history of medullary thyroid cancer.

5. History of pre-RYGB hypoglycemia symptoms or low documented plasma glucose
preoperatively.

6. Pregnant or plans to become pregnant throughout study duration

7. Breastfeeding

8. Medication exclusions in addition to the current use of diabetes medications. Subjects
will be excluded if they have previously taken GLP-1 agonists.