The Impact of Insulin Therapy on Protein Turnover in Pre-Diabetic Cystic Fibrosis Patients

Insulin insufficiency related to pancreatic fibrosis and β-cell dysfunction is present in
almost every cystic fibrosis (CF) patient. Progressive abnormalities in insulin secretion
begin in childhood, and, in adults, CF related diabetes (CFRD) is eventually present in more
than half of the CF population. CFRD is associated with weight loss, protein catabolism, loss
of lean body mass (LBM), and early death from lung disease and malnutrition. The negative
consequences of diabetes are just the "tip of the iceberg", since clinical deterioration has
been documented to begin in the pre-diabetic period. Non-diabetic glucose tolerance
abnormalities in CF are associated with protein catabolism, weight loss and lung function
decline, all of which correlate with the severity of insulin secretory defects, suggesting a
key pathologic role for insulin insufficiency. Insulin is a potent anabolic hormone, critical
for maintenance of body weight and muscle mass. In a placebo-controlled clinical trial,
insulin therapy improved body mass index (BMI) and LBM in patients with very early CFRD (CFRD
without fasting hyperglycemia), and this is now standard care for these patients. There is
growing preliminary evidence that insulin therapy is beneficial even earlier, in CF patients
with pre-diabetes due to insulin insufficiency. Given the universal prevalence of insulin
insufficiency in CF, the high lifetime risk of developing diabetes, the clinical impact of
insulin insufficiency on protein catabolism and survival in CF, and the critical importance
of maintaining body weight and LBM in this population, there is an urgent need to determine
whether insulin replacement therapy should be instituted for anabolic purposes prior to the
actual onset of diabetes and, if so, to ascertain the optimal regimen. The current protocol
describes a double-blind, placebo-controlled trial to determine whether insulin therapy
improves protein catabolism in youth with CF and abnormal glucose tolerance, and to explore
differences in efficacy between multiple daily pre-meal insulin dosing (as is currently
standard for early CFRD) versus a more convenient once daily basal insulin dose (as has been
used in small uncontrolled pilot studies). The findings of this study will provide a
mechanistic rationale for instituting insulin in youth with CF and pre-diabetes, and will
inform both research studies and clinical practice as to the best regimen for insulin
delivery in this population.

Inclusion Criteria:

1. Diagnosis of cystic fibrosis, age 10-25 years

2. A standard routine annual OGTT performed within 12 months of randomization

3. Abnormal glucose tolerance, with a fasting glucose level <126 mg/dl and

- The 1-hr OGTT glucose is ≥200 mg/dl but the 2-hr glucose is <140 (INDET), OR

- The 2-hour OGTT glucose is 140-199 mg/dl (impaired glucose tolerance, IGT).

Exclusion Criteria:

1. Diagnosis of CFRD, Consensus Conference definition (45)

2. Previous organ transplant, or transplant imminent during study period

3. BMI percentile >95

4. Treatment with systemic glucocorticoids (nasal or inhaled glucocorticoids are
acceptable)

5. Therapy with growth hormone or Megace

6. Nighttime continuous drip gastrostomy/jejunostomy feedings

7. Pregnancy or breast-feeding or plans to become pregnant during study period

8. Any change in medications during the 3 months prior to the study

• Exception: the new corrector/potentiator combination drug lumacaftor/ivacaftor is
expected to get FDA approval in early 2015, and most CF patients with severe
genotypes, including many eligible for this proposal, will receive this drug. This is
not a contraindication to participation in the current proposal (and participation in
other studies is not contraindicated in the PROSPECT post-marketing drug study).
Though the primary effects of the combination therapy appear to be apparent after 1
month, we will wait 6 months after initiation of lumacaftor/ivacaftor before
enrollment in this study to make sure subjects are in a steady state.

9. Any anticipated change in medication during the 3 month study period

10. Acute illness in the 6 weeks prior to enrollment