Cystic Fibrosis-Related Diabetes Research Program

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Cystic fibrosis-related diabetes (CFRD) not only burdens affected patients with a second, attention-demanding disease but threatens nutritional status, pulmonary function, and survival. Developing strategies to preserve β-cell function are crucial for interrupting CFRD development and its hazard to CF-relevant outcomes. Our multidisciplinary investigative team of experts in pediatric and adult diabetes, cystic fibrosis, and genetics strives to better understand the initiation and progression of abnormal glucose tolerance in pancreatic insufficient CF (PI-CF) and to test potential strategies for restoring β-cell function.

Recent studies demonstrated that insulin secretion defects are present at glucose thresholds traditionally considered normal, and such subtle glucose abnormalities associate with increased CFRD risk and may portend greater declines in pulmonary function. The study team also has shown that infusion of incretin hormone, glucagon-like peptide-1 (GLP-1), but not glucose-dependent insulinotropic polypeptide (GIP), augments glucose-dependent insulin secretion in PI-CF.

Cross-sectional studies in CF demonstrate marked reductions in meal-related early-phase insulin secretion and β-cell secretory capacity in early glucose intolerance. With worsening glucose tolerance, PI-CF subjects with impaired glucose tolerance and CFRD exhibit further compromised meal-related early-phase insulin secretion and β-cell secretory capacity. The extent to which emergence and progression of glucose intolerance is a manifestation of worsening β-cell secretory capacity is not known and will be investigated in longitudinal studies of youth and adults with PI-CF in whom mixed-meal tolerance tests will be performed to characterize early-phase insulin secretion and glucose-potentiated arginine tests will be completed to quantify β-cell secretory capacity.

The study team also is leveraging the genotyping and clinical phenotyping of participants in a pediatric and adult CF cohort to test the impact of T2D genetic variants, diet, CFTR modulator therapy, and pulmonary exacerbations on the emergence and progression of glucose intolerance and the relationship of glucose intolerance with nutritional status, pulmonary function, and body composition longitudinally over three to five years. Investigators also are testing whether the team’s findings of β-cell responsiveness to acute GLP-1 infusion has the potential to be translated into the use of chronic GLP-1 therapy as a mechanism to preserve β-cell function.

Additionally, they are testing whether resistance to the insulinotropic effects of glucose-dependent insulinotropic polypeptide (GIP) that the team has observed in individuals with PI-CF and glucose intolerance extend to individuals with PI-CF but normal glucose tolerance; these tests will help define if GIP-resistance is a function of CF or a manifestation of hyperglycemia. If successful, this work will provide the foundation for a multi-center study aimed at identifying and treating early insulin secretion defects in PI-CF and interrupting 1) progression to CFRD and 2) emergence of hyperglycemia-related CF-relevant outcomes.

Research Project Highlights

  • TCF7L2, ACSL5 and lipid mediators in CF-related diabetes: This study aims to understand the relationship of the type 2 diabetes-related genetic variant with fat-mediated insulin secretion in cystic fibrosis.
  • Evaluation of the entero-insular (incretin) axis in cystic fibrosis: The aims of this proposal are to better define the mechanisms responsible for insulin secretion defects in CF-related diabetes and to identify potential interventions to disrupt progressive insulin deficiency.