Beta-cell Response to Incretin Hormones in Cystic Fibrosis

Previously, cystic fibrosis related diabetes (CFRD) was considered to be a consequence of
damage to the pancreas therefore the cells contained in the pancreas--i.e.--islets that house
beta cells, which make and release insulin (similar to T1D). Recent evidence suggests that
other factors may also be associated that are similar to those with T2D. For example,
patients with T2D, have decreased secretion of incretins, hormones released by the small
intestine in response to nutrients from food which act, among other things, to increase
insulin secretion from Beta cells of the pancreas. When patients with T2D are treated with
incretin hormones, their pancreatic Beta cells release more insulin (measured as 'second
phase insulin secretion'). Currently, we do not know if patients with CFRD have decreased
incretin secretion like T2D or if treating CFRD patients with incretin hormones will improve
their insulin levels. This study will measure insulin release from the Beta cells from CFRD
patients (second phase insulin secretion) that are being given incretin hormones in the
veins. This will be compared with insulin release when the same patients are given a placebo
(salt containing solution). The patients and the research team will not know what is being
given until all the results are collected. The results will provide unbiased evidence if
incretins will help improve insulin release in CFRD patients.

Inclusion Criteria:

1. Confirmed diagnosis of cystic fibrosis, defined by positive sweat test or CFTR
mutation analysis according to CFF diagnostic criteria,

2. Age greater than or equal to 18y on date of consent

3. Pancreatic insufficiency

4. Recent OGTT consistent with Indeterminate-GT, IGT, CFRD w/o fasting hyperglycemia, or
an established diagnosis of CFRD without fasting hyperglycemia

5. For female subjects, negative urine pregnancy test at enrollment.

Exclusion Criteria:

1. Established diagnosis of non-CF diabetes (i.e. T1D) or CFRD with fasting hyperglycemia
(fasting glucose greater than126 mg/dL)

2. History of clinically symptomatic pancreatitis within last year

3. Prior lung or liver transplant

4. Severe CF liver disease, as defined by portal hypertension

5. Fundoplication-related dumping syndrome

6. Medical co-morbidities that are not CF-related or are unstable per investigator
opinion (i.e. history of bleeding disorders, immunodeficiency)

7. Acute illness or changes in therapy (including antibiotics) within 6 weeks prior to
study procedures

8. Treatment with oral or intravenous corticosteroids within 6 weeks of study

9. Hemoglobin less than10g/dL, within 90 days of Visit 1 or at Screening

10. Abnormal renal function, within 90 days of Visit 1 or at Screening; defined as
Creatinine greater than 2x upper limit of normal (ULN) or potassium greater than
5.5mEq/L on non-hemolyzed specimen

11. Inability to perform study specific procedures (MMTT, GPA)

12. Subjects, who in study team opinion, may be non-compliant with study procedures.