title: Differences in metabolic and mitogenic signallingof insulin glargine and AspB10 human insulin in rats [corrected].
abstract: OBJECTIVE
  In vitro, insulin glargine (A21Gly,B31Arg,B32Arg human insulin) has an insulin receptor (IR) profile similar to that of human insulin, but a slightly higher affinity for the IGF-1 receptor (IGF1R). AspB10 human insulin (AspB10), [corrected] the only insulin analogue with proven carcinogenic activity, has a greater affinity for IGF1R and IR, and a prolonged IR occupancy time. The pharmacological and signalling profile of therapeutic and suprapharmacological doses of glargine were analysed in different tissues of rats, and compared with human insulin and AspB10.
  
  
  METHODS
  Male Wistar rats were injected s.c. with human insulin or insulin analogue at doses of 1 to 200 U/kg, and the effects on blood glucose and the phosphorylation status of IR, IGF1R, Akt and extracellular signal-regulated protein kinase 1/2 in muscle, fat, liver and heart samples were investigated.
  
  
  RESULTS
  Glargine, AspB10 and human insulin lowered blood glucose, with the onset of action delayed with glargine. Glargine treatment resulted in phosphorylation levels of IR and Akt that were comparable with those achieved with human insulin, although delayed in time in some tissues. AspB10 treatment resulted in at least twofold higher phosphorylation levels and significantly longer duration of IR and Akt phosphorylation in most tissues. None of the insulin treatments resulted in detectable IGF1R phosphorylation in muscle or heart tissue, whereas intravenous injection of IGF-1 increased IGF1R phosphorylation.
  
  
  CONCLUSIONS
  The IR signalling pattern of AspB10 in vivo is distinctly different from that of human insulin and insulin glargine, and might challenge the notion that activation of IGF1R plays a role in the observed carcinogenic effect of AspB10.
authors: Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany. norbert.tennagels@sanofi.com
authors: N
authors: N
authors: Tennagels
authors: S
authors: S
authors: Welte
authors: M
authors: M
authors: Hofmann
authors: P
authors: P
authors: Brenk
authors: R
authors: R
authors: Schmidt
authors: U
authors: U
authors: Werner
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives / Q000494:pharmacology; D061267:Insulin Aspart / Q000494:pharmacology*; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D049528:Insulin, Long-Acting; C070690:insulin, Asp(B10)-; D000069036:Insulin Glargine; D061267:Insulin Aspart; D011972:Receptor, Insulin
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