Islet Interleukin-1β Immunoreactivity Is an Early Feature of Cystic Fibrosis That May Contribute to β-Cell Failure

Abstract

These findings reveal novel molecular pathways and therapeutic targets underlying islet pathology in CF subjects and may be important in developing new approaches to treat CFRD.

Survival in a bad neighborhood: pancreatic islets in cystic fibrosis

“…Similarly, the fraction of somatostatin-positive δ-cells is increased in humans with CF (Abdul- Karim et al 1986, Soejima & Landing 1986, Lohr et al 1989, Bogdani et al 2017, with two other studies showing the same trend (Hart et al 2018, Hull et al 2018. PP cell area has also been shown to be increased in subjects with CF vs non-CF controls (Lohr et al 1989, Hull et al 2018. A significant decrease in PP cells between CF subjects with and without diabetes was reported in one study (Hull et al 2018) with no difference being observed in another (Iannucci et al 1984).…”

“…In CF subjects with diabetes, studies demonstrating β-cell loss (relative to islet area) are relatively small (n ≤ 8 in at least one group) but consistent, reporting a decrease of ~25-30% (Iannucci et al 1984, Soejima & Landing 1986, Bogdani et al 2017. Interestingly, two larger studies (n = 12-18 subjects per group) failed to find significant loss in β-cell area when quantified per islet area (Couce et al 1996, Hull et al 2018 or per pancreas area (Hull et al 2018). Taken together, the literature is somewhat mixed but shows that loss of β cells may be a feature of CF both with and without diabetes.…”

“…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).…”

“…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). Such differences may be due to difficulties in distinguishing pancreas-intrinsic fat (i.e.…”

“…An increase in glucagon-positive α-cells has been described in CF subjects both with and without diabetes (Lohr et al 1989, Bogdani et al 2017, Hart et al 2018, Hull et al 2018), with only one study reporting no difference (Abdul-Karim et al 1986). Similarly, the fraction of somatostatin-positive δ-cells is increased in humans with CF (Abdul- Karim et al 1986, Soejima & Landing 1986, Lohr et al 1989, Bogdani et al 2017, with two other studies showing the same trend (Hart et al 2018, Hull et al 2018. PP cell area has also been shown to be increased in subjects with CF vs non-CF controls (Lohr et al 1989, Hull et al 2018.…”