title: Enhanced insulin action following subcutaneous co-administration of insulin and C-peptide in rats.
abstract: BACKGROUND
  This study was undertaken to examine if C-peptide (C) may interact with hexameric insulin and facilitate its disaggregation into the physiologically active monomeric form.
  
  
  METHODS
  Regular insulin (I) or an insulin analogue (IA) were injected s.c. in rats together with C or its C-terminal pentapeptide (PP). I or IA and C or PP were administered either as a physical mixture or into two separate s.c. depots. Whole body glucose utilization was evaluated using the euglycemic clamp technique. Phosphorylation of Akt/PKB and GSK in liver and skeletal muscles and ⁸⁶Rb⁺ uptake by L6 cells were measured.
  
  
  RESULTS
  S.c. injection of a mixture of I and C or I and PP resulted in a 30-55% greater (P < 0.01-0.001) and 15-27% (P < 0.05-0.001) longer stimulation of whole body glucose utilization than after separate injections. Insulin-stimulated phosphorylation of Akt/PKB in liver increased 35% more after injection of I and C in mixture compared with after separate injections. Phosphorylation of GSK3 was augmented by 50% (P < 0.05) following the injection of I and C in mixture compared with separate injections. Stimulation of myotubes with premixed I and C (1 nM) elicited 20% additional increase in ouabain-sensitive ⁸⁶Rb⁺ uptake (P < 0.05) in comparison with the effect when I and C were added separately.
  
  
  CONCLUSIONS
  Subcutaneous co-administration of insulin and C results in augmented insulin bioactivity at the level of tissue glucose uptake, intracellular signalling, and enzyme activation. These effects may be attributed to augmented C mediated disaggregation of hexameric insulin into its physiologically active monomeric form.
authors.affiliation: Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kubota
authors.forename: Y
authors.initials: Y
authors.lastname: Sato
authors.forename: O
authors.initials: O
authors.lastname: Khookhor
authors.forename: K
authors.initials: K
authors.lastname: Ekberg
authors.forename: A V
authors.initials: AV
authors.lastname: Chibalin
authors.forename: J
authors.initials: J
authors.lastname: Wahren
mesh_terms: D000818:Animals; D002096:C-Peptide / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D002460:Cell Line; D004338:Drug Combinations; D004343:Drug Implants; D004359:Drug Therapy, Combination; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D061268:Insulin Lispro / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology; D061386:Insulin, Regular, Human / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002096:C-Peptide; D004338:Drug Combinations; D004343:Drug Implants; D007004:Hypoglycemic Agents; D061268:Insulin Lispro; D061386:Insulin, Regular, Human; D009842:Oligopeptides; D010446:Peptide Fragments; D011994:Recombinant Proteins; C000592087:glutamyl-glycyl-seryl-leucyl-glutamine; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: C-peptide; co-administration; disaggregation; euglycemic clamp; insulin action; insulin hexamers