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

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-KitßTg) ageing mice (~60 weeks) to determine the effect of its activation on beta cell dysfunction and insulin secretion. METHODS: Wild-type and c-KitßTg 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-KitßTg mice, we generated beta cell-specific inducible insulin receptor knockout in ageing c-KitßTg mice (c-KitßTg;ßIRKO mice) and examined the ageing mice for glucose tolerance and islet histology. RESULTS: Ageing c-KitßTg 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-KitßTg mouse islets. Protein analyses of isolated islets showed increased insulin receptor, phosphorylated IRS-1Ser612 and cleaved poly(ADP-ribose) polymerase levels in ageing c-KitßTg mice. Ageing c-KitßTg mouse islets treated ex vivo with insulin demonstrated reduced Akt phosphorylation, indicating that prolonged c-Kit induced beta cell insulin insensitivity. Ageing c-KitßTg;ßIRKO mice displayed improved glucose tolerance and beta cell function compared with ageing c-KitßTg 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.