The complex interplay of the GI tract, its resident G-protein-coupled receptors (GPCRs), and glucose homeostasis significantly influences Type 2 Diabetes (T2D) treatment and management. A complex network of gut-derived hormones, food sensors, and microbial metabolites interacts with host receptors to influence insulin secretion, appetite regulation, and systemic metabolism. This chapter reviews gut receptor biology, computer-based screening, and receptor-focused treatments for diabetes. Advances in computational biology have enabled receptor-based in-silico screening to find novel ligands and therapeutic targets in the GI environment, opening up a promising route for drug discovery and personalized therapy. This chapter presents a detailed overview of contemporary in-silico methods, such as molecular docking, virtual screening, and pharmacophore modeling, and assesses their translational value. By combining computational insights and empirical evidence, we emphasize the therapeutic potential of targeting GI tract receptors in diabetes management and suggest future research options at the interface of systems biology, pharmacology, and clinical science.