Enhanced Absorption of Insulin Aspart as the Result of a Dispersed Injection Strategy Tested in a Randomized Trial in Type 1 Diabetic Patients
- Julia K. Mader, MD1,
- Thomas Birngruber, MS2,
- Stefan Korsatko, MD1,
- Sigrid Deller, MD1,
- Gerd Köhler, MD1,
- Susanne Boysen, MS3,
- Thomas Augustin, PHD2,
- Selma I. Mautner, PHD1,2,
- Frank Sinner, PHD1,2,
- Thomas R. Pieber, MD1,2⇓,
- on behalf of the AP@home consortium
- 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- 2Joanneum Research GmbH, HEALTH—Institute for Biomedicine and Health Sciences, Graz, Austria
- 3Novo Nordisk A/S, Maaloev, Denmark
- Corresponding author: Thomas R. Pieber, .
J.K.M. and T.B. contributed equally to this study.
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.
RESEARCH DESIGN AND 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.
- Received July 5, 2012.
- Accepted September 4, 2012.
- © 2012 by the American Diabetes Association.
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