<p>Glutamate and glutamine, two closely related amino acids, play vital roles in cellular metabolism, neurotransmission, immune regulation, and, in maintaining pancreatic β‑cell structure and function. The former serves as the primary excitatory neurotransmitter and is essential for energy metabolism, protein synthesis, and insulin secretion. Its counterpart, glutamine, the amide derivative of glutamate, supports mitochondrial activity, nucleotide biosynthesis, and serves as an alternative metabolic fuel during physiological stress. Dysregulation of glutamate and glutamine pathways has been increasingly associated with the pathogenesis of both type 1 and 2 diabetes. In type 1 diabetes, disruptions in the glutamate‑glutamine cycle contribute to pancreatic β‑cell dysfunction and autoimmune‑mediated destruction. In type 2 diabetes, altered glutamate metabolism promotes insulin resistance and pancreatic β‑cell apoptosis, largely through mechanisms involving oxidative stress and inflammation. The glutamate‑glutamine cycle within pancreatic β‑cells is essential for insulin production and cellular homeostasis. Impairment of this cycle may play a key role in the development of diabetic complications, including neuropathy, nephropathy, and retinopathy. Emerging evidence suggests that targeting glutamate and glutamine metabolism offers promising therapeutic strategies for diabetes and its associated complications. Potential interventions include modulation of specific receptors, regulation of key metabolic enzymes, and amino acid supplementation, each aimed at restoring the metabolic balance of these amino acids, enhancing insulin sensitivity, and reducing tissue damage. This review underscores the critical importance of understanding glutamate and glutamine dynamics in the pancreas, with the goal of identifying innovative approaches for the treatment and prevention of diabetes and its complications.</p> Graphical abstract <p></p>