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Diabetologia. 2016 Sep;59(9):1948-58. doi: 10.1007/s00125-016-4023-3. Epub 2016 Jun 18.

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

Author information

1
Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
2
Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium. lbaeyens@diabetes.ucsf.edu.
3
Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, 94143-0669, USA. lbaeyens@diabetes.ucsf.edu.
4
Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium. Harry.Heimberg@vub.ac.be.

Abstract

AIMS/HYPOTHESIS:

When 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.

METHODS:

Glycaemia 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.

RESULTS:

The 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/INTERPRETATION:

In 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.

KEYWORDS:

Acinar cell; Beta cell; Cell protection; Cytokine; Hyperglycaemia; Neurogenin 3; Transdifferentiation

PMID:
27318836
DOI:
10.1007/s00125-016-4023-3
[Indexed for MEDLINE]

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