title: Enhanced absorption of insulin aspart as the result of a dispersed injection strategy tested in a randomized trial in type 1 diabetic patients.
abstract: OBJECTIVE
  We investigated the impact of two different injection strategies on the pharmacokinetics and pharmacodynamics of insulin aspart in vivo in an open-label, two-period crossover study and verified changes in the surface-to-volume ratio ex vivo.
  
  
  METHODS
  Before the clinical trial, insulin aspart was injected ex vivo into explanted human abdominal skin flaps. The surface-to-volume ratio of the subcutaneous insulin depot was assessed by microfocus computed tomography that compared 1 bolus of 18 IU with 9 dispersed boluses of 2 IU. These two injection strategies were then tested in vivo, in 12 C-peptide-negative type 1 diabetic patients in a euglycemic glucose clamp (glucose target 5.5 ± 1.1 mmol/L) for 8 h after the first insulin administration.
  
  
  RESULTS
  The ex vivo experiment showed a 1.8-fold higher mean surface-to-volume ratio for the dispersed injection strategy. The maximum glucose infusion rates (GIR) were similar for the two strategies (10 ± 4 vs. 9 ± 4; P = 0.5); however, times to reach maximum GIR and 50% and 10% of the maximum GIR were significantly reduced by using the 9 × 2 IU strategy (68 ± 33 vs. 127 ± 93 min; P = 0.01; 38 ± 9 vs. 49 ± 16 min; P < 0.01; 23 ± 6 vs. 30 ± 10 min; P < 0.05). For 9 × 2 IU, the area under the GIR curve was greater during the first 60 min (219 ± 89 vs. 137 ± 75; P < 0.01) and halved until maximum GIR (242 ± 183 vs. 501 ± 396; P < 0.01); however, it was similar across the whole study period (1,361 ± 469 vs. 1,565 ± 527; P = 0.08).
  
  
  CONCLUSIONS
  A dispersed insulin injection strategy enhanced the effect of a fast-acting insulin analog. The increased surface-to-volume ratio of the subcutaneous insulin depot can facilitate insulin absorption into the vascular system.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Mader
authors.forename: Thomas
authors.initials: T
authors.lastname: Birngruber
authors.forename: Stefan
authors.initials: S
authors.lastname: Korsatko
authors.forename: Sigrid
authors.initials: S
authors.lastname: Deller
authors.forename: Gerd
authors.initials: G
authors.lastname: Köhler
authors.forename: Susanne
authors.initials: S
authors.lastname: Boysen
authors.forename: Thomas
authors.initials: T
authors.lastname: Augustin
authors.forename: Selma I
authors.initials: SI
authors.lastname: Mautner
authors.forename: Frank
authors.initials: F
authors.lastname: Sinner
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Pieber
mesh_terms: D000328:Adult; D002096:C-Peptide / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy; D005260:Female; D006801:Humans; D061267:Insulin Aspart / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D055815:Young Adult
chemical_list: D002096:C-Peptide; D061267:Insulin Aspart