Albumin binding and time-action of acylated insulin in various species
Insulins acylated with fatty acids at the epsilon-amino group of LysB29 constitute a new class of insulin analogs, which are prolonged-acting due to albumin binding. In the present study it is shown that the affinity of fatty acid acylated insulins for albumin varies considerably (> 50-fold) among species. The relative affinities of acylated insulin for albumin in human, pig, and rabbit serum are about 1:1:5:35. The several fold higher binding affinity in rabbit serum than in pig serum is reflected in a relatively more protracted effect after sc injection in rabbits than in pigs. Due to the similar binding affinities in pig serum and human serum, the pig model should provide a useful estimate of the degree of protraction of acylated insulin in humans. The results emphasize that species differences in ligand binding can be of major importance in the preclinical evaluation of highly albumin bound drugs.
Available from: Erdal Eren
- "Another LAIA is insulin detemir which is an acylated derivative of human insulin [Lys B29 (Nε -tetradecanoyl) des (B30) human insulin]. It has more reproducible absorption and a prolonged action profile.6 "
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ABSTRACT: The purpose of this study was to compare the efficacy and safety of insulin glargine and detemir with NPH insulin in children and adolescents with type 1 diabetes mellitus (DM).
Thirty four children and adolescents with type 1 DM (mean age 12.7 ± 3.4 years, diabetes duration 5.4 ± 3.0 years) were included in the study. All patients had been receiving intensive insulin therapy with insulin aspart and NPH for at least 6 months before switching from NPH to insulin glargine (Group 1, n=19) or detemir (Group 2, n=15). The medical records obtained within 6 months before and after treatment with insulin glargine and detemir were retrospectively reviewed and the data were compared in each group.
The mean age and duration of DM were similar in two groups (p>0.05). In both groups, switching from NPH to insulin glargine or detemir, resulted in a reduction in HbA(1c) (p0.05, for both). Patients in the detemir treated group had less increment in body mass index (BMI) SDS at the end of 6 months of therapy compared to NPH and glargine treated patients (p>0.05, for both). No side effects were noted throughout the study.
Both insulin glargine and detemir improved HbA(1c) at short-term and proved to be safe and well tolerated in children and adolescents with type 1 DM.
Journal of Clinical Research in Pediatric Endocrinology 06/2009; 1(4):181-7. DOI:10.4008/jcrpe.v1i4.56
Available from: ncbi.nlm.nih.gov
- "Membrane anchoring has also been proposed to facilitate peptide translocation along the lipid membrane and consequently to increase the lifetime of the specific interaction between the anchored peptide and its target receptor. This mechanism might contribute to the increased response of the insulin receptor as observed when subjected to acylated insulin (Kurtzhals et al., 1996; Markussen et al., 1996). Interaction of membrane-anchored peptides with lipid membranes will depend on the physicochemical properties of the membrane that are influenced by, for instance, temperature, the nature of the membrane headgroups, and the chemical composition of the acyl chains of the membrane. "
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ABSTRACT: A three-dimensional structure of a model decapeptide is obtained by performing molecular dynamics simulations of the peptide in explicit water. Interactions between an N-myristoylated form of the folded peptide anchored to dipalmitoylphosphatidylcholine fluid phase lipid membranes are studied at different applied surface tensions by molecular dynamics simulations. The lipid membrane environment influences the conformational space explored by the peptide. The overall secondary structure of the anchored peptide is found to deviate at times from its structure in aqueous solution through reversible conformational transitions. The peptide is, despite the anchor, highly mobile at the membrane surface with the peptide motion along the bilayer normal being integrated into the collective modes of the membrane. Peptide anchoring moderately alters the lateral compressibility of the bilayer by changing the equilibrium area of the membrane. Although membrane anchoring moderately affects the elastic properties of the bilayer, the model peptide studied here exhibits conformational flexibility and our results therefore suggest that peptide acylation is a feasible way to reinforce peptide-membrane interactions whereby, e.g., the lifetime of receptor-ligand interactions can be prolonged.
Biophysical Journal 07/2004; 86(6):3556-75. DOI:10.1529/biophysj.103.029140 · 3.97 Impact Factor
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ABSTRACT: In normal humans, blood glucose and insulin are maintained within a narrow range despite wide variations in physical activity and dietary intake. At present, reproducing this pattern is an impossible task in type 1 diabetes and extremely difficult in type 2 DM. New approaches using novel insulin analogs and routes of administration, attempting to replicate physiological insulin secretion in diabetic patients, are improving the profiles of glucose levels and, thus, the quality of life. Ultra-short-acting insulin analogues and ultra-long-acting analogues are being used for prandial and basal effects with better results, lower prevalence of hypoglycemia, and, hopefully, fewer chronic complications. Non-invasive routes of administration are being developed. The most promising appears to be inhaled insulin according to studies demonstrating excellent control, apparently without significant side effects, although in relatively short-term trials. Longer-term studies to assure the safety are still necessary before recommending its extended use. This is an extensive, up-to-date review of recent advances in insulin therapy.
Archives of Medical Research 05/2005; 36(3):258-72. DOI:10.1016/j.arcmed.2005.03.012 · 2.65 Impact Factor
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