Insulin Molecule (insulin + molecule)

Distribution by Scientific Domains


Selected Abstracts


Insulin analogues: an example of applied medical science

DIABETES OBESITY & METABOLISM, Issue 1 2009
B. Sheldon
Insulin analogues were developed to try and achieve more physiological insulin replacement from injection in the subcutaneous site. Their pharmacokinetics and pharmacodynamics differ from human insulin when injected subcutaneously because of alterations in the amino acid sequence of the insulin molecule. The rapid-acting insulin analogues, lispro, aspart and glulisine, have a rapid onset of action and shorter duration of action because of changes to the B26,30 portion of insulin inhibiting formation of dimers and hexamers. They appear to improve postprandial glucose, incidence of hypoglycaemia and patient satisfaction and, when used in combination with basal insulin analogues, improve glycosylated haemoglobin in comparison to conventional insulin therapy. Additionally, they have been successfully used in children, pregnant women, in pump therapy and as part of premixed biphasic regimens. The two basal insulin analogues, glargine and detemir, developed by adjusting the isoelectric point and adding a fatty acid residue, respectively, have a protracted duration of action and a relatively smooth profile. Their pharmacokinetic and pharmacodynamic profiles have been assessed using euglycaemic clamp protocols. Both analogues have a longer duration of action, less of a peak of activity and a reduced variability with repeated injection. There is some evidence to suggest that detemir may have a slight hepatoselective effect. Clinical studies have shown a lower relative risk of hypoglycaemia and detemir appears to have a weight-sparing action. Insulin analogues represent a successful example of applied medical science. [source]


Novel insulin analogues and its mitogenic potential

DIABETES OBESITY & METABOLISM, Issue 6 2006
Ivana Zib
Abstract:, Insulin analogues were developed to modify the structure of the human insulin molecule in order to more accurately approximate the endogenous secretion of insulin. With the help of recombinant technology and site-directed mutagenesis, the insulin molecule can be modified to either delay or shorten absorption time, providing better insulin treatment options and facilitating the achievement of glycaemic goals. Changing the structure of the insulin molecule, however, may significantly alter both its metabolic and mitogenic activity. Multiple factors such as residence time on the receptor, dissociation rate, rate of receptor internalization and the degree of phosphorylation of signalling proteins can affect the mitogenic potencies of insulin analogues. Changes in the structure of the insulin have raised concern about the safety of the insulin analogues. For example, questions have emerged about the relationship between the use of insulin lispro and insulin glargine and the progression of diabetic retinopathy. Two studies have shown progression of retinopathy with the use of insulin lispro. However, others have not confirmed these results, and causality could not be proven as progression of retinopathy can occur with rapid improvement in glycaemic control, and methods of assessments among studies were not consistent. Therefore, we examine the metabolic and mitogenic characteristics of the three insulin analogues, insulin lispro, insulin aspart and insulin glargine, that are currently on the market, as well as the two insulin analogues, insulin glulisine and insulin detemir, that are soon going to be available for clinical use. [source]


Identification of the nitration site of insulin by peroxynitrite

JOURNAL OF PEPTIDE SCIENCE, Issue 3 2007
Quan Chi
Abstract Our previous investigation indicated that insulin can be nitrated by peroxynitrite in vitro. In this study, the preferential nitration site of the four tyrosine residues in insulin molecule was confirmed. Mononitrated and dinitrated insulins were purified by RP-HPLC. Following reduction of insulin disulfide bridges, Native-PAGE indicated that A-chain was preferentially nitrated. Combination of enzymatic digestion of mononitrated insulin with endoproteinase Glu-C, mass spectrometry confirmed that Tyr-A14 was the preferential nitration site when insulin was treated with peroxynitrite. Tyr-A19, maybe, was the next preferential nitration site. According to the crystal structure, Tyr-B26 between the two tyrosine residues in insulin B-chain was likely easier to be nitrated by peroxynitrite. Copyright © 2006 European Peptide Society and John Wiley & Sons, Ltd. [source]


X-ray investigation of gene-engineered human insulin crystallized from a solution containing polysialic acid

ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 3 2010
V. I. Timofeev
Attempts to crystallize the noncovalent complex of recombinant human insulin with polysialic acid were carried out under normal and microgravity conditions. Both crystal types belonged to the same space group, I213, with unit-cell parameters a = b = c = 77.365,Å, , = , = , = 90.00°. The reported space group and unit-cell parameters are almost identical to those of cubic insulin reported in the PDB. The results of X-ray studies confirmed that the crystals obtained were cubic insulin crystals and that they contained no polysialic acid or its fragments. Electron-density maps were calculated using X-ray diffraction sets from earth-grown and microgravity-grown crystals and the three-dimensional structure of the insulin molecule was determined and refined. The conformation and secondary-structural elements of the insulin molecule in different crystal forms were compared. [source]


Zinc ions in ,-cells of obese, insulin-resistant, and type 2 diabetic rats traced by autometallography

APMIS, Issue 12 2003
L. G. SØNDERGAARD
Zinc ions in the secretory granules of ,-cells are known to glue insulin molecules, creating osmotically stable hexamers. When the secretory granules open to the surface, the zinc ion pressure decreases rapidly and pH levels change from acid to physiological, which results in free insulin monomers and zinc ions. The released zinc ions have been suggested to be involved in a paracrine regulation of ,- and ,-cells. Since zinc is intimately involved in insulin metabolism and because zinc homeostasis is known to be disturbed in type 2 diabetes, we decided to study the ultrastructural localisation of zinc ions in insulin-resistant and type 2 diabetic rats as compared to controls. By means of autometallography, the only method available for demonstrating zinc ions at ultrastructural levels, we found zinc ions in the secretory granules and adjacent to the plasma membrane. The membrane-related staining outside the plasma membrane reflects release of zinc ions during exocytosis. No apparent difference was found in the ultrastructural localisation of zinc ions when we compared the obese Zucker (fa/fa) rats, representing the insulin resistance syndrome, and the GK rats, representing type 2 diabetes, with controls. This suggests that the ultrastructural localisation of zinc ions is unaffected by the development of type 2 diabetes in rats in a steady state of glycaemia. [source]


A neutron crystallographic analysis of T6 porcine insulin at 2.1,Å resolution

ACTA CRYSTALLOGRAPHICA SECTION D, Issue 10 2009
Wakari Iwai
Neutron diffraction data for T6 porcine insulin were collected to 2.1,Å resolution from a single crystal partly deuterated by exchange of mother liquor. A maximum-likelihood structure refinement was undertaken using the neutron data and the structure was refined to a residual of 0.179. The hydrogen-bonding network of the central core of the hexamer was observed and the charge balance between positively charged Zn ions and their surrounding structure was interpreted by considering the protonation and/or deprotonation states and interactions of HisB10, water and GluB13. The observed double conformation of GluB13 was essential to interpreting the charge balance and could be compared with the structure of a dried crystal of T6 human insulin at 100,K. Differences in the dynamic behaviour of the water molecules coordinating the upper and lower Zn ions were observed and interpreted. The hydrogen bonds in the insulin molecules, as well as those involving HisB10 and GluB13, are discussed. The hydrogen/deuterium (H/D) exchange ratios of the amide H atoms of T6 porcine insulin in crystals were obtained and showed that regions highly protected from H/D exchange are concentrated in the centre of a helical region of the B chains. From the viewpoint of soaking time versus H/D-exchange ratios, the amide H atoms can be classified into three categories. [source]