Insulin aggregation

Insulin aggregation and precipitation was an impediment to the development of implantable devices for insulin delivery as noted by several investigators working with conventional insulin infusion devices [51-54]. The potential causes of the observed aggregation and precipitation are thermal effects, mechanical stress, the nature of the materials in contact with the insulin solution, formulation factors, and the purity of the insulin preparation. 

J. R. Brennan, S. P. Gebhart, and W. O. Blackard, Pump-induced insulin aggregation A problem with the biostator, Diabetes, 34, 353 (1985). 

Huff, M. E., Balch, W. E., and Kelly, J. W. (2003). Pathological and functional amyloid formation orchestrated by the secretory pathway. Curr. Opin. Struct. Biol. 13, 674-682. Jansen, R., Dzwolak, W., and Winter, R. (2005). Amyloidogenic self-assembly of insulin aggregates probed by high resolution atomic force microscopy. Biophys. J. 88, 1344-1353. 

V. Sluzky, J. A. Tamada, A. M. Klibanov, and R. Langer, Kinetics of insulin aggregation in aqueous solutions upon agitation in the presence of hydrophobic surfaces, Proc. 

Velosulin contains phosphate buffer, which favors its use to prevent insulin aggregation in pump tubing but precludes its being mixed with lente insulin. 

Kwon, Y. M., Baudys, M., Knutson, K., and Kim, S. W. (2001), In situ study of insulin aggregation induced by water-organic solvent interface, Pharm. Res., 18,1754-1759. 

Bovine and human insulins Dextrin, Emdex (spray-dried dextrose) and hydroxypropyl P-cyclodextrin minimized insulin aggregation [22]... 

Sluzky, V. Klibanov, A.M. Langer, R. Mechanism of insulin aggregation and stabilization in agitated aqueous solutions. Biotechnol. Bioeng. 1992, 40, 895-903. 

Jansen, R., Dzwolak, W., and Winter, R. (2005) Amyloidogenic self-assembly of insulin aggregates probed by high resolution atomic force microscopy. Biophysical Journal, 88, 1344-1353. 

In order to clarify the mechanisms affecting the acceleration of insulin proteolysis by diacylation, the effect of acylation on insulin aggregation was investigated using circular dichroism (CD) [57]. On the CD spectra of both mono- and diacyl derivatives, an attenuation of negative maxima... 

The primary limitation currently facing the development and use of these implantable micropumps is the precipitation of insulin on the pump components (7,11,14,31), although bicarbonate (33), certain serum components (25), or amino acides (32) may minimize or prevent insulin aggregation. These precipitates, if they accumulate, tend to occlude the flow channels in the pump and particularly the fine bore tubing or valves that are integral parts of these devices. Additional concern is related to the reliability and inherent safety of these devices and to their ability to use small, concentrated insulin reservoirs. 

Brennan JR, Gebhart SS, Blackard WG (1985) Pump induced insulin aggregation. A problem with the Biostator. Diabetes 34 353-359... 

Bringer, J., Heldt, A., and Groddcy, G. M., 1981, Prevention of insulin aggregation by dicarboxyhc amino acids during prolonged infusion. Diabetes 30 83-85. 

Feingold, V., Jenkins, A. B., and Kraegen, E. W., 1984, Effect of contact material on vibration-induced insulin aggregation, Diabetologia 27 373-378. 

Lougheed, W. D., Woulfe-Flanagan, H., Clement, J. R., and Albisser, A. M., 1980, Insulin aggregation in artificial delivery systems, Diabetologia 19 1-9. 

---