Umeå University's logo

Introduction: The mechanisms underlying T-cell-mediated destruction of pancreatic islet β-cells in spontaneous lydiabetic BioBreeding (BB) rats remain unclear. Identifying genetic factors influencing this process is essential for understanding insulitis and diabetes pathogenesis.

Aims: This study aims to elucidate genetic interactions that modulate β-cell loss by using cross-intercross breeding to refine diabetes- and lymphopenia-associated loci on chromosome 4.

Methods: Since 1980, systematic breeding has introduced increasing proportions of Diabetes Resistant (DR) DNA into BB rats' Diabetes Prone (DP) background. Two congenic lines were generated: sBBM (1.02–1.26Mbp DP DNA) and xshBBM (∼0.09Mbp DP DNA). Whole-genome sequencing (WGS) was performed to identify genetic variants.

Results: Both lines retain a frameshift mutation in Gimap5, linked to insulitis, diabetes, and lymphopenia. However, xshBBM rats remain diabetes-free, suggesting the presence of a protective genetic factor. Our WGS analysis identifies Gimap4 as a candidate genetic rescuer. Wild-type (WT) Gimap4 prevents insulitis and subsequent diabetes and eliminates serum IgE elevation, an early insulitis biomarker. Sequencing reveals that the mutated Gimap4 carries a frameshift mutation that alters its protein sequence.

Conclusions: Our findings suggest a genetic interaction between Gimap5 and Gimap4, where WT Gimap4 mitigates the deleterious effects of the Gimap5 mutation, preventing insulitis and diabetes development. This discovery offers new insights into the genetic regulation of T-cell-mediated β-cell killing and should prove helpful for novel therapeutic strategies.