Insulin stabilization mechanisms

J. Brange, Chemical Stability of Insulin. 4. Mechanisms and Kinetics of Chemical Transformations in Pharmaceutical Formulation , Acta Pharm. Nordica 1992, 4, 209-222. 

Strickley, R.G., and B.D. Anderson, Solid-state stability of human insulin. I. Mechanism and the effect of water on the kinetics of degradation in lyophiles from pH 2-5 solutions. Pharm Res, 1996.13(8) 1142-53. 

Mechanism of Action Anantihyperglycemicthat decreases hepaticproduction of glucose. Decreases absorption of glucose and improves insulin sensifivify. Therapeutic Effect Improves glycemicconfrol, stabilizes or decreases body weight, and improves lipid profile. 

A sustained drug release is favourable for drugs with short elimination half-life. It can be controlled by hydration and diffusion mechanisms or ionic interactions between the drug and the polymeric carrier. In the case of diffusion control the stability of the carrier system is essential, as its disintegration leads to a burst release. Therefore, the cohesiveness of the polymer network plays a crucial role in order to control the release over several hours. Due to the formation of disulphide bonds within the network thiomers offer adequate cohesive stability. Almost zero-order release kinetics could be shown for insulin embedded in thiolated polycarbophil matrices (Clausen and Bernkop-Schnurch 2001). In the case of peptide and protein drugs release can be controlled via ionic interactions. An anionic or cationic polymer has to be chosen depending... 

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

Burke Ml, Rougvie MA (1972) Cross-protein structures. I. Insulin fibrils. Biochemistry 11 2435-2439 Burley SK, Petsko GA (1985) Aromatic-aromatic interaction a mechanism of protein stmeture stabilization. Science 229 23-28... 

In an elegant series of experiments Miele et al. (45) have shown that VEGF mRNA induction by insulin and IGF-I in NIH3T3 fibroblasts transfected with either human IR or IGF-IR occurred by preferential use of the PI3K pathway in case of insulin/IR or the MAPK pathway in case of IGF-I/IGF-IR. Although the authors depicted no direct link to HIF-1, one can speculate that two different mechanisms led to the elevated VEGF mRNA levels. In the first case the mechanism was, in all likelihood, an increased HIF-la protein amount rather than enhanced trans-activation ability, whereas in the second case it was an enhanced /ran -activation ability rather than an elevated HIF-la amount. However, in vivo phosphorylated and dephosphorylated HIF-la seems to have different functions since phosphorylated HIF-la is the major form that binds to HIF-ljS and activates transcription, whereas the dephosphorylated form binds to and stabilizes p53, which in turn initiates cell cycle arrest and apoptosis (46). 

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