Stable liquid glucagon formulations for rescue treatment and bi-hormonal closed-loop pancreas.
Stable liquid glucagon formulations for rescue treatment and bi-hormonal closed-loop pancreas.
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DOI：
10.1007/s11892-012-0320-5
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发表时间：
2012-12
影响因子：
4.2
通讯作者：
Ward, W. Kenneth
中科院分区：
文献类型：
--
作者：
Jackson, Melanie A.;Caputo, Nicholas;Castle, Jessica R.;David, Larry L.;Roberts, Charles T., Jr.;Ward, W. Kenneth
在研究环境中通过自动化系统皮下给予小剂量胰高血糖素可预防糖尿病患者的大多数低血糖病例。然而，胰高血糖素非常不稳定，不能保存在便携式泵中。胰高血糖素迅速形成淀粉样原纤维，甚至在重建后的第一天内。聚集最终导致不溶性凝胶，其堵塞泵导管。纤维化在酸性pH下迅速发生，但在约10的碱性pH值下不存在或最小。胰高血糖素也随着时间的推移而降解;这个问题在碱性pH下更严重。一些研究表明，其主要降解途径是脱酰胺，这导致天冬酰胺转化为天冬氨酸。评估胰高血糖素受体（GluR）活化的胰高血糖素生物活性的基于细胞的测定可以筛选有希望的胰高血糖素制剂。然而，哺乳动物肝细胞通常是有问题的，因为它们在培养过程中可能失去GluR表达。在工程细胞系统中，环腺苷酸（cAMP）或其下游效应物蛋白激酶A（PKA）的测定更可靠，适用于廉价的高通量生物活性评估。
Small doses of glucagon given subcutaneously in the research setting by an automated system prevent most cases of hypoglycemia in persons with diabetes. However, glucagon is very unstable and cannot be kept in a portable pump. Glucagon rapidly forms amyloid fibrils, even within the first day after reconstitution. Aggregation eventually leads to insoluble gels, which occlude pump catheters. Fibrillation occurs rapidly at acid pH, but is absent or minimal at alkaline pH values of ~10. Glucagon also degrades over time; this problem is greater at alkaline pH. Several studies suggest that its primary degradative pathway is deamidation, which results in a conversion of asparagine to aspartic acid. A cell-based assay for glucagon bioactivity that assesses glucagon receptor (GluR) activation can screen promising glucagon formulations. However, mammalian hepatocytes are usually problematic as they can lose GluR expression during culture. Assays for cyclic AMP (cAMP) or its downstream effector, protein kinase A (PKA), in engineered cell systems, are more reliable and suitable for inexpensive, high-throughput assessment of bioactivity.
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DOI：
10.1126/science.1173155
发表时间：
2009-07-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Maji SK;Perrin MH;Sawaya MR;Jessberger S;Vadodaria K;Rissman RA;Singru PS;Nilsson KP;Simon R;Schubert D;Eisenberg D;Rivier J;Sawchenko P;Vale W;Riek R
通讯作者：
Riek R
影响因子：
16.2
作者：
Castle JR;Engle JM;El Youssef J;Massoud RG;Yuen KC;Kagan R;Ward WK
通讯作者：
Ward WK
影响因子：
5.6
作者：
Pedersen, JS;Dikov, D;Otzen, DE
通讯作者：
Otzen, DE
DOI：
10.1073/pnas.131200398
发表时间：
2001-08-28
影响因子：
11.1
作者：
Jiang, YW;Cypess, AM;Sakmar, TP
通讯作者：
Sakmar, TP
影响因子：
3.7
作者：
Onoue, S;Ohshima, K;Yajima, T
通讯作者：
Yajima, T