Jonassen Ib, Havelund Svend, Ribel Ulla, Plum Anne, Loftager Mette, Hoeg-Jensen Thomas, Volund Aage, Markussen Jan
Preformulation & Delivery, Novo Nordisk A/S, Novo Allé, 6B2.56.2, DK-2880, Bagsvaerd, Denmark.
Pharm Res. 2006 Jan;23(1):49-55. doi: 10.1007/s11095-005-9047-1. Epub 2006 Dec 21.
This study was conducted to assess the suitability of insulin analogs acylated by various cholic acid derivatives for use as basal insulin, and to test the most promising of these, LysB29(Nepsilon-lithocholyl-gamma-Glu) des(B30) human insulin (NN344) in pigs.
Circular dichroism spectroscopy and size-exclusion chromatography were used to explore the physicochemical properties of the analogs, and affinities for albumin and insulin receptors were determined. After subcutaneous injection in pigs, disappearance half-times were measured, and the plasma profile and glucose-lowering effect in a euglycemic clamp were assessed for NN344.
NN344 showed glucose-lowering activity lasting more than 24 h. Glucose infusion rate was essentially constant from 5 to 19 h after injection. NN344 seemed to be a dodecamer in the presence of zinc ions and phenol. Without phenol, the apparent molecular mass was >5000 kDa. Formation of such a self-assembly at the site of s.c. injection and its subsequent slow decomposition might explain the long duration of action of NN344. A measurable affinity for albumin of the lithocholic acid ligand may also contribute to the prolonged action.
NN344 is a candidate for a neutral soluble basal insulin that might offer people with diabetes a prolonged duration, smooth, and predictable basal insulin supplement.
本研究旨在评估经各种胆酸衍生物酰化的胰岛素类似物作为基础胰岛素使用的适用性，并在猪身上测试其中最有前景的LysB29（Nε-石胆酰-γ-谷氨酸）去（B30）人胰岛素（NN344）。
采用圆二色光谱法和尺寸排阻色谱法探究类似物的物理化学性质，并测定其对白蛋白和胰岛素受体的亲和力。在猪皮下注射后，测量消失半衰期，并评估NN344在正常血糖钳夹试验中的血浆谱和降糖效果。
NN344显示出持续超过24小时的降糖活性。注射后5至19小时，葡萄糖输注速率基本恒定。在锌离子和苯酚存在下，NN344似乎是一种十二聚体。没有苯酚时，表观分子量>5000 kDa。在皮下注射部位形成这种自组装及其随后的缓慢分解可能解释了NN344作用时间长的原因。石胆酸配体对白蛋白的可测量亲和力也可能有助于延长作用时间。
NN344是一种中性可溶性基础胰岛素的候选药物，可能为糖尿病患者提供作用时间延长、平稳且可预测的基础胰岛素补充剂。
