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Evidence for a causal relationship between early exocrine pancreatic disease and cystic fibrosis-related diabetes: a

David Soave1, Melissa R Miller2, Katherine Keenan3

  • 1Program in Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, CanadaDivision of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

Diabetes
|February 20, 2014
PubMed

Insights

Lower newborn immunoreactive trypsinogen (IRT) levels in cystic fibrosis (CF) predict higher risk for CF-related diabetes (CFRD). Early detection may allow interventions to delay CFRD onset.

Area of Science:

  • Endocrinology
  • Genetics
  • Pediatrics

Background:

  • Circulating immunoreactive trypsinogen (IRT) is a biomarker for exocrine pancreatic disease in cystic fibrosis (CF).
  • IRT levels in newborns with severe CFTR genotypes typically decline rapidly, indicating progressive pancreatic damage.
  • A less elevated newborn IRT may correlate with more severe pancreatic disease and increased risk of CF-related diabetes (CFRD).

Purpose of the Study:

  • To investigate the association between newborn IRT levels and the risk of developing CFRD in individuals with severe CFTR genotypes.
  • To explore a potential causal relationship between exocrine pancreatic function and CFRD risk.

Main Methods:

  • Analysis of two independent CF cohorts to assess the relationship between newborn IRT and CFRD risk.
  • Utilizing Mendelian randomization with the SLC26A9 rs7512462 genotype as an instrumental variable for IRT levels.

Main Results:

  • A lower newborn IRT estimate was significantly associated with a higher risk of CFRD in individuals with severe CFTR genotypes.
  • Increased loge(IRT) at birth showed an inverse association with CFRD risk in both Canadian and Colorado CF samples.
  • Mendelian randomization provided evidence supporting a causal link between exocrine pancreatic status and CFRD risk.

Conclusions:

  • Newborn IRT levels can potentially predict CFRD risk in early life for individuals with CF.
  • Maintaining ductal fluid flow in the exocrine pancreas may be a strategy to delay CFRD onset.
  • These findings highlight the intricate relationship between exocrine and endocrine pancreatic function in CF.

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