Role of beta-cell cilia on the development of diabetes in obese mouse models

Aim:

The development of type 2 diabetes in response to obesity depends on the genetic background. New Zealand Obese (NZO) mice show beta-cell failure, whereas obese B6-ob/ob mice are protected from diabetes due to an adaptive beta-cell proliferation. Cilia are hair-like projections from the plasma membrane that serve as sensory organelles in nearly every eukaryotic cell. Ciliary defects lead to a number of diseases (ciliopathies) including diabetes. Our aim was to investigate pathways that explain the different diabetes susceptibility of NZO and B6-ob/ob mice with regard to ciliary function.

Methods:

Transcriptome analyses and immunohistochemical stainings were performed with islets from 18-week-old NZO and B6-ob/ob mice fed a carbohydrate-free diet, followed by a 2 day carbohydrate challenge. Bioinformatic analysis was conducted to identify pathways that protect B6-ob/ob mice from type 2 diabetes.

Results:

Statistical tests revealed a significant enrichment of cilia annotated genes among differentially expressed gens in NZO and B6-ob/ob islets. After a carbohydrate challenge 89 cilia-genes were differentially expressed between the two strains; two third of them were higher in B6-ob/ob islets. Functional clustering revealed a role of these genes in receptor trafficking as well as the regulation of cilia function. Immunofluorescent stainings showed a higher presence of cilia in B6-ob/ob-islets compared to NZO, whereas the carbohydrate challenge led to their striking reduction specifically in B6-ob/ob islets.

Conclusion:

Our data indicate that ciliary turnover in islets might play a role in the different diabetes susceptibilities of NZO and B6-ob/ob mice.