Natural Proteolytic Peptide Inhibitors of Alpha‐Glucosidase and Alpha‐Amylase as a Strategy to Manage Type 2 Diabetes—A Review

ABSTRACT Diabetes mellitus (DM) is a chronic metabolic disorder affecting a significant amount of the world's population, especially in middle‐income or low‐income countries (according to International Diabetes Federation, four in five adults live with diabetes in middle‐ and low‐income countries). It is marked by elevated blood glucose levels, primarily due to impaired insulin function. Controlling postprandial hyperglycemia is a key therapeutic goal, often achieved by inhibiting digestive enzymes such as α‐glucosidase (AG) and α‐amylase (AA), which regulate carbohydrate breakdown. In this review, we compile and analyze bioactive peptides with inhibitory effects on AG, AA, or both, based on length, amino acid composition, isoelectric point (pI), and half‐maximal inhibitory concentration (IC 50 ) values. Additionally, structural and sequence comparisons of AG and AA enzymes were performed using DALI and EMBOSS tools, revealing conserved and distinct structural and sequence motifs that may influence the orientation of the binding/inhibition mode of the peptide. Docking results indicated interactions at both canonical and allosteric sites, supporting noncompetitive or uncompetitive mechanisms. The insights obtained from this review underscore the promise of peptides as candidates for antidiabetic therapeutics or functional food applications, warranting further in vivo and explorations into the mechanisms of action.