Monomeric insulin absorption

Insulin lispro induces more rapid and constant release of insulin from the injection site, since it consists of monomeric insulin. The change of one or more amino acids in the insulin molecule prevents insulin from forming dimers or hexamers. More rapid absorption, rapid availability, and rapid inactivation make the action better than that of endogenously secreted insulin. When the interval between meals is long, the premeal blood glucose concentration increases rapidly. 

Recent development of insulin analogues has altered the rates of absorption. Insulin with aspartate and glutamate substituted at positions B9 and B27 respectively crystallizes poorly and has been termed "monomeric insulin (Vora et al., 1988). This insulin is absorbed more rapidly from subcutaneous depots and thus may be useful in meeting postprandial demands. In contrast, other insulin analogues tend to crystallize at the site of injection and are absorbed more slowly (Markussen et al., 1988). Insulins with enhanced biological potency have been produced by substitution of aspartate for histidine at position BIO and by modification of the C-terminal residues of the B-chain (Schwartz et al., 1989). 

The polymerization of insuHn and proinsulin to dimers and hexamers is a very important process which takes place in the pancreas and impacts upon the pharmaceutical application of insuHn, because the dissociation of the polymers is the rate-limiting processes in the absorption and action in the tissues of the biological active monomeric insulin [45]. The polymerization diminishes osmotic pressure and hy-drophobicity and improves solubility. A positive correlation between expression yield and the degree of polymerization was found [46] that supports yeast in vivo polymerization of insulin precursors and accentuates its importance. However, polymerization can also account for a drawback by retention of product in the vacuole [47]. Intracellular retention of a substantial quantity of the synthesized insulin precursor indicated that the insulin precursor followed two different intracellular routes in the late secretory pathway [12, 47]. Constitutive secretion to the culture supernatant may reflect saturation of a sorting mechanism in the late Golgi due to overexpression. The kexin cleaves the leader-insulin precursor peptide in a late Golgi compartment to yield free insulin precursor, and... 

Some proteins self-associate in aqueous solution to form oligomers. Insulin, for example, exists in several associated states the zinc hexamer of insulin is a complex of insulin and zinc which dissolves slowly into dimers and eventually monomers following its subcutaneous administration, so giving it long-acting properties. In most cases, however, it is desirable to prevent association such that only monomeric or dimeric forms are present in the formulations and a more rapid absorption is achieved. Recent studies have been directed towards engineering insulin molecules which are not prone to association, " or the prevention of association through the addition of surfactants. Protein self-association is a reversible process, i.e. alteration of the solvent properties can lead to the re-formation of the monomeric native protein. There is an important distinction between this association... 

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