Identification of Four Mouse Diabetes Candidate Genes Altering β-Cell Proliferation

PLoS Genetics
O KluthAnnette Schürmann

Abstract

Beta-cell apoptosis and failure to induce beta-cell regeneration are hallmarks of type 2-like diabetes in mouse models. Here we show that islets from obese, diabetes-susceptible New Zealand Obese (NZO) mice, in contrast to diabetes-resistant C57BL/6J (B6)-ob/ob mice, do not proliferate in response to an in-vivo glucose challenge but lose their beta-cells. Genome-wide RNAseq based transcriptomics indicated an induction of 22 cell cycle-associated genes in B6-ob/ob islets that did not respond in NZO islets. Of all genes differentially expressed in islets of the two strains, seven mapped to the diabesity QTL Nob3, and were hypomorphic in either NZO (Lefty1, Apoa2, Pcp4l1, Mndal, Slamf7, Pydc3) or B6 (Ifi202b). Adenoviral overexpression of Lefty1, Apoa2, and Pcp4l1 in primary islet cells increased proliferation, whereas overexpression of Ifi202b suppressed it. We conclude that the identified genes in synergy with obesity and insulin resistance participate in adaptive islet hyperplasia and prevention from severe diabetes in B6-ob/ob mice.

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Citations

Jan 21, 2017·Current Opinion in Endocrinology, Diabetes, and Obesity·Alan D AttieJoseph H Nadeau
Feb 27, 2018·Diabetologia·Mandy StadionAnnette Schürmann
May 11, 2019·Current Diabetes Reviews·Anshul ShakyaSurajit Kumar Ghosh
Oct 25, 2016·Obesity Reviews : an Official Journal of the International Association for the Study of Obesity·I PorrecaC Ambrosino
Aug 21, 2020·Diabetes·Meriem OuniAnnette Schürmann
Nov 25, 2020·Scientific Reports·Manjunath SiddappaMoray J Campbell
Feb 5, 2021·Life Science Alliance·Lea BühlerStephan Herzig
Apr 22, 2021·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Sayeed Ur RehmanHadi Al-Hasani
Aug 28, 2021·International Journal of Molecular Sciences·Ilka WilhelmiAnnette Schürmann

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Methods Mentioned

BETA
RNAseq
ubiquitination
FCS

Software Mentioned

edgeR
Zeiss
Haploview
DEseq
R package
AxioVision
NIS
JMP
MetaCore

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