Telomir-Zn restores glucose homeostasis and reduces insulin resistance in a diet-induced zebrafish model of type 2 diabetes

Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia driven by insulin resistance and metabolic dysregulation. Therapeutic strategies that restore insulin sensitivity remain a major unmet clinical need. In this study, we evaluated the metabolic effects of Telomir-Zn and its non-ion-chelated ligand, Telomir-1, in a diet-induced zebrafish model of non-insulin-dependent diabetes mellitus (NIDDM). Adult zebrafish were fed a high‑calorie diet for six weeks to induce obesity-associated metabolic dysfunction characterized by insulin resistance and hyperglycemia. Fish were then treated with Telomir‑Zn or Telomir-1 at three dose levels (0.5, 1.5, and 5 µg) for 14 days. Metabolic outcomes included fasting blood glucose, oral glucose tolerance testing (OGTT), fasting insulin concentrations, and insulin resistance assessed using the homeostatic model assessment of insulin resistance (HOMA-IR). Telomir‑Zn produced a significant and dose‑dependent reduction in fasting glucose levels and improved glucose clearance during OGTT. Treatment also reduced fasting insulin levels and significantly improved insulin sensitivity. Insulin resistance was markedly reduced, with HOMA-IR values decreasing from approximately 10 to 12 in diabetic fish to approximately 3 in treated groups. These findings demonstrate that Telomir-Zn restores key metabolic parameters associated with insulin resistance in a zebrafish model of T2DM and support further investigation of metal-modulating small molecules as a potential therapeutic strategy for metabolic disease.