Genetics of Insulin and Incretins in Cystic Fibrosis
Genetics of Insulin and Incretins in Cystic Fibrosis
Cystic fibrosis related diabetes (CFRD) is associated with worse CF-relevant outcomes.

 The mechanisms underlying CFRD development are not fully understood, but recent evidence
 suggests Type 2 Diabetes Mellitus (T2DM) mechanisms may be involved and may involve incretins
 (gut secreted hormones that augment insulin secretion in response to a nutrient load).

 This study will examine the prevalence of Genome wide association study (GWAS)-implicated
 T2DM alleles (including TCF7L2) across the spectrum of glucose abnormalities in CF and will
 use this information to compare incretin and insulin secretion in non-diabetic children and
 adults with high risk and low risk alleles.
CFRD is associated with worse nutritional status, greater pulmonary function decline, and
 increased mortality, highlighting its relevance in CF and arises primarily from compromised
 insulin secretion--traditionally considered a by-product of pancreatic exocrine tissue damage
 and fibrosis. Recent developments in the field of diabetes are propelling a re-examination of
 this basic explanation. Genome-wide association studies have associated genetic variants in
 TCF7L2, a transcription factor implicated in enteroendocrine function, with increased
 susceptibility to T2DM and CFRD.

 The Objectives of this study are to perform targeted sequencing of TCF7L2 and other
 GWAS-associated T2DM genes in the pediatric and adult CF populations and then to compare
 insulin secretory capacity, β-cell sensitivity to glucose, and incretin secretion in
 non-diabetic CF subjects with high and low-risk alleles.

 Phase 1 will include 350 subjects (Children age>= 2 years, adolescents, and adults) for
 TCF7L2 genotype and ten other GWAS-implicated T2DM genes. The distribution of TCF7L2 and
 other GWAS-implicated T2 DM genes across the spectrum of glucose abnormalities will be
 described. Phase 1 requires a single blood sample and review of medical records.

 Phase 2 will include a subset of 30 non-diabetic children (age >8) and adults who will have
 insulin and incretin secretion studies performed to look at how the body secretes insulin and
 other hormones in relation to having or not having these "diabetes" genes. These studies
 include Glucose Potentiated Arginine Tests (GPA, which measures β-cell secretory capacity and
 sensitivity to glucose) and Mixed Meal Tolerance Test (MMTT, which measures incretin and
 insulin secretion).
FIRST PHASE OF STUDY:

 Inclusion Criteria

 1. Subjects age >2y

 2. Diagnosis of Cystic Fibrosis

 3. For subjects< 18 years, parental/guardian permission (informed consent) and if
 appropriate, child assent

 Exclusion Criteria 1. Established diagnosis of non-CFRD (cystic fibrosis related diabetes)
 (e.g T1DM)

 .

 SECOND PHASE OF STUDY:

 Inclusion Criteria

 1. Subjects age >8y

 2. Diagnosis of Cystic Fibrosis

 3. pancreatic insufficient

 4. negative urine pregnancy test at enrollment

 5. TCF7L2 rs7903146 genotype of T/T or C/C

 6. For subjects< 18 years, parental/guardian permission (informed consent) from both
 parents and if appropriate, child assent

 Exclusion Criteria

 1. Established diagnosis of non-CF diabetes (i.e. T1DM) or CFRD

 2. History of clinically symptomatic pancreatitis within last year

 3. Prior lung or liver transplant

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

 5. Fundoplication-related dumping syndrome

 6. Medical co-morbidities that are not CF-related or are unstable per the 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 <10 g/dL, within 90 days of Day 1 or at Screening

 10. Abnormal renal function, within 90 days of Day 1 or at Screening; defined as
 creatinine >2x upper limit of normal (ULN) or potassium > 5.5 milliequivalent per
 liter {mEq/L} on non-hemolyzed specimen

 11. Weight< 26 kg (limit for blood draw is 5 mL/kg/day; GPA requires 130 mL)

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

 13. Parents/guardians or subjects who, in study team opinion, may be non-compliant with
 study procedure

 14. Pregnant or lactating females.