Birds and bees do not express RAGE: comparative physiology and non-conventional model organisms hold the key to hyperglycemia tolerance.

Much of the diversity of life is fueled by sugar. The Maillard reaction and subsequent formation of advanced glycated end products (AGEs) are key contributors to hyperglycemia-associated pathologies. Interestingly, birds maintain glucose levels higher than mammals yet avoid diabetic complications. This resistance is attributed to adaptations such as reduced glycation susceptibility of serum proteins, efficient glucose transport mechanisms, and metabolic routing of excess glucose into fat rather than glycogen. Birds possess physiological traits including insulin resistance, constitutive glucose transporter expression, and enhanced antioxidant responses mediated by Nrf2 pathways, enabling them to tolerate high metabolic rates and oxidative stress. Nectar-feeding birds show genetic adaptations such as positive selection in MLXIPL, facilitating high sugar metabolism. Similarly, insects like bees rely on trehalose, a non-reducing sugar, as their primary circulating carbohydrate, which protects against glycation damage. Comparative physiology of birds, insects, and other non-conventional organisms highlights alternative metabolic strategies that avoid hyperglycemia-induced damage. These insights suggest that studying diverse biological systems can provide valuable understanding of metabolic regulation and potential therapeutic strategies for human diseases such as diabetes. Comparative approaches may uncover evolutionary mechanisms that mitigate glycation and oxidative damage while sustaining high energy demands.