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A combination of cytokines EGF and CNTF protects the functional beta cell mass in mice with short-term hyperglycaemia

Authors
  • Lemper, Marie1
  • De Groef, Sofie1
  • Stangé, Geert1
  • Baeyens, Luc1, 2
  • Heimberg, Harry1
  • 1 Vrije Universiteit Brussel, Diabetes Research Center, Laarbeeklaan 103, Brussels, 1090, Belgium , Brussels (Belgium)
  • 2 University of California San Francisco, Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, San Francisco, CA, 94143-0669, USA , San Francisco (United States)
Type
Published Article
Journal
Diabetologia
Publisher
Springer-Verlag
Publication Date
Jun 18, 2016
Volume
59
Issue
9
Pages
1948–1958
Identifiers
DOI: 10.1007/s00125-016-4023-3
Source
Springer Nature
Keywords
License
Yellow

Abstract

Aims/hypothesisWhen the beta cell mass or function declines beyond a critical point, hyperglycaemia arises. Little is known about the potential pathways involved in beta cell rescue. As two cytokines, epidermal growth factor (EGF) and ciliary neurotrophic factor (CNTF), restored a functional beta cell mass in mice with long-term hyperglycaemia by reprogramming acinar cells that transiently expressed neurogenin 3 (NGN3), the current study assesses the effect of these cytokines on the functional beta cell mass after an acute chemical toxic insult.MethodsGlycaemia and insulin levels, pro-endocrine gene expression and beta cell origin, as well as the role of signal transducer and activator of transcription 3 (STAT3) signalling, were assessed in EGF+CNTF-treated mice following acute hyperglycaemia.ResultsThe mice were hyperglycaemic 1 day following i.v. injection of the beta cell toxin alloxan, when the two cytokines were applied. One week later, 68.6 ± 4.6% of the mice had responded to the cytokine treatment and increased their insulin+ cell number to 30% that of normoglycaemic control mice, resulting in restoration of euglycaemia. Although insulin− NGN3+ cells appeared following acute EGF+CNTF treatment, genetic lineage tracing showed that the majority of the insulin+ cells originated from pre-existing beta cells. Beta cell rescue by EGF+CNTF depends on glycaemia rather than on STAT3-induced NGN3 expression in acinar cells.Conclusions/interpretationIn adult mice, EGF+CNTF allows the rescue of beta cells in distress when treatment is given shortly after the diabetogenic insult. The rescued beta cells restore a functional beta cell mass able to control normal blood glucose levels. These findings may provide new insights into compensatory pathways activated early after beta cell loss.

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