Enhanced Absorption of Insulin Aspart as the Result of a Dispersed Injection Strategy Tested in a Randomized Trial in Type 1 Diabetic Patients

Abstract

OBJECTIVEWe 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 METHODSBefore 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.RESULTSThe 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).CONCLUSIONSA 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.

A prolonged run-in period of standard subcutaneous microdialysis ameliorates quality of interstitial glucose signal in patients after major cardiac surgery

“…Although an offset was found when comparing subcutaneous and arterial blood glucose values, the subcutaneous signal could follow trends in blood glucose adequately in both groups. MARD for calibration at hour 1 was in both groups similar to microdialysis results seen in a previous study in patients with diabetes and could even outperform these results when introducing a 6-h run-in period in the SICU but not in the MICU group 20 . Clarke Error Grid Analysis also supports these findings: for SICU there was an increase in the number of values laying in zone A after introduction of the 6 hours run-in period (80.4 vs. 87.9%).…”

“…Subcutaneous microdialysis samples were collected over a predefined time period of 60 minutes. To account for the long sampling interval of one hour, the reference blood glucose measurements corresponding to a start and an end glucose value of the interstitial samples were averaged and then paired with the according interstitial glucose value, as described previously 20 . Bland-Altman plot was used to indicate the relative differences between the paired glucose readings on the y-axis in relation to the average blood glucose concentration on the x-axis 21 , 22 .…”

Concentrated insulins in current clinical practice

“…This is due to the limited capacity of syringes and pens, resulting in the need for additional injections for people to receive a full dose. A practice observed in clinical care has been to divide a single subcutaneous insulin injection into multiple separate injections, when the total amount of a single injection exceeds a prespecified volume [15][16][17]. With concentrated insulins, decreased injection volume and fewer injections have demonstrated reduced measures of disease burden and ultimately improved experience with injections [18].…”

Impact of the mode of protraction of basal insulin therapies on their pharmacokinetic and pharmacodynamic properties and resulting clinical outcomes

“…The reason that up‐concentration of IGlar U100 alters its time–action profile and potency whereas IDeg U100 and IDeg U200 are interchangeable has yet to be elucidated, but probably reflects differences in mechanism of protraction. As noted above, for insulin analogues that precipitate, up‐concentration further delays absorption of a given dose by creating larger precipitates and thereby reducing the surface area from which absorption can occur . In contrast, the mechanism of protraction of IDeg is such that the release of zinc from multihexamer chains is the rate‐limiting step for IDeg absorption .…”