Diabetes mellitus (diabetes) is a major health burden with the highest mortality rate, affecting an estimated 537 million adults worldwide. The treatment of diabetes remains complex owing to insulin resistance, β-cell dysfunction, metabolic inflammation, and progressive organ damage. While G-protein-coupled receptors (GPCRs) selectively suppress many pathological diseases, the functional characteristics of orphan GPCRs (oGPCRs) remain unexplored as therapeutic targets for diabetes. This review comprehensively evaluates oGPCRs and their roles in diabetes. Orphan receptors are classified based on their functional groups: i) insulin secretagogues such as GPR119 and GPR142, ii) transcriptional and regulatory modulators such as GPR27, and iii) metabolic sensors such as GPR75 and GPR91. We further explored the biological roles of these receptors in the pancreas, adipose tissue, liver, and kidneys. In addition, we mapped the convergence of oGPCR signaling with the pharmacological properties of FDA-approved antidiabetic therapies. The major roles of incretin signaling, AMPK-mediated energy sensing, insulin secretion pathways, inflammatory signaling networks, and sodium-glucose cotransporter 2 (SGLT2) -associated organ protection are addressed. We also report the functionality of these receptors on a receptor-by-receptor basis and prioritize them based on biological relevance, druggability, and translational feasibility. Furthermore, potential repurposable drugs targeting oGPCR pathways, along with existing nondiabetic medications, are highlighted. Finally, we discuss how emerging technologies, including single-cell RNA sequencing, spatial transcriptomics, and artificial intelligence- and structure-based drug design, accelerate GPCR deorphanization and therapeutic development. Overall, this report highlights the significant role of oGPCRs as therapeutic targets and drug repurposing opportunities for developing precision medicine and emphasizes the need for further research on oGPCR signaling in the treatment of diabetes.
