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Diabetologia

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01-08-2019 | Insulins | Article

Long-term c-Kit overexpression in beta cells compromises their function in ageing mice

Authors: Amanda Oakie, Zhi-Chao Feng, Jinming Li, Jenna Silverstein, Siu-Pok Yee, Rennian Wang

Published in: Diabetologia | Issue 8/2019

Abstract

Aims/hypothesis

c-Kit signalling regulates intracellular pathways that enhance beta cell proliferation, insulin secretion and islet vascularisation in mice up to 28 weeks of age and on short-term high-fat diet. However, long-term c-Kit activation in ageing mouse islets has yet to be examined. This study utilises beta cell-specific c-Kit-overexpressing transgenic (c-KitβTg) ageing mice (~60 weeks) to determine the effect of its activation on beta cell dysfunction and insulin secretion.

Methods

Wild-type and c-KitβTg mice, aged 60 weeks, were examined using metabolic tests to determine glucose tolerance and insulin secretion. Pancreas histology and proteins in isolated islets were examined to determine the expression of beta cell transcription factors, proliferation and intracellular signalling. To determine the role of insulin receptor signalling in ageing c-KitβTg mice, we generated beta cell-specific inducible insulin receptor knockout in ageing c-KitβTg mice (c-KitβTg;βIRKO mice) and examined the ageing mice for glucose tolerance and islet histology.

Results

Ageing c-KitβTg mice progressively developed glucose intolerance, compared with age-matched wild-type littermates, due to impaired insulin secretion. Increased beta cell mass, proliferation and nuclear forkhead box transcription factor O1 (FOXO1) expression and reduced exocytotic protein levels were detected in ageing c-KitβTg mouse islets. Protein analyses of isolated islets showed increased insulin receptor, phosphorylated IRS-1^Ser612 and cleaved poly(ADP-ribose) polymerase levels in ageing c-KitβTg mice. Ageing c-KitβTg mouse islets treated ex vivo with insulin demonstrated reduced Akt phosphorylation, indicating that prolonged c-Kit induced beta cell insulin insensitivity. Ageing c-KitβTg;βIRKO mice displayed improved glucose tolerance and beta cell function compared with ageing c-KitβTg mice.

Conclusions/interpretation

These findings indicate that long-term c-Kit overexpression in beta cells has a negative impact on insulin exocytosis and that temporally dependent regulation of c-Kit–insulin receptor signalling is important for optimal beta cell function.

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Title: Long-term c-Kit overexpression in beta cells compromises their function in ageing mice
Authors: Amanda Oakie
Zhi-Chao Feng
Jinming Li
Jenna Silverstein
Siu-Pok Yee
Rennian Wang
Publication date: 01-08-2019
Publisher: Springer Berlin Heidelberg
Keywords: Insulins
Insulins
Tamoxifen
Published in: Diabetologia / Issue 8/2019
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-019-4890-5

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