title: Metabolic effect and receptor signalling profile of a non-metabolisable insulin glargine analogue.
abstract: BACKGROUND
  Insulin glargine (GLA) is rapidly metabolized in vivo to metabolite M1, which has in vitro metabolic and mitogenic profiles comparable with human insulin (HI).
  
  
  OBJECTIVE
  To investigate the pharmacologic and signalling profiles of a non-metabolizable analogue (A21Gly,DiD-Arg) insulin (D-GLA).
  
  
  METHODS
  Rats were injected s.c. with 1, 12.5 or 200 U/kg of GLA or D-GLA; blood glucose and phosphorylation status of the insulin receptor (IR), Akt and IGF-1 receptor (IGF1R) in tissue samples were investigated after 1 h. Plasma samples were analysed for insulin by LC-MS/MS.
  
  
  RESULTS
  Blood glucose lowering was prolonged with D-GLA. D-GLA comprised ≥98% of insulin after D-GLA injection; M1 comprised 76-92% after GLA injection. IR and Akt phosphorylation were comparable with GLA and D-GLA. Neither analogue stimulated IGF1R phosphorylation.
  
  
  CONCLUSIONS
  Suprapharmacological doses of D-GLA did not activate IGF1R in vivo. Mitogenic effects of insulin and insulin analogues might be solely based on IR growth-promoting activity.
authors.affiliation: R&D Diabetes Division .
authors.forename: Ulrich
authors.initials: U
authors.lastname: Werner
authors.forename: Marcus
authors.initials: M
authors.lastname: Korn
authors.forename: Ronald
authors.initials: R
authors.lastname: Schmidt
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wendrich
authors.forename: Norbert
authors.initials: N
authors.lastname: Tennagels
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053719:Tandem Mass Spectrometry
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D049528:Insulin, Long-Acting; D000069036:Insulin Glargine; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt
keywords: (A21Gly,DiD-arg) insulin; IGF-1 receptor; insulin glargine; insulin receptor; receptor phosphorylation