Absorption insulin molecule

If peptide chains can be oriented in a regular fashion, it may be useful to measure infrared linear dichroism.24 25 Absorption spectra are recorded by passing plane polarized light through the protein in two mutually perpendicular directions, with the electric vector either parallel to the peptide chains or perpendicular to the chains. Such a pair of spectra is shown in Fig. 23-3A for oriented fibrils of insulin. In this instance, the insulin molecules are thought to assume a P conformation and to be stacked in such a way that they extend transverse to the fibril axis (a cross-P structure). When the electric vector is parallel to the fibril axis, it is perpendicular to the peptide chains. Since the amide I band is dominated by a carbonyl stretching motion that is perpendicular to the... 

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. 

Soybean-derived sterol mixture (SS), soybean-derived steryl glucosides (SG), and their individual components have been extensively studied for their ability to promote the nasal absorption of drugs, particularly insulin [79,80], Maitani et al. [79] demonstrated that the nasal administration of SG plus insulin to rabbits resulted in significant reductions in blood glucose. The effect of SG was dose dependent to 1%, with a plateau being reached thereafter. Muramatsu et al. [81] have demonstrated that SG perturbs the phospholipids in artificial membranes (i.e., liposomes). Furthermore, circular dichroism studies with insulin in the presence or absence of SG have indicated that the enhancer had little effect on the dissociation of insulin hexamers to monomers. These results suggest that the action of SS and SG involves interaction with the nasal membrane rather than interaction with insulin molecules. 

Recent work with insulin provides evidence that the total lung volume at the end of the delivery impacts the kinetics of absorption of this peptide delivery of fine particle insulin aerosol resulted in faster absorption with a higher plasma peak level in humans when the inhalation was done with a deep breath (close to vital capacity), as compared with a more shallow breath (about 50% of the vital capacity).The kinetics following the latter was similar to subcutaneous absorption of insulin. The exact reasons for this observation are unknown. However, the lung does have the above-described water channels that could expand during breathing. If the size of the peptide or protein molecule approaches the diameter of these channels, it would be expected that the channel expansion would lead to faster absorption. For molecules whose size exceeds the channel diameter, the lung volume does not play a role in their pulmonary absorption rate. ... 

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... 

Self-association of the insulin molecule into oligomers and macromolecular aggregates leads to complications in the development of long-term insulin therapeutic systems and limits the rate of subcutaneous absorptions, a process which... 

Regular crystalline insulin naturally self-associates into a hexam-eric (six insulin molecules) stmcture when injected subcutaneously. Before absorption through a blood capillary can occur, the hexamer must dissociate first to dimers, and then to monomers. This principle is the premise for additives such as protamine and zinc described below, and modification of amino acids for insulin analogs. Lispro, aspart, and glulisine insulins dissociate rapidly to monomers, thus absorption... 

The switch in position of amino acids in lispro does not affect the action of this synthetic insulin on cells because it is not in a critical invariant region, but it does affect the ability of insulin to bind zinc. Normally, human insulin is secreted from the pancreas as a zinc hexa-mer in which six insulin molecules are bound to the zinc atom. When zinc insulin is injected, the binding to zinc slows the absorption from the subcutaneous (under the skin) injection site. Lispro cannot bind zinc to form a hexamer, and thus it is absorbed much more quickly than other insulins. 

The targeting of the lipid absorption and metabolism pathways has yielded several promising venues for the treatment of dyslipidemia and insulin resistance. Small molecule inhibitors of MTP have conferred significant reductions in total and LDL cholesterol, as well as plasma TG, in human subjects. While some mechanism-related side effects due to increased hepatic and intraintestinal TG... 

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