A major pathological defect in diabetes is insulin resistance, which is characterized by the impaired capacity of peripheral tissues to utilize glucose effectively in the face of hyperinsulinemia. Peripheral insulin resistance is the central pathogenesis of major metabolic disorders, and thus insulin resistance in skeletal muscle impacts whole-body glucose homeostasis. There are currently a limited number of options to treat type 2 diabetes mellitus (T2DM), and oral and injectable medications often become less effective over time. Thus, there is an urgent need to identify new targets for the development of novel treatment strategies. Carnosine (β-alanyl-L-histidine) is an endogenously synthesized dipeptide that is widely and abundantly distributed in skeletal muscles. A diabetic model of glucolipotoxicity was generated by incubating myotubes in standard tissue culture media supplemented with 28mM glucose, 200μM palmitic acid, and 200μM oleic acid. Intracellular reactive species content was assayed using 2, 7-dichlorofluorescein diacetate dye (DCFDA), whereas 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) content, were assayed and quantified using respective ELISA assays. Glucose uptake was determined through 2-deoxy glucose-6-phosphate (2-DG6P) luminescence. Carnosine supplementation resulted in the protection of cells against GLT-mediated generation of reactive species, and thereby enhanced glucose uptake into skeletal muscle. Thus, this dipeptide could offer potential therapeutic benefits to individuals that are insulin-resistant or diabetic.
