Type 2 diabetes mellitus (T2D) is a significant global health issue, characterized by high blood glucose levels due to insufficient insulin production. G protein-coupled receptors (GPCRs) play a crucial role in regulating β-cell function, including growth, apoptosis, and insulin secretion. Recent advancements in understanding GPCR signaling and the role of GPCR kinases (GRKs) have highlighted their potential as therapeutic targets. GRKs modulate GPCR signaling by phosphorylating activated GPCRs, leading to their internalization and desensitization. Genome-wide association studies (GWAS) have linked GRKs and arrestins to T2D. This review discusses the signaling of key GPCRs in β-cells, such as the incretin receptors GLP-1R and GIPR, fatty acid receptors FFA1 and FFA4, and muscarinic receptors. It also explores the role of orphan receptors and the importance of further investigating islet-enriched GPCRs for novel therapeutic strategies. The review emphasizes the need to understand the complex biology of β-cells and islet cells to develop more effective and less side-effect-prone treatments for diabetes.Type 2 diabetes mellitus (T2D) is a significant global health issue, characterized by high blood glucose levels due to insufficient insulin production. G protein-coupled receptors (GPCRs) play a crucial role in regulating β-cell function, including growth, apoptosis, and insulin secretion. Recent advancements in understanding GPCR signaling and the role of GPCR kinases (GRKs) have highlighted their potential as therapeutic targets. GRKs modulate GPCR signaling by phosphorylating activated GPCRs, leading to their internalization and desensitization. Genome-wide association studies (GWAS) have linked GRKs and arrestins to T2D. This review discusses the signaling of key GPCRs in β-cells, such as the incretin receptors GLP-1R and GIPR, fatty acid receptors FFA1 and FFA4, and muscarinic receptors. It also explores the role of orphan receptors and the importance of further investigating islet-enriched GPCRs for novel therapeutic strategies. The review emphasizes the need to understand the complex biology of β-cells and islet cells to develop more effective and less side-effect-prone treatments for diabetes.