<p>Diabetes is a complex condition that requires continuous medical care and risk-reduction strategies. Therefore, technological improvements and the development of new insulins are necessary. This work aimed to develop insulin functionalized with vanadate (V1) or decavanadate (DV10) and probe its effectiveness on glucose and lipid homeostasis in a like-T1D murine model. Seven different molar combinations of HUMALOG ^® 75/25 insulin with V1 or DV10 were characterized using molecular docking, UV/visible, and FT-IR spectroscopy, confirming stable interactions between V1 or DV10 with the insulin. Then, a like-T1D model was generated in Wistar rats. The acute pharmacodynamics and pharmacokinetics of functionalized insulin were evaluated. Ins-V1 9:1 and 7:3 ratios demonstrated functional bioequivalence to commercial Lispro insulin, reducing glycemia by approximately 67.7% and 60%, within 60&#xa0;min. The ins-DV10 3:7 and 5:5 ratios exhibited lower average glycemia than Lispro (<i>p</i> &lt; 0.01), indicating greater cumulative efficacy. In the long term (30 days), the ins-V1 and ins-DV10 combination administered successfully reversed hyperglycemia and dyslipidemia. Treatments enhanced glycogen storage by 50%–80% and reduced tissue steatosis by 22%–62.5% in the liver, muscle, heart, and kidney. Ins-DV10 (3:7 and 1:9) were better than any ins-V1 combination. Remarkably, acute V1 treatment alone improved dyslipidemia and hyperglycemia, but in the long term, DV10 alone showed the greatest efficacy in both serum and tissues. In conclusion, functionalization with a higher proportion of DV10 significantly enhances the pharmacokinetics and pharmacodynamics of lispro-protamine insulin. Therefore, it could be considered a treatment strategy for managing glucose and lipid homeostasis in diabetes.</p>