Tiffner Katrin, Boulgaropoulos Beate, Höfferer Christian, Birngruber Thomas, Porksen Niels, Linnebjerg Helle, Garhyan Parag, Lam Eric Chen Quin, Knadler Mary Pat, Pieber Thomas R, Sinner Frank
1 HEALTH-Institute for Biomedicine and Health Sciences , Joanneum Research Forschungsgesellschaft mbH, Graz, Austria .
2 Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz , Graz, Austria .
Diabetes Technol Ther. 2017 May;19(5):305-314. doi: 10.1089/dia.2016.0384. Epub 2017 Mar 22.
Restoration of the physiologic hepatic-to-peripheral insulin gradient may be achieved by either portal vein administration or altering insulin structure to increase hepatic specificity or restrict peripheral access. Basal insulin peglispro (BIL) is a novel, PEGylated basal insulin with a flat pharmacokinetic and glucodynamic profile and altered hepatic-to-peripheral action gradient. We hypothesized reduced BIL exposure in peripheral tissues explains the latter, and in this study assessed the adipose tissue interstitial fluid (ISF) concentrations of BIL compared with human insulin (HI).
A euglycemic glucose clamp was performed in patients with type 1 diabetes during continuous intravenous (IV) infusion of BIL or HI, while the adipose ISF insulin concentrations were determined using open-flow microperfusion (OFM). The ratio of adipose ISF-to-serum concentrations and the absolute steady-state adipose ISF concentrations were assessed using a dynamic no-net-flux technique with subsequent regression analysis.
Steady-state BIL concentrations in adipose tissue ISF were achieved by ∼16 h after IV infusion. Median time to reach steady-state glucose infusion rate across doses ranged between 8 and 22 h. The average serum concentrations (coefficient of variation %) of BIL and HI were 11,200 pmol/L (23%) and 425 pmol/L (15%), respectively. The ISF-to-serum concentration ratios were 10.2% for BIL and 22.9% for HI.
This study indicates feasibility of OFM to measure BIL in ISF. The observed low ISF-to-serum concentration ratio of BIL is consistent with its previously demonstrated reduced peripheral action.
恢复生理性肝-外周胰岛素梯度可通过门静脉给药或改变胰岛素结构以增加肝脏特异性或限制外周摄取来实现。基础胰岛素聚乙二醇化赖脯胰岛素（BIL）是一种新型的聚乙二醇化基础胰岛素，具有平稳的药代动力学和糖动力学特征以及改变的肝-外周作用梯度。我们推测外周组织中BIL暴露减少可解释后者，并且在本研究中评估了BIL与人类胰岛素（HI）相比在脂肪组织间质液（ISF）中的浓度。
在1型糖尿病患者持续静脉输注BIL或HI期间进行正常血糖葡萄糖钳夹试验，同时使用开放流微灌注（OFM）测定脂肪ISF胰岛素浓度。使用动态无净通量技术及随后的回归分析评估脂肪ISF与血清浓度的比值以及绝对稳态脂肪ISF浓度。
静脉输注后约16小时达到脂肪组织ISF中的稳态BIL浓度。各剂量达到稳态葡萄糖输注速率的中位时间在8至22小时之间。BIL和HI的平均血清浓度（变异系数%）分别为11200 pmol/L（23%）和425 pmol/L（15%）。BIL的ISF与血清浓度比值为10.2%，HI为22.9%。
本研究表明OFM测量ISF中BIL的可行性。观察到的BIL的低ISF与血清浓度比值与其先前证明的外周作用降低一致。
