Vasodilatory effects of glucagon: A possible new approach to enhanced subcutaneous insulin absorption in artificial pancreas devices

Ingrid Anna Teigen, Misbah Riaz, Marte Kierulf Åm, Sverre Christian Christiansen, Sven Magnus Carlsen, Ingrid Anna Teigen, Misbah Riaz, Marte Kierulf Åm, Sverre Christian Christiansen, Sven Magnus Carlsen

Abstract

Patients with diabetes mellitus type 1 depend on exogenous insulin to keep their blood glucose concentrations within the desired range. Subcutaneous bihormonal artificial pancreas devices that can measure glucose concentrations continuously and autonomously calculate and deliver insulin and glucagon infusions is a promising new treatment option for these patients. The slow absorption rate of insulin from subcutaneous tissue is perhaps the most important factor preventing the development of a fully automated artificial pancreas using subcutaneous insulin delivery. Subcutaneous insulin absorption is influenced by several factors, among which local subcutaneous blood flow is one of the most prominent. We have discovered that micro-doses of glucagon may cause a substantial increase in local subcutaneous blood flow. This paper discusses how the local vasodilative effects of micro-doses of glucagon might be utilised to improve the performance of subcutaneous bihormonal artificial pancreas devices. We map out the early stages of our hypothesis as a disruptive novel approach, where we propose to use glucagon as a vasodilator to accelerate the absorption of meal boluses of insulin, besides using it conventionally to treat hypoglycaemia.

Keywords: artificial pancreas; diabetes mellitus type 1; glucagon; pharmacokinctics; subcutaneous infusion.

Conflict of interest statement

The authors SMC and SCC are among the inventors of a pending patent application on the use of micro-doses of glucagon to enhance SC CGM performance and SC insulin absorption. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Teigen, Riaz, Åm, Christiansen and Carlsen.

References

    1. AHFS Drug Information: American Society of Health-System Pharmacists. (2022a). Dasiglucagon Hydrochloride. Available at: [Accessed July 29, 2022].
    1. AHFS Drug Information: American Society of Health-System Pharmacists. (2022b). Insulin aspart. Available at: [Accessed April 19, 2022].
    1. AHFS Drug Information: American Society of Health-System Pharmacists. (2022c). Insulin glulisine. Available at: [Accessed April 19, 2022].
    1. AHFS Drug Information: American Society of Health-System Pharmacists. (2022d). Insulin lispro. Available at: [Accessed April 19, 2022].
    1. AHFS Drug Information: American Society of Health-System Pharmacists. (2022e). Insulins general statement. Available at: [Accessed April 19, 2022].
    1. Åm M. K., Dirnena-Fusini I., Fougner A. L., Carlsen S. M., Christiansen S. C. (2020). Intraperitoneal and subcutaneous glucagon delivery in anaesthetized pigs: Effects on circulating glucagon and glucose levels. Sci. Rep. 10, 13735. 10.1038/s41598-020-70813-5
    1. Åm M. K., Munkerud E. Y., Berge M. H., Christiansen S. C., Carlsen S. M. (2022). The effect of glucagon on local subcutaneous blood flow in non-diabetic volunteers; A proof-of-concept study. Eur. J. Pharmacol. 926, 175045. 10.1016/j.ejphar.2022.175045
    1. Bakhtiani P. A., El Youssef J., Duell A. K., Branigan D. L., Jacobs P. G., Lasarev M. R., et al. (2015). Factors affecting the success of glucagon delivered during an automated closed-loop system in type 1 diabetes. J. Of Diabetes Its Complicat. 29, 93–98. 10.1016/j.jdiacomp.2014.09.001
    1. Bakhtiani P. A., Zhao L. M., El Youssef J., Castle J. R., Ward W. K. (2013). A review of artificial pancreas technologies with an emphasis on Bi-hormonal therapy. Diabetes Obes. Metab. 15, 1065–1070. 10.1111/dom.12107
    1. Bantle J. P., Neal L., Frankamp L. M. (1993). Effects of the anatomical region used for insulin injections on glycemia in type I diabetes subjects. Diabetes Care 16, 1592–1597. 10.2337/diacare.16.12.1592
    1. Bengtsen M. B., Moller N. (2021). Mini-Review: Glucagon responses in type 1 diabetes - a matter of complexity. Physiol. Rep. 9, e15009. 10.14814/phy2.15009
    1. Binder C. (1969). Absorption of injected insulin. A clinical-pharmacological study. Acta Pharmacol. Toxicol. (Copenh). 27 (2), 1–83. 10.1111/j.1600-0773.1969.tb03069.x
    1. Birkeland K. I. (2006). Insulin treatment of type 1 diabetes in adults. Tidsskr. Nor. Laegeforen. 126, 776–778.
    1. Blauw H., Wendl I., Devries J. H., Heise T., Jax T. (2016). Pharmacokinetics and pharmacodynamics of various glucagon dosages at different blood glucose levels. Diabetes Obes. Metab. 18, 34–39. 10.1111/dom.12571
    1. Braverman I. M., Schechner J. S., Silverman D. G., Keh-Yen A. (1992). Topographic mapping of the cutaneous microcirculation using two outputs of laser-Doppler flowmetry: Flux and the concentration of moving blood cells. Microvasc. Res. 44, 33–48. 10.1016/0026-2862(92)90100-4
    1. Castle J. R., Engle J. M., El Youssef J., Massoud R. G., Ward W. K. (2010). Factors influencing the effectiveness of glucagon for preventing hypoglycemia. J. Diabetes Sci. Technol. 4, 1305–1310. 10.1177/193229681000400603
    1. Castle J. R., Youssef J. E., Branigan D., Newswanger B., Strange P., Cummins M., et al. (2016). Comparative pharmacokinetic/pharmacodynamic study of liquid stable glucagon versus lyophilized glucagon in type 1 diabetes subjects. J. Diabetes Sci. Technol. 10, 1101–1107. 10.1177/1932296816653141
    1. Charkoudian N. (2003). Skin blood flow in adult human thermoregulation: How it works, when it does not, and why. Mayo Clin. Proc. 78, 603–612. 10.4065/78.5.603
    1. Chatwin H., Broadley M., Valdersdorf Jensen M., Hendrieckx C., Carlton J., Heller S., et al. (2021). 'Never again will I Be carefree': A qualitative study of the impact of hypoglycemia on quality of life among adults with type 1 diabetes. BMJ Open Diabetes Res. Care 9, e002322. 10.1136/bmjdrc-2021-002322
    1. Christiansen S. C., Fougner A. L., Stavdahl O., Kolle K., Ellingsen R., Carlsen S. M. (2017). A review of the current challenges associated with the development of an artificial pancreas by A double subcutaneous approach. Diabetes Ther. 8, 489–506. 10.1007/s13300-017-0263-6
    1. Cryer P. E. (2012). Minireview: Glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology 153, 1039–1048. 10.1210/en.2011-1499
    1. Dirnena-Fusini I., Åm M. K., Fougner A. L., Carlsen S. M., Christiansen S. C. (2018). Intraperitoneal, subcutaneous and intravenous glucagon delivery and subsequent glucose response in rats: A randomized controlled crossover trial. BMJ Open Diabetes Res. Care 6, E000560. 10.1136/bmjdrc-2018-000560
    1. El Youssef J., Castle J. R., Bakhtiani P. A., Haidar A., Branigan D. L., Breen M., et al. (2014). Quantification of the glycemic response to microdoses of subcutaneous glucagon at varying insulin levels. Diabetes Care 37, 3054–3060. 10.2337/dc14-0803
    1. El-Khatib F. H., Jiang J., Gerrity R. G., Damiano E. R. (2007). Pharmacodynamics and stability of subcutaneously infused glucagon in A type 1 diabetic swine model in vivo . Diabetes Technol. Ther. 9, 135–144. 10.1089/dia.2006.0006
    1. El-Khatib F. H., Russell S. J., Nathan D. M., Sutherlin R. G., Damiano E. R. (2010). A bihormonal closed-loop artificial pancreas for type 1 diabetes. Sci. Transl. Med. 2, 27ra27. 10.1126/scitranslmed.3000619
    1. El-Laboudi A. H., Oliver N. (2015). Towards A physiological prandial insulin profile: Enhancement of subcutaneously injected prandial insulin using local warming devices. Diabetes Ther. 6, 257–272. 10.1007/s13300-015-0125-z
    1. Farah A. E. (1983). Glucagon and the circulation. Pharmacol. Rev. 35, 181–217.
    1. Funtanilla V. D., Candidate P., Caliendo T., Hilas O. (2019). Continuous glucose monitoring: A review of available systems. P Trans. 44, 550–553.
    1. Gast K., Schüler A., Wolff M., Thalhammer A., Berchtold H., Nagel N., et al. (2017). Rapid-acting and human insulins: Hexamer dissociation kinetics upon dilution of the pharmaceutical formulation. Pharm. Res. 34, 2270–2286. 10.1007/s11095-017-2233-0
    1. Gerich J. E., Langlois M., Noacco C., Karam J. H., Forsham P. H. (1973). Lack of glucagon response to hypoglycemia in diabetes: Evidence for an intrinsic pancreatic alpha cell defect. Science 182, 171–173. 10.1126/science.182.4108.171
    1. Gingras V., Taleb N., Roy-Fleming A., Legault L., Rabasa-Lhoret R. (2018). The challenges of achieving postprandial glucose control using closed-loop systems in patients with type 1 diabetes. Diabetes Obes. Metab. 20, 245–256. 10.1111/dom.13052
    1. Gradel A. K. J., Porsgaard T., Lykkesfeldt J., Seested T., Gram-Nielsen S., Kristensen N. R., et al. (2018). Factors affecting the absorption of subcutaneously administered insulin: Effect on variability. J. Of Diabetes Res. 2018, 1205121. 10.1155/2018/1205121
    1. Graf C. J., Woodworth J. R., Seger M. E., Holcombe J. H., Bowsher R. R., Lynch R. (1999). Pharmacokinetic and glucodynamic comparisons of recombinant and animal-source glucagon after iv, im, and Sc injection in healthy volunteers. J. Of Pharm. Sci. 88, 991–995. 10.1021/js99007p
    1. Haidar A. (2019). Insulin-and-glucagon artificial pancreas versus insulin-alone artificial pancreas: A short review. Diabetes Spectr. 32, 215–221. 10.2337/ds18-0097
    1. Hiyoshi T., Fujiwara M., Yao Z. (2017). Postprandial hyperglycemia and postprandial hypertriglyceridemia in type 2 diabetes. J. Biomed. Res. 33, 1–16. 10.7555/JBR.31.20160164
    1. Hövelmann U., Bysted B. V., Mouritzen U., Macchi F., Lamers D., Kronshage B., et al. (2018). Pharmacokinetic and pharmacodynamic characteristics of dasiglucagon, A novel soluble and stable glucagon analog. Diabetes Care 41, 531–537. 10.2337/dc17-1402
    1. Hövelmann U., Olsen M. B., Mouritzen U., Lamers D., Kronshage B., Heise T. (2019). Low doses of dasiglucagon consistently increase plasma glucose levels from hypoglycaemia and euglycaemia in people with type 1 diabetes mellitus. Diabetes Obes. Metab. 21, 601–610. 10.1111/dom.13562
    1. Ito A., Horie I., Miwa M., Sako A., Niri T., Nakashima Y., et al. (2021). Impact of glucagon response on early postprandial glucose excursions irrespective of residual Β-cell function in type 1 diabetes: A cross-sectional study using A mixed meal tolerance test. J. Diabetes Investig. 12, 1367–1376. 10.1111/jdi.13486
    1. Kildegaard J., Buckley S. T., Nielsen R. H., Povlsen G. K., Seested T., Ribel U., et al. (2019). Elucidating the mechanism of absorption of fast-acting insulin aspart: The role of niacinamide. Pharm. Res. 36, 49. 10.1007/s11095-019-2578-7
    1. Knebel T., Neumiller J. J. (2019). Medtronic minimed 670g hybrid closed-loop system. Clin. Diabetes 37, 94–95. 10.2337/cd18-0067
    1. Knop F. K. (2018). Eje prize 2018: A gut feeling about glucagon. Eur. J. Endocrinol. 178, R267–R280. 10.1530/eje-18-0197
    1. Leohr J., Dellva M. A., Carter K., Labell E., Linnebjerg H. (2021). Ultra rapid lispro (urli) accelerates insulin lispro absorption and insulin action vs Humalog(®) consistently across study populations: A pooled analysis of pharmacokinetic and glucodynamic data. Clin. Pharmacokinet. 60, 1423–1434. 10.1007/s40262-021-01030-0
    1. Lindholm A., Jacobsen L. V. (2001). Clinical pharmacokinetics and pharmacodynamics of insulin aspart. Clin. Pharmacokinet. 40, 641–659. 10.2165/00003088-200140090-00002
    1. Mader J. K., Birngruber T., Korsatko S., Deller S., Köhler G., Boysen S., et al. (2013). Enhanced absorption of insulin aspart as the result of A dispersed injection strategy tested in A randomized trial in type 1 diabetic patients. Diabetes Care 36, 780–785. 10.2337/dc12-1319
    1. Nathan D. M., Genuth S., Lachin J., Cleary P., Crofford O., Davis M., et al. (1993). 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. 329, 977–986. 10.1056/NEJM199309303291401
    1. Pallayova M., Taheri S. (2014). Targeting diabetes distress: The missing piece of the successful type 1 diabetes management puzzle. Diabetes Spectr. 27, 143–149. 10.2337/diaspect.27.2.143
    1. Peyser T., Dassau E., Breton M., Skyler J. S. (2014). The artificial pancreas: Current status and future prospects in the management of diabetes. Ann. N. Y. Acad. Sci. 1311, 102–123. 10.1111/nyas.12431
    1. Pitt J. P., Mccarthy O. M., Hoeg-Jensen T., Wellman B. M., Bracken R. M. (2020). Factors influencing insulin absorption around exercise in type 1 diabetes. Front. Endocrinol. 11, 573275. 10.3389/fendo.2020.573275
    1. Raju S., Sanford P., Herman S., Olivier J. (2012). Postural and ambulatory changes in regional flow and skin perfusion. Eur. J. Vasc. Endovasc. Surg. 43, 567–572. 10.1016/j.ejvs.2012.01.019
    1. Ranjan A., Schmidt S., Madsbad S., Holst J. J., Nørgaard K. (2016). Effects of subcutaneous, low-dose glucagon on insulin-induced mild hypoglycaemia in patients with insulin pump treated type 1 diabetes. Diabetes Obes. Metab. 18, 410–418. 10.1111/dom.12627
    1. Reichard P., Pihl M., Rosenqvist U., Sule J. (1996). Complications in iddm are caused by elevated blood glucose level: The stockholm diabetes intervention study (sdis) at 10-year follow up. Diabetologia 39, 1483–1488. 10.1007/s001250050602
    1. Reichard P. (1992). Risk factors for progression of microvascular complications in the stockholm diabetes intervention study (sdis). Diabetes Res. Clin. Pract. 16, 151–156. 10.1016/0168-8227(92)90087-8
    1. Robinson S., Newson R. S., Liao B., Kennedy-Martin T., Battelino T. (2021). Missed and mistimed insulin doses in people with diabetes: A systematic literature review. Diabetes Technol. Ther. 23, 844–856. 10.1089/dia.2021.0164
    1. Schmelzeisen-Redeker G., Schoemaker M., Kirchsteiger H., Freckmann G., Heinemann L., Del Re L. (2015). Time delay of cgm sensors: Relevance, causes, and countermeasures. J. Diabetes Sci. Technol. 9, 1006–1015. 10.1177/1932296815590154
    1. Siegmund T., Heinemann L., Kolassa R., Thomas A. (2017). Discrepancies between blood glucose and interstitial glucose-technological artifacts or physiology: Implications for selection of the appropriate therapeutic target. J. Diabetes Sci. Technol. 11, 766–772. 10.1177/1932296817699637
    1. Simmons K. L., Williams G. (1992). Attempts to accelerate glucagon absorption: Effects of adding A vasodilator and of injection using A 'sprinkler' needle. Eur. J. Clin. Invest. 22, 434–437. 10.1111/j.1365-2362.1992.tb01486.x
    1. Skjaervold N. K., Lyng O., Spigset O., Aadahl P. (2012). Pharmacology of intravenous insulin administration: Implications for future closed-loop glycemic control by the intravenous/intravenous route. Diabetes Technol. Ther. 14, 23–29. 10.1089/dia.2011.0118
    1. Søeborg T., Rasmussen C. H., Mosekilde E., Colding-Jørgensen M. (2009). Absorption kinetics of insulin after subcutaneous administration. Eur. J. Pharm. Sci. 36, 78–90. 10.1016/j.ejps.2008.10.018
    1. Taleb N., Coriati A., Khazzaka C., Bayonne J., Messier V., Rabasa-Lhoret R. (2017). Stability of commercially available glucagon formulation for dual-hormone artificial pancreas clinical use. Diabetes Technol. Ther. 19, 589–594. 10.1089/dia.2017.0204
    1. Teigen I. A., Åm M. K., Carlsen S. M., Christiansen S. C. (2022). Pharmacokinetics of glucagon after intravenous, intraperitoneal and subcutaneous administration in A pig model. Basic Clin. Pharmacol. Toxicol. 130, 623–631. 10.1111/bcpt.13731
    1. Teigen I. A., Åm M. K., Carlsen S. M., Christiansen S. C. (2021). Pharmacokinetics of intraperitoneally delivered glucagon in pigs: A hypothesis of first pass metabolism. Eur. J. Drug Metab. Pharmacokinet. 46, 505–511. 10.1007/s13318-021-00692-2
    1. The Norwegian Medicines Agency Medicine Database. (2022). Lyumjev. Available at: [Accessed May 20, 2022].
    1. Vora J. P., Burch A., Peters J. R., Owens D. R. (1992). Relationship between absorption of radiolabeled soluble insulin, subcutaneous blood flow, and anthropometry. Diabetes Care 15, 1484–1493. 10.2337/diacare.15.11.1484
    1. Weisman A., Bai J. W., Cardinez M., Kramer C. K., Perkins B. A. (2017). Effect of artificial pancreas systems on glycaemic control in patients with type 1 diabetes: A systematic review and meta-analysis of outpatient randomised controlled trials. Lancet Diabetes Endocrinol. 5, 501–512. 10.1016/s2213-8587(17)30167-5
    1. Yosten G. L. C. (2018). Alpha cell dysfunction in type 1 diabetes. Peptides 100, 54–60. 10.1016/j.peptides.2017.12.001
    1. Zijlstra E., Jahnke J., Fischer A., Kapitza C., Forst T. (2018). Impact of injection speed, volume, and site on pain sensation. J. Diabetes Sci. Technol. 12, 163–168. 10.1177/1932296817735121

Source: PubMed

3
Iratkozz fel