title: Effects of human insulin and insulin aspart preparations on levels of IGF-I, IGFBPs and IGF bioactivity in patients with type 1 diabetes.
abstract: BACKGROUND
  Insulin aspart (IAsp) and its biphasic preparations BIAsp50 and BIAsp70 (containing 50% and 70% IAsp, respectively) have distinct glucose-lowering properties as compared to human insulin (HI). We investigated whether this affected the circulating IGF-system which depends on the hepatic insulin exposure.
  
  
  METHODS
  In a randomized, four-period crossover study, 19 patients with type 1 diabetes received identical doses (0.2 U/kg sc) of IAsp, BIAsp70, BIAsp50 and HI together with a standardized meal. Serum total IGF-I and IGFBP-1 to -3 were measured by immunoassays for nine hours post-prandially. Bioactive IGF was determined by an in-house, cell-based IGF-I receptor kinase activation (KIRA) assay.
  
  
  RESULTS
  Despite marked differences in peripheral insulin concentrations and plasma glucose, the four insulin preparations resulted in parallel decreases in IGFBP-1 levels during the first 3 hours, and parallel increases during the last part of the study (3-9 hours). Thus, only minor significances were seen. Insulin aspart and human insulin resulted in a lower area under the curve (AUC) during the first 3 hours as compared to BIAsp70 (p = 0.009), and overall, human insulin resulted in a lower IGFBP-1 AUC than BIAsp70 (p = 0.025). Nevertheless, responses and AUCs of bioactive IGF were similar for all four insulin preparations. Changes in levels of bioactive IGF were inversely correlated to those of IGFBP-1, increasing during the first 3 hours, whereafter levels declined (-0.83 ≤ r ≤ -0.30; all p-values <0.05).Total IGF-I and IGFBP-3 remained stable during the 9 hours, whereas IGFBP-2 changed opposite of IGFBP-1, increasing after 3-4 hours whereafter levels gradually declined. The four insulin preparations resulted in similar profiles and AUCs of total IGF-I, IGFBP-2 and IGFBP-3.
  
  
  CONCLUSIONS
  Despite distinct glucose-lowering properties, the tested insulin preparations had similar effects on IGF-I concentration and IGF bioactivity, IGFBP-2 and IGFBP-3 as compared to HI; only small differences in IGFBP-1 were seen and they did not affect bioactive IGF. Thus, insulin aspart containing preparation behaves as HI in regards to the circulating IGF-system. However, bioactive IGF appeared to be more sensitive to insulin exposure than total IGF-I. The physiological significance of this finding remains to be determined.
  
  
  BACKGROUND
  NCT00888732.
authors.affiliation: Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, DK-8000 Aarhus C, Denmark. zhulin.ma@ki.au.dk.
authors.forename: Zhulin
authors.initials: Z
authors.lastname: Ma
authors.forename: Jens Sandahl
authors.initials: JS
authors.lastname: Christiansen
authors.forename: Torben
authors.initials: T
authors.lastname: Laursen
authors.forename: Chunsen
authors.initials: C
authors.lastname: Wu
authors.forename: Torsten
authors.initials: T
authors.lastname: Lauritzen
authors.forename: Tina
authors.initials: T
authors.lastname: Parkner
authors.forename: Jan
authors.initials: J
authors.lastname: Frystyk
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