Cre and Reduced Ins1 Protect Mice From T1D

Søs Skovsø, Peter Overby, Jasmine Memar-Zadeh, Jason T C Lee, Jenny C C Yang, Iryna Shanina, Vaibhav Sidarala, Elena Levi-D’Ancona, Jie Zhu, Scott A Soleimanpour, Marc S Horwitz, James D Johnson
Endocrinology, Volume 163, Issue 11, November 2022, bqac144
https://doi.org/10.1210/endocr/bqac144

Abstract

A central goal of physiological research is the understanding of cell-specific roles of disease-associated genes. Cre-mediated recombineering is the tool of choice for cell type-specific analysis of gene function in preclinical models. In the type 1 diabetes (T1D) research field, multiple lines of nonobese diabetic (NOD) mice have been engineered to express Cre recombinase in pancreatic β cells using insulin promoter fragments, but tissue promiscuity remains a concern. Constitutive Ins1^{tm1.1(cre)Thor} (Ins1^Cre) mice on the C57/bl6-J background have high β-cell specificity with no reported off-target effects. We explored whether NOD:Ins1^Cre mice could be used to investigate β-cell gene deletion in T1D disease modeling. We studied wild-type (Ins1^WT/WT), Ins1 heterozygous (Ins1^Cre/WT or Ins1^Neo/WT), and Ins1 null (Ins1^Cre/Neo) littermates on a NOD background. Female Ins1^Neo/WT mice exhibited significant protection from diabetes, with further near-complete protection in Ins1^Cre/WT mice. The effects of combined neomycin and Cre knockin in Ins1^Neo/Cre mice were not additive to the Cre knockin alone. In Ins1^Neo/Cre mice, protection from diabetes was associated with reduced insulitis at age 12 weeks. Collectively, these data confirm previous reports that loss of Ins1 alleles protects NOD mice from diabetes development and demonstrates, for the first time, that Cre itself may have additional protective effects. This has important implications for the experimental design and interpretation of preclinical T1D studies using β-cell-selective Cre in NOD mice.

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