Structural abnormalities in islets from very young children with cystic fibrosis may contribute to cystic fibrosis-related diabetes

Marika Bogdani,Jean-Pierre Bellocq,Alvin C Powers,Scott M Blackman,Lydia Aguilar-Bryan,Cecilia Ridaura

doi:10.1038/s41598-017-17404-z

Abstract

Cystic fibrosis (CF)-related diabetes (CFRD) is thought to result from beta-cell injury due in part to pancreas exocrine damage and lipofibrosis. CFRD pancreata exhibit reduced islet density and altered cellular composition. To investigate a possible etiology, we tested the hypothesis that such changes are present in CF pancreata before the development of lipofibrosis. We evaluated pancreas and islet morphology in tissues from very young CF children (<4 years of age), and adult patients with CF and CFRD. The relative number of beta-cells in young CF tissues was reduced by 50% or more when compared to age-matched controls. Furthermore, young CF tissues displayed significantly smaller insulin-positive areas, lower proportion of beta-cells positive for the proliferation marker Ki67 or the ductal marker CK19 vs. control subjects, and islet inflammatory cell infiltrates, independently of the severity of the exocrine lesion and in the absence of amyloid deposits. CFRD pancreata exhibited greater islet injury with further reduction in islet density, decreased relative beta-cell number, and presence of amyloid deposits. Together, these results strongly suggest that an early deficiency in beta-cell number in infants with CF may contribute to the development of glucose intolerance in the CF pediatric population, and to CFRD, later in life.

Highlights

Cystic fibrosis (CF) is the most common lethal genetic disorder of childhood in the Caucasian population and is due to recessive mutations in ABCC7, the gene encoding the CF transmembrane conductance regulator (CFTR)
Greater destruction of the acinar tissue with age was noticeable in tissues from young CF patients 1 to 4 years of age, with 75% showing severe exocrine damage as compared to tissues from younger (
Morphological and clinical studies have suggested that impaired glucose tolerance in CF and CFRD results from beta-cell dysfunction and insulin deficiency[16]

Summary

Introduction

Cystic fibrosis (CF) is the most common lethal genetic disorder of childhood in the Caucasian population and is due to recessive mutations in ABCC7, the gene encoding the CF transmembrane conductance regulator (CFTR). With the development of new therapies and extended life expectancy CF patients represent the population with the highest risk for age-related diabetes mellitus (CFRD), currently affecting ~20% of adolescents and ~50% of young adults[2,3,4]. Because the anatomic component of pancreatic insufficiency/fibrosis per se cannot adequately explain CFRD, we hypothesized that beta-cell mass may be reduced in the CF pancreas prior to development of fibrosis. To test this hypothesis, we studied pancreatic tissues from a cohort of children (

Methods

Results

Conclusion