A novel LepR knockout hamster model for type 2 diabetes and its complications: a complementary platform to conventional rodent models

BackgroundType 2 diabetes (T2D) is a progressive metabolic disorder characterized by systemic metabolic dysfunction and multi-organ complications that considerably increase morbidity and mortality. Leptin signaling via leptin receptor (LepR) is vital for maintaining energy homeostasis and insulin sensitivity; its disruption is strongly associated with obesity-induced T2D. However, currently available rodent models cannot effectively mimic the critical features of T2D in humans, particularly dyslipidemia, hypertension, and progressive diabetic nephropathy (DN). Lipoprotein metabolism in golden hamsters (Mesocricetus auratus) is similar to that in humans; therefore, they can serve as a potentially improved model for metabolic disease.MethodsWe generated a LepR knockout golden hamster model using CRISPR/Cas9 genome editing to further investigate the role of LepR in T2D pathogenesis.ResultsLepR-deficient (db/db) golden hamsters developed progressive obesity, sustained hyperglycemia, impaired glucose clearance, insulin resistance, and marked dyslipidemia, including elevated total cholesterol and low-density lipoprotein cholesterol levels. Notably, the model developed metabolic dysfunction-associated steatotic liver disease (MASLD) with early fibrotic remodeling, spontaneous hypertension, and early-stage renal injury characterized by proteinuria, impaired glomerular filtration barrier integrity, and interstitial fibrosis. Transcriptomic profiling of the adipose tissue, liver, and kidney revealed the coordinated activation of the inflammatory pathway and dysregulation of lipid metabolism and extracellular matrix remodeling. Cross-species integration analysis with human DN datasets revealed conserved transcriptional programs, thereby supporting the relevance of this model in human diseases.ConclusionThe LepR-deficient golden hamster model replicates key human T2D-associated metabolic, hepatic and renal phenotypes, providing a complementary preclinical platform for mechanistic studies of diabetes and its complications.