Genetics of Insulin and Incretins in Cystic Fibrosis

Study Overview
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Brief Summary
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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.

Detailed Description
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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 450-500 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 or saliva sample and review of medical records.

Official Title
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Evaluation of the Enteroinsular Axis in Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Genetic: Blood or Saliva Sample Collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Subjects age >2y Diagnosis of Cystic Fibrosis 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) .

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with Cystic Fibrosis<br>Blood or saliva sample collection and medical record review. | Genetic: Blood or Saliva Sample Collection<br>* A blood or saliva sample will be obtained for genotyping of TCF7L2 and approximately ten other genes implicated in type 2 diabetes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood sample for DNA to genotype TCF7L2 and about 10 other GWAS-implicated T2DM genes. | To examine the prevalence of GWAS-implicated T2DM alleles (including TCF7L2) across the spectrum of glucose abnormalities in children and adults with CF. | 1 day |