Orphan GPCRs in Diabetes Mellitus: Metabolic Control, Inflammation, Drug Development

Diabetes mellitus represents a significant global health burden, impacting approximately 537 million adults and contributing to elevated mortality rates. The management of this condition remains challenging due to insulin resistance, beta-cell dysfunction, metabolic inflammation, and progressive organ damage. Within the context of metabolic research, identifying novel therapeutic targets is essential for improving patient outcomes and disease progression.

This review comprehensively evaluates orphan G-protein-coupled receptors (oGPCRs) and their potential roles in diabetes management. Orphan receptors are categorized based on functional groups, including insulin secretagogues such as GPR119 and GPR142, transcriptional and regulatory modulators like GPR27, and metabolic sensors such as GPR75 and GPR91. The authors explored the biological functions of these receptors across multiple tissues, including the pancreas, adipose tissue, liver, and kidneys.

The study mapped the convergence of oGPCR signaling with pharmacological properties of FDA-approved antidiabetic therapies. Major roles addressed include incretin signaling, AMPK-mediated energy sensing, insulin secretion pathways, inflammatory signaling networks, and sodium-glucose cotransporter 2 (SGLT2)-associated organ protection. The authors prioritized these receptors based on biological relevance, druggability, and translational feasibility.

Potential repurposable drugs targeting oGPCR pathways, alongside existing nondiabetic medications, are highlighted as promising therapeutic options. Emerging technologies such as single-cell RNA sequencing, spatial transcriptomics, and artificial intelligence- and structure-based drug design are discussed for accelerating GPCR deorphanization and therapeutic development. Overall, this report emphasizes the significant role of oGPCRs as therapeutic targets and underscores the need for further research on oGPCR signaling in diabetes treatment.