Background/Aims: Sex differences in diabetes susceptibility and progression have gained increasing attention, yet the underlying molecular mechanisms remain poorly understood. To investigate these differences, we generated diabetic mouse model of conditional knockout of the transcription factor Isl1 in endocrine progenitors (Neurod1-Cre; Isl1f/f, herein Isl1CKO). Isl1CKO mice develop severe diabetes around 2 weeks of age yet survive for up to one month. Isl1CKO islets are fragmented, fail to generate δ and PP endocrine lineages, retain predominantly immature β cells, and exhibit aberrant α-cell identity. To elucidate transcriptional responses and compensatory mechanisms, we performed single-cell RNA sequencing (scRNA-seq) on FACS sorted endocrine cells from 1 month-old mice. This revealed transcriptomic divergence between sexes, with distinct clustering patterns indicating sex-dependent cellular states. Phenotypically, Isl1CKO females displayed same weight gain as control females, while males experienced significant growth impairment. Transcriptomic analysis of 1 month old mice uncovered sex-specific upregulation of chromatin remodelers in female Isl1CKO mice, including elevated expression of transcriptional repressors such as Foxp1, Sin3b, and Gatad2b. These changes may buffer against transcriptional dysregulation. Additionally, female endocrine cells exhibited enrichment of gene programs related to the FOXO pathway, the AP-1 complex, and circadian rhythm —suggesting enhanced cellular resilience and metabolic adaptability. Interestingly, both males and females show upregulation of peptide-loading complex genes, which could lead to higher peptide presentation and possible immunogenicity of endocrine cells. Together, these findings reveal sex differences on the transcriptomic level of diabetic pancreatic endocrine cells and identify potential compensatory molecular pathways in females that may support survival and endocrine function in the absence of Isl1. This work provides new insights into sex-specific mechanisms of endocrine cell regulation and uncovers potential therapeutic targets for sex-aware precision medicine.