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

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.

Cystic fibrosis–related diabetes is caused by islet loss and inflammation

“…Third, we presume pancreatic autolysis also caused the approximately 65% reduction in β cell area. However, we cannot rule out that β cell development was affected by CFTR dysfunction, as inhibition of CFTR has been shown to augment endocrine cell development (62) and, recently, β deficiency and impaired growth capacity of β cells in infants and young children with CF have been reported (63). Our studies also used CF pancreata and islets from chronically ill individuals taking many medications prior to death.…”

Survival in a bad neighborhood: pancreatic islets in cystic fibrosis

“…β-cell loss appears to be particularly severe in younger subjects (Bogdani et al 2017), but does not differ between subjects that exhibit fatty vs fibrotic exocrine pancreas pathology (Lohr et al 1989). The manner in which β-cell measures are expressed affects interpretation of the dataβ-cell area, when expressed relative to islet area, is reduced in most studies (Abdul-Karim et al 1986, Lohr et al 1989, Couce et al 1996, Bogdani et al 2017. β-cell normalized to pancreatic area was found to be decreased in one study (Hart et al 2018), but unchanged in others (Bogdani et al 2017, Hull et al 2018).…”

“…Although there are no systematic outcome studies of the long-term implications of earlylife glycemic abnormalities in humans with CF, anecdotal evidence comes from a case report which describes an infant with hyperglycemia at 3 months, who developed waxing and waning glucose intolerance through childhood, finally culminating in CFRD with insulin requirement at 13 years (Fattorusso et al 2017), much earlier than the usual onset of CFRD, which has a median age of onset typically in the third decade of life. Exocrine pancreatic disease in CF begins prior to birth, and is progressive thereafter, with 23% of children <1 year of age having severe exocrine pancreatic loss, compared to 75% of 1-4 year olds (Andersen 1958, Bogdani et al 2017). This early exocrine pancreatic pathology may have an important bearing on later CFRD risk.…”

“…In fact, a greater degree of exocrine pancreatic disease at birth, as reflected by lower circulating immunoreactive trypsinogen levels, predicts increased risk for CFRD in later life (Soave et al 2014). Early life exocrine pancreatic disease may also drive endocrine pancreas pathology, as young children with CF already exhibit loss of islet β cells and islet inflammation (Bogdani et al 2017, Hull et al 2018. Such early pathological changes in the endocrine pancreas may be functionally important, since cross-sectional data from a cohort of children aged 3 months to 5 years showed the greatest frequency of AGT at 2-4 years of age followed by a lower AGT frequency at 5-6 years (Yi et al 2016a).…”

“…In subjects with CF without a diabetes diagnosis, compared to non-CF controls, most studies report a decrease in β-cell area (Abdul-Karim et al 1986, Lohr et al 1989, Couce et al 1996, Hart et al 2018 ranging from 11 to 52%. β-cell loss appears to be particularly severe in younger subjects (Bogdani et al 2017), but does not differ between subjects that exhibit fatty vs fibrotic exocrine pancreas pathology (Lohr et al 1989). The manner in which β-cell measures are expressed affects interpretation of the dataβ-cell area, when expressed relative to islet area, is reduced in most studies (Abdul-Karim et al 1986, Lohr et al 1989, Couce et al 1996, Bogdani et al 2017.…”