Muscle Accrual and Function in Cystic Fibrosis-Impact of Glucose Intolerance

Cystic Fibrosis (CF) is a lethal inherited disease that primarily affects the lungs but also
confers a high risk of diabetes, with up to 40-50% of adults experiencing Cystic
Fibrosis-related diabetes (CFRD). CFRD is associated with an accelerated decline in lung
function, nutritional status and survival and despite treatment mortality in patients with
CFRD remains high. Airway inflammation and susceptibility to infections caused by
hyperglycemia, and the catabolic effect of insulin deficiency are posited mechanisms of
CFRD-associated morbidity. Respiratory failure caused by airway disease is well known but the
contribution of respiratory muscle dysfunction may be critical. In Type 2 Diabetes Mellitus
(T2DM) glucose and insulin defects are closely correlated with muscle function. The pulmonary
muscles are crucial to respiration and airway clearance in CF. Muscle function is dependent
on its mass, composition, and energy metabolism. Lean body mass (LBM) deficits are present in
CF and improvement in LBM improves pulmonary function. Using T2DM as a model for muscle
dysfunction, the study hypothesis is that glucose intolerance exacerbates LBM deficits,
negatively affects muscle composition, and alters muscle metabolism leading to respiratory
muscle dysfunction and a decline in pulmonary function.

CF subjects without CFRD and healthy controls will undergo 3 study visits (baseline then
annually for 2 years) and CFRD subjects will undergo 2 study visits (baseline and 6 months
after baseline). Evaluations will include neurologic exams, anthropometric assessments, 3-day
dietary recall, MRI scans, oral glucose tolerance tests (CF subjects only), blood work,
pulmonary function testing, muscle strength testing, exercise testing, bone density scans,
and adverse event assessment.

Inclusion Criteria for CF subjects without CFRD:

1. Males or females age 16 to 22 years.

2. Confirmed diagnosis of CF per CF Foundation guidelines

3. Parental/guardian permission (informed consent) and if appropriate, child assent.

Exclusion Criteria for CF subjects without CFRD

1. Chronic systemic glucocorticoid use e.g. for allergic bronchopulmonary aspergillosis

2. Organ transplantation

3. Forced Expiratory Volume (FFEV) 1%-predicted < 40%

4. Established diagnosis of CFRD and treatment with insulin or hypoglycemic agent

5. Parents/guardians or subjects who, in the opinion of the Investigator, may be
non-compliant with study schedules or procedures.

6. Pregnancy or breastfeeding (if female)

7. Pre-existing neurological or neuromuscular disease

All study visits for CF subjects will be scheduled during periods of baseline health.
Visits will not be performed within 4 weeks of an acute respiratory illness or pulmonary
exacerbation.

Inclusion Criteria for healthy controls

1. Age-, sex-, ethnicity-, and BMI-matched at time of enrollment to CF subjects without
CFRD

2. Parental/guardian permission (informed consent) and if appropriate, child assent.

Exclusion Criteria for healthy controls

1. Parents/guardians or subjects who, in the opinion of the Investigator, may be
non-compliant with study schedules or procedures.

2. Pregnancy or breastfeeding (if female)

3. Pre-existing neurological or neuromuscular disease

Inclusion Criteria for CF subjects with new CFRD

1. Males or females age 12 years or above.

2. Confirmed diagnosis of CF per CF Foundation guidelines.

3. New diagnosis of CFRD based on a) a clinically indicated Oral glucose tolerance test
(OGTT) b) hyperglycemia (PG>200 mg/dL) persisting >48 hours and/or c) elevated HbA1C
and within 4 weeks of starting insulin therapy.

4. Parental/guardian permission (informed consent) and if appropriate, child assent.

Exclusion Criteria for CF subjects with new CFRD

1. Chronic systemic glucocorticoid use e.g. for allergic bronchopulmonary aspergillosis

2. Organ transplantation

3. Parents/guardians or subjects who, in the opinion of the Investigator, may be
non-compliant with study schedules or procedures.

4. Pregnancy or breastfeeding (if female)

5. Pre-existing neurological or neuromuscular disease