Synergistic Effect of Leucine and Glutamine to Restore Metabolic Homeostasis and Redox Balance by Targeting chico-Akt axis in A High Sucrose Diet-Induced Drosophila Model of Type 2 Diabetes

Abstract

Type 2 diabetes(T2D) continues to be a global health concern due to its rising prevalence and severe socioeconomic consequences. While existing pharmacotherapies attempt to control blood glucose levels and minimize complications, challenges come with their high cost, side effects, and narrow therapeutic window. Hence, there is a pressing need for novel treatment options to address the disease’s intricate pathogenesis. In that scenario, the role of amino acids in insulin signalling and type 2 diabetes is yet to be explored. The current study highlights the synergistic role of leucine and glutamine as an anti-diabetic regimen in a high sucrose diet-induced Drosophila model of T2D. Biochemical analysis revealed that supplementation alleviates hyperglycemia and hyperlipidaemia, indicating metabolic restoration. Improved redox balance is indicated by decreased protein carbonylation, increased thiol levels, enhanced DPPH radical scavenging, elevated antioxidant enzyme activity, and decreased lipid peroxidation. Histological assessment found reduced reactive oxygen species (ROS) accumulation, restoration of actin filament architecture, and decreased apoptotic cell death in the gut and malpighian tubules. Furthermore, Malpighian tubule efflux activity was notably enhanced following treatment. At the molecular level, the supplementation predominantly targets downstream components of insulin signaling pathways, chico and Akt, while secondarily stimulating insulin secretion, which typically diminishes in the later stages of chronic hyperglycemia. Upregulation of cytoskeletal genes and nephrocyte markers further highlighted the multi-targeted effects of the treatment. Together, these findings identify leucine and glutamine co-supplementation as a promising and multifaceted strategy to counteract metabolic, oxidative, and cytoskeletal impairments associated with T2D, offering a potential nutraceutical intervention for diabetes management.