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Exp Clin Endocrinol Diabetes 2020; 128(05): 332-338
DOI: 10.1055/a-0658-1089
Article
© Georg Thieme Verlag KG Stuttgart · New York

Subcutaneous Administration of Insulin is Associated With Regional Differences in Injection Depot Variability and Kinetics in The Rat

Anna Katrina Jógvansdóttir Gradel
1   Department of Veterinary and Animal Sciences, Section of Experimental Animal Models, Ridebanevej 9, 1870 Frederiksberg C, Faculty of Health & Medical Sciences, University of Copenhagen, Copenhagen, Denmark
2   Insulin Research, Global Drug Discovery, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Måløv, Denmark
,
Trine Porsgaard
2   Insulin Research, Global Drug Discovery, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Måløv, Denmark
,
Jens Lykkesfeldt
1   Department of Veterinary and Animal Sciences, Section of Experimental Animal Models, Ridebanevej 9, 1870 Frederiksberg C, Faculty of Health & Medical Sciences, University of Copenhagen, Copenhagen, Denmark
,
Per Bruun Brockhoff
3   Department of Applied Mathematics and Computer Science, Richards Petersens Plads 324, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
,
Torben Seested
4   Department of Histology and Imaging, Global Drug Discovery, Novo Nordisk A/S, Novo Nordisk Park 1, Måløv, Denmark
,
Hanne Hoffmann Frølund Refsgaard
2   Insulin Research, Global Drug Discovery, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Måløv, Denmark
› Author Affiliations Funding This work was funded in part by The LifePharm Centre for In Vivo Pharmacology at University of Copenhagen (AKJG and JL) and by Novo Nordisk A/S.
Further Information

Publication History

Received 08 June 2018
Revised 10 July 2018

Accepted 12 July 2018

Publication Date:
03 August 2018 (online)

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Abstract

Background In humans, subcutaneous administration of insulin in the abdominal region or arm is associated with a faster absorption compared to the thigh or buttocks. We hypothesised that this is partly caused by differences in injection depot structure and kinetics and that the variability in insulin exposure differs between injection sites.

Material and methods Regional effects on insulin pharmacokinetics were evaluated in a series of studies in Sprague Dawley rats dosed subcutaneously with insulin aspart in the neck or flank. Injection depots were visualised using µCT after subcutaneous dosing with insulin aspart mixed with the contrast agent iomeprol, and insulin exposure was determined between the scans by Luminescent Oxygen Channeling Immunoassay.

Results Insulin absorption was significantly delayed by subcutaneous dosing in the flank compared to the neck region (p<0.01 or less). This delay was associated with smaller depots, as measured by reduced depot volume and surface area (p<0.001). Furthermore, the delayed absorption correlated with a slower depot disappearance (p<0.001). Regional differences in depot variability were not reflected by similar differences in pharmacokinetic variability.

Conclusion Structure and kinetics of subcutaneous injection depots—as detected by µCT scans—predict insulin exposure and may thus contribute to the regional differences in insulin pharmacokinetics. The present methodology is applicable for visualisation of insulin injection depots in vivo. Our results did however not support a link between the variability in depot size and insulin pharmacokinetics.

Key words

In vivo pharmacology - insulin pharmacokinetics - variability - µCT imaging
 

  • References

  • 1 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulponylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). The Lancet. 1988; 352: 837-853
    PubMedGoogle Scholar
  • 2 The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977-986
    CrossrefPubMedGoogle Scholar
  • 3 Brownlee M, Hirsch IB. Glycemic variability: A hemoglobin A1c–independent risk factor for diabetic complications. JAMA. 2006; 295: 1707-1708
    CrossrefPubMedGoogle Scholar
  • 4 Nalysnyk L, Hernandez-Medina M, Krishnarajah G. Glycaemic variability and complications in patients with diabetes mellitus: Evidence from a systematic review of the literature. Diabetes Obes Metab 2010; 12: 288-298
    CrossrefPubMedGoogle Scholar
  • 5 Heinemann L. Variability of insulin absorption and insulin action. Diabetes Technol Ther 2002; 4: 663-682
    PubMedGoogle Scholar
  • 6 Heinemann L. Variability of insulin action: Does it matter?. Insulin 2008; 3: 37-45
    CrossrefPubMedGoogle Scholar
  • 7 Mudaliar SR, Lindberg FA, Joyce M. et al. Insulin aspart (B28 asp-insulin): A fast-acting analog of human insulin: absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects. Diabetes Care. 1999; 22: 1501-1506
    CrossrefPubMedGoogle Scholar
  • 8 Galloway A, Spradlin CT, Nelson RK. et al. Factors influencing the absorption, serum insulin concentration, and blood glucose responses after injections of regular insulin and various insulin mixtures. Diabetes Care. 1981; 4: 366-376
    CrossrefPubMedGoogle Scholar
  • 9 Ter Braak EW, Woodworth JR, Bianchi R. et al. Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin. Diabetes Care. 1996; 19: 1437-1440
    CrossrefPubMedGoogle Scholar
  • 10 Hövelmann U, Heise T, Nosek L. et al. Pharmacokinetic properties of fast-acting insulin aspart administered in different subcutaneous injection regions. Clin Drug Investig 2017; 37: 503-509
    CrossrefPubMedGoogle Scholar
  • 11 Vora JP, Burch A, Peters JR. et al. Relationship between absorption of radiolabeled soluble insulin, subcutaneous blood flow, and anthropometry. Diabetes Care. 1992; 15: 1484-1493
    CrossrefPubMedGoogle Scholar
  • 12 Søeborg T, Rasmussen CH, Mosekilde E. et al. Absorption kinetics of insulin after subcutaneous administration. Eur J Pharm Sci 2009; 36: 78-90
    CrossrefPubMedGoogle Scholar
  • 13 Søeborg T, Rasmussen CH, Mosekilde E. et al. Bioavailability and variability of biphasic insulin mixtures. Eur J Pharm Sci 2012; 46: 198-208
    CrossrefPubMedGoogle Scholar
  • 14 Binder C, Lauritzen T, Faber O. et al. Insulin pharmacokinetics. Diabetes Care. 1984; 7: 188-199
    CrossrefPubMedGoogle Scholar
  • 15 Mosekilde E, Jensen KS, Binder C. et al. Modeling absorption kinetics of subcutaneous injected soluble insulin. J Pharmacokinet Biopharm 1989; 17: 67-87
    CrossrefPubMedGoogle Scholar
  • 16 Bantle JP, Weber MS, Shailaja MSR. et al. Rotation of the anatomic regions used for insulin injections and day-to-day variability of plasma glucose in type I diabetic subjects. JAMA. 1990; 263: 1802-1806
    CrossrefPubMedGoogle Scholar
  • 17 Petersen SB, Lovmand JM, Honoré L. et al. Comparison of a Luminescent Oxygen Channeling Immunoassay and an ELISA for detecting Insulin Aspart in human serum. Pharm Biomed Anal 2010; 51: 217-224
    CrossrefPubMedGoogle Scholar
  • 18 Bates D, Mächler M, Bolker BM. et al. Fitting linear mixed-effects models using lme4. J Stat Softw 2015; 67: 1-48
    CrossrefPubMedGoogle Scholar
  • 19 Kuznetsova A, Brockhoff PB, Christensen RHB. lmerTest Package: Tests in Linear Mixed Effects Models. J Stat Softw 2017; 82: 1-26
    Google Scholar
  • 20 Forkman J. Estimator and tests for common coefficients of variation in normal distributions. Commun Stat Theory Methods 2009; 38: 233-251
    CrossrefPubMedGoogle Scholar
  • 21 Chusyd DE, Wand D, Huffman DM. et al. Relationship between rodent white adipose fat pads and human white adipose fat depots. Front Nutr. 2016; 3: Article 10
    PubMedGoogle Scholar
  • 22 Rasmussen CH, Røge RM, Ma Z. et al. Insulin aspart pharmacokinetics: An assessment of its variability and underlying mechanisms. Eur J Pharm Sci 2014; 62: 65-75
    CrossrefPubMedGoogle Scholar
  • 23 Kang S, Brange J, Burch A. et al. Subcutaneous insulin absorption explained by insulin's physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans. Diabetes Care 1991; 14: 942-948
    CrossrefPubMedGoogle Scholar
  • 24 Thomsen M, Poulsen M, Bech M. et al. Visualization of subcutaneous insulin injections by x-ray computed tomography. Phys Med Biol 2012; 57: 7191-7203
    CrossrefPubMedGoogle Scholar
  • 25 Kampf C, Bodin B. Källskog et al. Marked increase in white adipose tissue blood perfusion in the type 2 diabetic GK rat. Diabetes 2005; 54: 2620-2627
    CrossrefPubMedGoogle Scholar
  • 26 Jockel JPL, Roebrock P, Shergold OA. Insulin depot formation in subcutaneous tissue. J Diabetes Sci Technol 2013; 7: 227-237
    CrossrefPubMedGoogle Scholar
  • 27 Sidossis L, Kajimura S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest 2015; 125: 478-486
    CrossrefPubMedGoogle Scholar
  • 28 Iomeron 350 - Summary of Product Characteristics (SmPC); February 28, 2018. Available at https://www.medicines.org.uk/emc/product/3893/smpc Accessed May 3, 2018
    PubMed
  • 29 NovoRapid® Summary of Product Characteristics; 05 July 2017. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000258/WC500030372.pdf Accessed May 3, 2018
    PubMed
  • 30 Thomsen M, Rasmussen CH, Refsgaard HH. et al. Spatial distribution of soluble insulin in pig subcutaneous tissue: Effect of needle length, injection speed and injected volume. Eur J Pharm Sci 2015; 79: 96-101
    CrossrefPubMedGoogle Scholar