Sex hormone modulation of diabetes susceptibility in rats

lab animal Research highlights Diabetes https://doi.org/10.1038/s41684-026-01715-8 Sex hormone modulation of diabetes susceptibility in rats Check for updates Sex differences in type 2 diabetes (T2D) are well established, with men generally showing more severe and earlier symptoms of metabolic decline than women. In rodent models, this dimorphism often appears as clear sex differences in disease onset timing, insulin secretory capacity and islet integrity. However, the specific hormonal mechanisms that drive sex-biased vulnerability in T2D and their influence on pancreatic islet physiology remain insufficiently understood. In a study in Experimental Animals, researchers used the Zucker fatty diabetes mellitus (ZFDM) rat, a model in which all homozygous male animals spontaneously develop diabetes while females, despite being obese, never develop diabetes. To better understand the mechanisms behind the role of sex hormones, the team removed endogenous sex hormones in the animals. Orchiectomy in males did not alter diabetes incidence compared with sham-operated males, though it slightly lowered non-fasting glucose levels. By contrast, ovariectomy impaired glucose tolerance, worsened islet fibrosis and accelerated β-cell loss in females. To study the protective role of female hormones, males were supplemented with 17β-estradiol (E2), a functional estrogen. E2 suppressed diabetes onset, an effect partly resulting from reduced food intake. Pair-feeding experiments confirmed that dietary restriction alone, at ~ 70–75% of ad libitum intake, also delayed diabetes. To further dissect the systemic effects of E2 from the direct islet actions, the team exposed ZFDM islets isolated from males to E2 and performed transcriptomic profiling. E2 treatment shifted gene expression toward a normal obese non-diabetic profile, up-regulating genes involved in insulin secretion and down-regulating cell-cycle and DNA-replication programs linked to stressed β-cells. These findings indicate that E2 enhances insulin secretory mechanisms and normalizes abnormal proliferative signaling in diabetic islets. Overall, the study shows that female hormones provide a robust, multi-layered protection against diabetes in ZFDM rats, acting through systemic metabolic effects and direct transcriptional remodeling of pancreatic islets. The results stress the potential of sex hormone regulation and controlled caloric intake as modulators of diabetes susceptibility. Jorge Ferreira Original reference: Yokoi, N. et al. Exp. Anim. (2026) https://doi.org/10.1538/expanim.25-0122 A selective open access biology journal from Nature Portfolio For research that reaches beyond boundaries Communications Biology publishes high-quality research, reviews and commentary in all areas of the biological sciences. Research papers published by the journal represent significant advances for a specialized area of research. Our mission: • Look for potential in every paper • Champion the work of specialists globally • Carry our communities’ voices further • Promote open science and accessibility nature.com/commsbio @CommsBio 06NBX Lab Animal | Volume 55 | April 2026 | 107 107  (...truncated)