ABSTRACT
Humanin (HN) is a novel 24-amino acid mitochondrial-derived peptide that has demonstrated diverse cytoprotective effects, including an emerging role in diabetes. The purpose of this study was to examine the pharmacokinetics of humanin analogues, which show great potential as therapeutic agents (HNG and the non-IGFBP-3 binding, HNGF6A). 11-week-old male IGFBP-3(-/-) and wild type (WT) mice were divided into 3 groups: WT mice treated with HNG, WT mice treated with HNGF6A, and IGFBP-3(-/-) mice treated with HNG. Plasma was obtained from mice following ip injection with HN analogues, and HN levels were measured with ELISA. WT mice treated with HNGF6A and IGFBP-3(-/-) mice treated with HNG displayed a longer half-life of HN compared with WT mice treated with HNG. Following HNG injection, both IGF-1 and IGFBP-3 levels decreased over time. Adult male Sprague Dawley rats were also ip injected with HNG, and HN levels were measured in various tissues (plasma, liver, heart, and brain) by ELISA. The half-life of HN was found to be longer in rats compared with mice. In rats, HN levels were found to be highest in plasma, present in liver, and undetectable in brain or heart. The current study provides evidence of HN and IGFBP-3 association in the circulation and suggests that native HN may modulate the distribution of IGF-1 and IGFBP-3. The results also demonstrate varying kinetic profiles of HN analogues and interspecies variation in rodents. Sustainable levels of circulating HN measured in plasma underline the potential value of HN analogues as a new therapeutic intervention in the treatment of diabetes.
Subject(s)
Drugs, Investigational/pharmacokinetics , Hypoglycemic Agents/pharmacokinetics , Insulin-Like Growth Factor Binding Protein 3/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/pharmacokinetics , Animals , Biotransformation , Drugs, Investigational/administration & dosage , Drugs, Investigational/chemistry , Drugs, Investigational/metabolism , Enzyme-Linked Immunosorbent Assay , Half-Life , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/metabolism , Injections, Intraperitoneal , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor Binding Protein 3/genetics , Insulin-Like Growth Factor Binding Protein 3/metabolism , Insulin-Like Growth Factor I/metabolism , Intracellular Signaling Peptides and Proteins/administration & dosage , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/metabolism , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Rats , Rats, Sprague-Dawley , Species Specificity , Tissue DistributionABSTRACT
BACKGROUND: In the last 2 decades, recombinant human growth hormone (rhGH) therapy for children with idiopathic short stature (ISS) has demonstrated varying degrees of efficacy. Based on prediction models for this population developed from registry databases and extensive clinical experience, these differences have been attributed to age at diagnosis, dose of rhGH, parental height, treatment compliance, GH sensitivity, effectiveness of GH receptors, potency of the postreceptor signaling cascade, insulin-like growth factor I transcriptional and translational efficiency and epiphyseal responsiveness. CONCLUSIONS: Although there are no universally accepted biochemical criteria for determining when to initiate GH therapy for children with ISS, both molecular and biochemical factors may contribute to the success of therapy and play a significant role to maximize adult height.