Genetics of Insulin and Incretins in Cystic Fibrosis

Evaluation of the Enteroinsular Axis 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.

Study Overview

• Status: Recruiting
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Genetic: Blood or Saliva Sample Collection

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 550

Contacts and Locations

• Study Contact: Name: Rachel Walega; Phone Number: 267-586-5969; Email: WALEGAR1@chop.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • The Children's Hopsital of Philadelphia
      • Contact: Rachel Walega; Phone Number: 267-586-5969; Email: WALEGAR1@chop.edu
      • Principal Investigator: Andrea Kelly, MD
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • The University of Pennsylvania
      • Contact: Rachel Walega; Phone Number: 267-586-5969; Email: WALEGAR1@chop.edu
      • Principal Investigator: Michael Rickels, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Patients with Cystic Fibrosis age >2 yrs

Description

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)

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Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: University of Pennsylvania
• Investigators: Principal Investigator: Andrea Kelly, MD, Children's Hospital of Philadelphia

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: May 9, 2013
• First Submitted That Met QC Criteria: May 9, 2013
• First Posted (Estimated): May 13, 2013

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 10, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: 12-009589

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO