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The development of effective and safe insulin analogs remains pivotal in advancing diabetes management. This study addresses the limitations of existing insulin therapies by introducing insulin lisargine, a novel long-acting insulin analog that resolves impurity formation associated with trypsin cleavage in glargine insulin. Insulin lisargine is characterized by glycine substitution at A21 and the addition of lysine and arginine at B31 and B32, respectively. High-performance liquid chromatography (HPLC) and mass spectrometry confirmed its high purity and precise molecular weight. X-ray crystallography at 2.0 Å resolution revealed structural features closely resembling human insulin, crucial for optimizing drug formulations and understanding receptor interactions.In vivo experiments demonstrated that insulin lisargine exhibits superior glucose-lowering effects compared to glargine insulin (Lantus). At a dosage of 1.5 IU/kg, lisargine achieved glucose-lowering effects equivalent to glargine in normal rats. However, at 5 IU/kg, it significantly outperformed glargine in type 1 diabetic rats. Long-term safety assessments revealed a comparable safety profile between lisargine and glargine, with no significant toxicity observed. These findings position insulin lisargine as a promising candidate for diabetes management, offering enhanced blood glucose control, improved production efficiency, and reliable safety. The study’s findings provide a foundation for the development of more effective insulin analogs, addressing critical needs in diabetes therapy.

Background Recombinant insulin Lisargine is a new type of insulin. In this study, we aimed to compare its pharmacodynamic (PD) and pharmacokinetic (PK) with Lantus. Methods The PD test was performed by exploring the effect of single administration on blood glucose of normal rats and STZ-induced diabetic rats, and the effect of multiple administrations on blood glucose of STZ-induced diabetic rats. Further PD tests include receptor affinity test, receptor autophosphorylation test and adipocyte glucose uptake test. Four IU and 8 IU per dog Lisargine was used for PK test, insulin was measured and area under curve (AUC) was calculated. Results With single injection, Lisargine 1.5 IU/kg had significant hypoglycemic effects at 1 and 2 h, similar to that of Lantus. Lisargine 5 IU/kg and 10 IU/kg lowered the blood glucose of STZ-induced diabetic rats at 1, 2, 4 & 6 h significantly. With multiple injections, Lantus lowered blood glucose at 2, 4 & 6 h, Lisargine 2.5 IU/kg, 5 IU/kg, and 10 IU/kg lowered blood glucose at 2 & 4 h significantly, compared with vehicle. There was no difference for receptor affinity test, receptor autophosphorylation test and adipocyte glucose uptake test between Lisargine and Lantus. The PK of Lisargine and Lantus of healthy Beagle dogs was very similar. Conclusions This animal study demonstrated that PK and PD of Lisargine and Lantus were similar, suggesting the bioequivalence of these products.