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Novel Preparations of Glucagon for the Prevention and Treatment of Hypoglycemia

  • Therapies and New Technologies in the Treatment of Diabetes (M Pietropaolo, Section Editor)
  • Published:
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Abstract

Purpose of Review

New more stable formulations of glucagon have recently become available, and these provide an opportunity to expand the clinical roles of this hormone in the prevention and management of insulin-induced hypoglycemia. This is applicable in type 1 diabetes, hyperinsulinism, and alimentary hypoglycemia. The aim of this review is to describe these new formulations of glucagon and to provide an overview of current and future therapeutic opportunities that these may provide.

Recent Findings

Four main categories of glucagon formulation have been studied: intranasal glucagon, biochaperone glucagon, dasiglucagon, and non-aqueous soluble glucagon. All four have demonstrated similar glycemic responses to standard glucagon formulations when administered during hypoglycemia. In addition, potential roles of these formulations in the management of congenital hyperinsulinism, alimentary hypoglycemia, and exercise-induced hypoglycemia in type 1 diabetes have been described.

Summary

As our experience with newer glucagon preparations increases, the role of glucagon is likely to expand beyond the emergency use that this medication has been limited to in the past. The innovations described in this review likely represent early examples of a pending large repertoire of indications for stable glucagon.

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Abbreviations

T1D:

Type 1 diabetes

GLP-1:

Glucagon-like peptide

HAAF:

Hypoglycemia-associated autonomic failure

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 1987;79(3):777–81. https://doi.org/10.1172/JCI112884.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Abraham MB, Jones TW, Naranjo D, Karges B, Oduwole A, Tauschmann M, et al. ISPAD clinical practice consensus guidelines 2018: assessment and management of hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. 2018;19(Suppl 27):178–92. https://doi.org/10.1111/pedi.12698.

    Article  PubMed  Google Scholar 

  3. • Hawkes CP, Lado JJ, Givler S, De Leon DD. The effect of continuous intravenous glucagon on glucose requirements in infants with congenital hyperinsulinism. JIMD rep. 2019;45:45–50. https://doi.org/10.1007/8904_2018_140. This study demonstrates the effect of a continuous intravenous glucagon infusion on glucose requirement on infants with congenital hyperinsulinism.

    Article  PubMed  Google Scholar 

  4. Salehi M, Vella A, McLaughlin T, Patti ME. Hypoglycemia after gastric bypass surgery: current concepts and controversies. J Clin Endocrinol Metab. 2018;103(8):2815–26. https://doi.org/10.1210/jc.2018-00528.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kedia N. Treatment of severe diabetic hypoglycemia with glucagon: an underutilized therapeutic approach. Diabetes Metab Syndr Obes. 2011;4:337–46. https://doi.org/10.2147/DMSO.S20633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Harris G, Diment A, Sulway M, Wilkinson M. Glucagon administration – underevaluated and undertaught. Practical Diabetes Int. 2001;18(1):22–5. https://doi.org/10.1002/pdi.138.

    Article  Google Scholar 

  7. Rickels MR, Schutta MH, Mueller R, Kapoor S, Markmann JF, Naji A, et al. Glycemic thresholds for activation of counterregulatory hormone and symptom responses in islet transplant recipients. J Clin Endocrinol Metab. 2007;92(3):873–9. https://doi.org/10.1210/jc.2006-2426.

    Article  CAS  Google Scholar 

  8. De Feo P, Perriello G, Torlone E, Ventura MM, Fanelli C, Santeusanio F, et al. Contribution of cortisol to glucose counterregulation in humans. Am J Phys. 1989;257(1 Pt 1):E35–42.

    Google Scholar 

  9. De Feo P, Perriello G, Torlone E, Ventura MM, Santeusanio F, Brunetti P, et al. Demonstration of a role for growth hormone in glucose counterregulation. Am J Phys. 1989;256(6 Pt 1):E835–43.

    Google Scholar 

  10. Cryer PE. Minireview: glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology. 2012;153(3):1039–48. https://doi.org/10.1210/en.2011-1499.

    Article  CAS  PubMed  Google Scholar 

  11. Hawkes CP, Grimberg A, Dzata VE, De Leon DD. Adding glucagon-stimulated GH testing to the diagnostic fast increases the detection of GH-sufficient children. Horm Res Paediatr. 2016;85:265–72. https://doi.org/10.1159/000444678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hawkes CP, Mavinkurve M, Fallon M, Grimberg A, Cody DC. Serial GH measurement after IV placement alone can detect levels above stimulation test thresholds in children. J Clin Endocrinol Metab. 2015:jc20153102. doi:https://doi.org/10.1210/jc.2015-3102.

    Article  CAS  Google Scholar 

  13. Cooperberg BA, Cryer PE. Insulin reciprocally regulates glucagon secretion in humans. Diabetes. 2010;59(11):2936–40. https://doi.org/10.2337/db10-0728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Heller SR, Cryer PE. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans. Diabetes. 1991;40(2):223–6.

    Article  CAS  Google Scholar 

  15. Dagogo-Jack SE, Craft S, Cryer PE. Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. J Clin Invest. 1993;91(3):819–28. https://doi.org/10.1172/JCI116302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Davis SN, Mann S, Galassetti P, Neill RA, Tate D, Ertl AC, et al. Effects of differing durations of antecedent hypoglycemia on counterregulatory responses to subsequent hypoglycemia in normal humans. Diabetes. 2000;49(11):1897–903.

    Article  CAS  Google Scholar 

  17. Rickels MR. Hypoglycemia associated autonomic failure, counterregulatory responses, and therapeutic options in type 1 diabetes. Ann N Y Acad Sci. 2019. https://doi.org/10.1111/nyas.14214.

    Article  CAS  Google Scholar 

  18. Hirsch IB, Marker JC, Smith LJ, Spina RJ, Parvin CA, Holloszy JO, et al. Insulin and glucagon in prevention of hypoglycemia during exercise in humans. Am J Phys. 1991;260(5 Pt 1):E695–704. https://doi.org/10.1152/ajpendo.1991.260.5.E695.

    Article  CAS  Google Scholar 

  19. Mallad A, Hinshaw L, Schiavon M, Dalla Man C, Dadlani V, Basu R, et al. Exercise effects on postprandial glucose metabolism in type 1 diabetes: a triple-tracer approach. Am J Physiol Endocrinol Metab. 2015;308(12):E1106–15. https://doi.org/10.1152/ajpendo.00014.2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Francescato MP, Stel G, Stenner E, Geat M. Prolonged exercise in type 1 diabetes: performance of a customizable algorithm to estimate the carbohydrate supplements to minimize glycemic imbalances. PLoS One. 2015;10(4):e0125220. https://doi.org/10.1371/journal.pone.0125220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Galassetti P, Tate D, Neill RA, Morrey S, Wasserman DH, Davis SN. Effect of antecedent hypoglycemia on counterregulatory responses to subsequent euglycemic exercise in type 1 diabetes. Diabetes. 2003;52(7):1761–9.

    Article  CAS  Google Scholar 

  22. Galassetti P, Tate D, Neill RA, Richardson A, Leu SY, Davis SN. Effect of differing antecedent hypoglycemia on counterregulatory responses to exercise in type 1 diabetes. Am J Physiol Endocrinol Metab. 2006;290(6):E1109–17. https://doi.org/10.1152/ajpendo.00244.2005.

    Article  CAS  PubMed  Google Scholar 

  23. Sandoval DA, Guy DL, Richardson MA, Ertl AC, Davis SN. Acute, same-day effects of antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes mellitus. Am J Physiol Endocrinol Metab. 2006;290(6):E1331–8. https://doi.org/10.1152/ajpendo.00283.2005.

    Article  CAS  PubMed  Google Scholar 

  24. Sandoval DA, Guy DL, Richardson MA, Ertl AC, Davis SN. Effects of low and moderate antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes. Diabetes. 2004;53(7):1798–806.

    Article  CAS  Google Scholar 

  25. Davey RJ, Howe W, Paramalingam N, Ferreira LD, Davis EA, Fournier PA, et al. The effect of midday moderate-intensity exercise on postexercise hypoglycemia risk in individuals with type 1 diabetes. J Clin Endocrinol Metab. 2013;98(7):2908–14. https://doi.org/10.1210/jc.2013-1169.

    Article  CAS  PubMed  Google Scholar 

  26. Tsalikian E, Mauras N, Beck RW, Tamborlane WV, Janz KF, Chase HP, et al. Impact of exercise on overnight glycemic control in children with type 1 diabetes mellitus. J Pediatr. 2005;147(4):528–34. https://doi.org/10.1016/j.jpeds.2005.04.065.

    Article  CAS  PubMed  Google Scholar 

  27. Adzick NS, De Leon DD, States LJ, Lord K, Bhatti TR, Becker SA, et al. Surgical treatment of congenital hyperinsulinism: results from 500 pancreatectomies in neonates and children. J Pediatr Surg. 2019;54(1):27–32. https://doi.org/10.1016/j.jpedsurg.2018.10.030.

    Article  PubMed  Google Scholar 

  28. Neylon OM, Moran MM, Pellicano A, Nightingale M, O'Connell MA. Successful subcutaneous glucagon use for persistent hypoglycaemia in congenital hyperinsulinism. J Pediatr Endocrinol Metab. 2013;26(11–12):1157–61. https://doi.org/10.1515/jpem-2013-0115.

    Article  CAS  PubMed  Google Scholar 

  29. Mohnike K, Blankenstein O, Pfuetzner A, Potzsch S, Schober E, Steiner S, et al. Long-term non-surgical therapy of severe persistent congenital hyperinsulinism with glucagon. Horm Res. 2008;70(1):59–64. https://doi.org/10.1159/000129680.

    Article  CAS  PubMed  Google Scholar 

  30. Ferrara C, Patel P, Becker S, Stanley CA, Kelly A. Biomarkers of insulin for the diagnosis of Hyperinsulinemic hypoglycemia in infants and children. J Pediatr. 2016;168:212–9. https://doi.org/10.1016/j.jpeds.2015.09.045.

    Article  CAS  PubMed  Google Scholar 

  31. Hussain K, Bryan J, Christesen HT, Brusgaard K, Aguilar-Bryan L. Serum glucagon counterregulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism. Diabetes. 2005;54(10):2946–51.

    Article  CAS  Google Scholar 

  32. Kefurt R, Langer FB, Schindler K, Shakeri-Leidenmuhler S, Ludvik B, Prager G. Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test. Surg Obes Relat Dis. 2015;11(3):564–9. https://doi.org/10.1016/j.soard.2014.11.003.

    Article  PubMed  Google Scholar 

  33. Goldfine AB, Patti ME. How common is hypoglycemia after gastric bypass? Obesity (Silver Spring). 2016;24(6):1210–1. https://doi.org/10.1002/oby.21520.

    Article  Google Scholar 

  34. Salehi M, Prigeon RL, D'Alessio DA. Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans. Diabetes. 2011;60(9):2308–14. https://doi.org/10.2337/db11-0203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bradley D, Conte C, Mittendorfer B, Eagon JC, Varela JE, Fabbrini E, et al. Gastric bypass and banding equally improve insulin sensitivity and beta cell function. J Clin Invest. 2012;122(12):4667–74. https://doi.org/10.1172/JCI64895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Goldfine AB, Mun EC, Devine E, Bernier R, Baz-Hecht M, Jones DB, et al. Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal. J Clin Endocrinol Metab. 2007;92(12):4678–85.

    Article  CAS  Google Scholar 

  37. Salehi M, Gastaldelli A, D'Alessio DA. Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass. Gastroenterology. 2014;146(3):669–80 e2. https://doi.org/10.1053/j.gastro.2013.11.044.

    Article  CAS  PubMed  Google Scholar 

  38. Salehi M, Gastaldelli A, D'Alessio DA. Altered islet function and insulin clearance cause hyperinsulinemia in gastric bypass patients with symptoms of postprandial hypoglycemia. J Clin Endocrinol Metab. 2014;99(6):2008–17. https://doi.org/10.1210/jc.2013-2686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005;353(3):249–54. https://doi.org/10.1056/NEJMoa043690.

    Article  PubMed  Google Scholar 

  40. Calabria AC, Gallagher PR, Simmons R, Blinman T, De Leon DD. Postoperative surveillance and detection of postprandial hypoglycemia after fundoplasty in children. J Pediatr. 2011;159(4):597–601 e1. https://doi.org/10.1016/j.jpeds.2011.03.049.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Tharakan G, Behary P, Wewer Albrechtsen NJ, Chahal H, Kenkre J, Miras AD, et al. Roles of increased glycaemic variability, GLP-1 and glucagon in hypoglycaemia after Roux-en-Y gastric bypass. Eur J Endocrinol. 2017;177(6):455–64. https://doi.org/10.1530/EJE-17-0446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Maruyama H, Hisatomi A, Orci L, Grodsky GM, Unger RH. Insulin within islets is a physiologic glucagon-release inhibitor. J Clin Invest. 1984;74(6):2296–9.

    Article  CAS  Google Scholar 

  43. Toft-Nielsen M, Madsbad S, Holst JJ. Exaggerated secretion of glucagon-like peptide-1 (GLP-1) could cause reactive hypoglycaemia. Diabetologia. 1998;41(10):1180–6.

    Article  CAS  Google Scholar 

  44. Rickels MR, Naji A. Reactive hypoglycaemia following GLP-1 infusion in pancreas transplant recipients. Diabetes Obes Metab. 2010;12(8):731–3. https://doi.org/10.1111/j.1463-1326.2010.01208.x.

    Article  CAS  Google Scholar 

  45. Abrahamsson N, Borjesson JL, Sundbom M, Wiklund U, Karlsson FA, Eriksson JW. Gastric bypass reduces symptoms and hormonal responses in hypoglycemia. Diabetes. 2016;65(9):2667–75. https://doi.org/10.2337/db16-0341.

    Article  CAS  PubMed  Google Scholar 

  46. Steiner SS, Li M, Hauser R, Pohl R. Stabilized glucagon formulation for bihormonal pump use. J Diabetes Sci Technol. 2010;4(6):1332–7. https://doi.org/10.1177/193229681000400606.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Food and Drug Administration. GlucaGen. NDA 20–918/S-012. 2004. https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20918s012lbl.pdf. Accessed 03/09/2019.

  48. Food and Drug Administration. Glucagon for Injection. NDA 20–928. 1999. https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20928.pdf. Accessed 03/09/2019.

  49. Ghodke S, Nielsen SB, Christiansen G, Hjuler HA, Flink J, Otzen D. Mapping out the multistage fibrillation of glucagon. FEBS J. 2012;279(5):752–65. https://doi.org/10.1111/j.1742-4658.2011.08465.x.

    Article  CAS  PubMed  Google Scholar 

  50. Pedersen JS. The nature of amyloid-like glucagon fibrils. J Diabetes Sci Technol. 2010;4(6):1357–67. https://doi.org/10.1177/193229681000400609.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Taleb N, Haidar A, Messier V, Gingras V, Legault L, Rabasa-Lhoret R. Glucagon in artificial pancreas systems: potential benefits and safety profile of future chronic use. Diabetes Obes Metab. 2017;19(1):13–23. https://doi.org/10.1111/dom.12789.

    Article  CAS  PubMed  Google Scholar 

  52. Hovelmann U, Bysted BV, Mouritzen U, Macchi F, Lamers D, Kronshage B, et al. Pharmacokinetic and pharmacodynamic characteristics of dasiglucagon, a novel soluble and stable glucagon analog. Diabetes Care. 2018;41(3):531–7. https://doi.org/10.2337/dc17-1402.

    Article  CAS  PubMed  Google Scholar 

  53. Glezer S, Hovelmann U, Teng S, Lamers D, Odoul M, Correia J, et al. BioChaperone glucagon (BCG), a stable ready-to-use liquid glucagon formulation, is well tolerated and quickly restores euglycemia after insulin-induced hypoglycemia. Diabetes. 2018;67(Supplement 1):305–OR. https://doi.org/10.2337/db18-305-OR.

    Article  Google Scholar 

  54. Castle JR, Youssef JE, Branigan D, Newswanger B, Strange P, Cummins M, et al. Comparative pharmacokinetic/pharmacodynamic study of liquid stable glucagon versus lyophilized glucagon in type 1 diabetes subjects. J Diabetes Sci Technol. 2016;10(5):1101–7. https://doi.org/10.1177/1932296816653141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Haymond MW, DuBose SN, Rickels MR, Wolpert H, Shah VN, Sherr JL, et al. Efficacy and safety of mini-dose glucagon for treatment of nonsevere hypoglycemia in adults with type 1 diabetes. J Clin Endocrinol Metab. 2017;102(8):2994–3001. https://doi.org/10.1210/jc.2017-00591.

    Article  PubMed  Google Scholar 

  56. • Rickels MR, Ruedy KJ, Foster NC, Piche CA, Dulude H, Sherr JL, et al. Intranasal glucagon for treatment of insulin-induced hypoglycemia in adults with type 1 diabetes: a randomized crossover noninferiority study. Diabetes Care. 2016;39(2):264–70. https://doi.org/10.2337/dc15-1498. In this study, the authors demonstrate the comparable efficacy of intranasal glucagon with standard intramuscular glucagon in managing hypoglycemia in patients with type 1 diabetes.

    Article  CAS  PubMed  Google Scholar 

  57. Meiffren G, Teng S, Ranson A, Gaudier M, Duracher D, Soula R et al. Preclinical efficacy of a stable aqueous formulation of human glucagon with BioChaperone Technology (BC GLU). American Diabetes Association 77th Scientific Sessions; San Diego, CA 2017. p. 1150-P.

  58. Wilson LM, Castle JR. Stable liquid glucagon: beyond emergency hypoglycemia rescue. J Diabetes Sci Technol. 2018;12(4):847–53. https://doi.org/10.1177/1932296818757795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ranson A, Hövelmann U, Seroussi C, Lamers D, Correia J, Zijlstra E et al. Biochaperone glucagon, a stable ready-to-use liquid glucagon formulation enabled by biochaperone technology, is well tolerated and quickly restores euglycemia after insulin-induced hypoglycemia. Advanced Technologies & Treatment for Diabetes; 20–23 February 2019; Berlin, Germany 2019.

  60. A trial to investigate the safety and the pharmacokinetic, pharmacodynamic characteristics of two BioChaperone® glucagon formulations compared to marketed GlucaGen® in Subjects With T1DM. https://ClinicalTrials.gov/show/NCT03176524.

  61. Newswanger B, Ammons S, Phadnis N, Ward WK, Castle J, Campbell RW, et al. Development of a highly stable, nonaqueous glucagon formulation for delivery via infusion pump systems. J Diabetes Sci Technol. 2015;9(1):24–33. https://doi.org/10.1177/1932296814565131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cersosimo E, Cummins MJ, Kinzell JH, Michalek J, Newswanger BJ, Prestrelski SJ, et al. A phase 2 comparative safety PK/PD study of stable nonaqueous glucagon (g-Pen) vs. Lilly glucagon for treatment of severe hypoglycemia. Diabetes Care. 2014;63(Supplement 1A):LB1.

    Google Scholar 

  63. Pontiroli AE. Intranasal glucagon: a promising approach for treatment of severe hypoglycemia. J Diabetes Sci Technol. 2015;9(1):38–43. https://doi.org/10.1177/1932296814557518.

    Article  CAS  PubMed  Google Scholar 

  64. Locemia Solutions ULC. Safety and efficacy of a novel glucagon formulation in type 1 diabetic patients following insulin-induced hypoglycemia (AMG102). https://clinicaltrials.gov/ct2/show/results/NCT01556594. Accessed 03/13/19 2019.

  65. Food and Drug Administration. BAQSIMI (glucagon) nasal powder. NDA 210134. 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210134s000lbl.pdf. Accessed 30 Aug 2019.

  66. Palylyk-Colwell E, Ford C. A transdermal glucagon patch for severe hypoglycemia. CADTH Issues in Emerging Health Technologies. Ottawa (ON)2016. p. 1–7.

  67. Safety and efficacy of ZP-glucagon to injectable glucagon for hypoglycemia. https://ClinicalTrials.gov/show/NCT02459938.

  68. Hompesch M, Grosjean P, Morrow L, Hijazi Y, Ishibai M, Teichert L et al. 1066-P / 1066 - The novel glucagon receptor agonist SAR438544, first in human safety, pharmacokinetic, and pharmacodynamic data from a study in healthy volunteers. American Diabetes Association 77th Scientific Sessions; 2017; San Diego 2017.

  69. Sanofi Announces Q2 2016 Results. http://www.news.sanofi.us/2016-07-29-Sanofi-Announces-Q2-2016-Results.

  70. Uribe-Bruce L, Morrow L, Canney L, Pichotta P, Hompesch M, Krasner A et al. Pharmacokinetic (Pk) and pharmacodynamic (PD) profiles of BiOD-961 compared with marketed glucagons. American Diabetes Association 2015.

  71. • Haymond MW, Schreiner B. Mini-dose glucagon rescue for hypoglycemia in children with type 1 diabetes. Diabetes Care. 2001;24(4):643–5. This seminal study established the mini-dose glucagon approach to managing impending hypoglycemia in pediatric patients with type 1 diabetes.

    Article  CAS  Google Scholar 

  72. Haymond MW, Redondo MJ, McKay S, Cummins MJ, Newswanger B, Kinzell J, et al. Nonaqueous, mini-dose glucagon for treatment of mild hypoglycemia in adults with type 1 diabetes: a dose-seeking study. Diabetes Care. 2016;39(3):465–8. https://doi.org/10.2337/dc15-2124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. • Rickels MR, DuBose SN, Toschi E, Beck RW, Verdejo AS, Wolpert H, et al. Mini-dose glucagon as a novel approach to prevent exercise-induced hypoglycemia in type 1 diabetes. Diabetes Care. 2018;41(9):1909–16. https://doi.org/10.2337/dc18-0051. This is the first study to demonstrate effective prevention of exercise-induced hypogylcemia with mini-dose glucagon when compared to insulin reduction and glucose ingestion in individuals with type 1 diabetes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hovelmann U, Olsen MB, Mouritzen U, Lamers D, Kronshage B, Heise T. Low doses of dasiglucagon consistently increase plasma glucose levels from hypoglycaemia and euglycaemia in people with type 1 diabetes mellitus. Diabetes Obes Metab. 2019;21(3):601–10. https://doi.org/10.1111/dom.13562.

    Article  CAS  PubMed  Google Scholar 

  75. Steineck IIK, Ranjan A, Schmidt S, Clausen TR, Holst JJ, Norgaard K. Preserved glucose response to low-dose glucagon after exercise in insulin-pump-treated individuals with type 1 diabetes: a randomised crossover study. Diabetologia. 2019;62(4):582–92. https://doi.org/10.1007/s00125-018-4807-8.

    Article  CAS  PubMed  Google Scholar 

  76. Yale JF, Dulude H, Egeth M, Piche CA, Lafontaine M, Carballo D, et al. Faster use and fewer failures with needle-free nasal glucagon versus injectable glucagon in severe hypoglycemia rescue: a simulation study. Diabetes Technol Ther. 2017;19(7):423–32. https://doi.org/10.1089/dia.2016.0460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sherr JL, Ruedy KJ, Foster NC, Piche CA, Dulude H, Rickels MR, et al. Glucagon nasal powder: a promising alternative to intramuscular glucagon in youth with type 1 diabetes. Diabetes Care. 2016;39(4):555–62. https://doi.org/10.2337/dc15-1606.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Haidar A, Rabasa-Lhoret R, Legault L, Lovblom LE, Rakheja R, Messier V, et al. Single- and dual-hormone artificial pancreas for overnight glucose control in type 1 diabetes. J Clin Endocrinol Metab. 2016;101(1):214–23. https://doi.org/10.1210/jc.2015-3003.

    Article  CAS  PubMed  Google Scholar 

  79. The bihormonal ilet bionic pancreas feasibility study. https://ClinicalTrials.gov/show/NCT03840278.

  80. Glucagon infusion in T1D patients with recurrent severe hypoglycemia: effects on counterregulatory responses. https://clinicaltrials.gov/ct2/show/NCT03490942.

  81. Thornton P, Truong L, Reynolds C, Rodriguez L, Cummins M, Junaidi K. Continuous infusion of subcutaneous ready-to-use stable liquid glucagon has similar efficacy to intravenous reconstituted glucagon in children with congenital hyperinsulinism. Pediatric Academic Society; Baltimore, MD 2019.

  82. Open-label trial evaluating efficacy and safety of dasiglucagon in children with congenital hyperinsulinism. https://ClinicalTrials.gov/show/NCT03777176.

  83. CSI-glucagon for prevention of hypoglycemia in children with congenital hyperinsulinism. https://ClinicalTrials.gov/show/NCT02937558.

  84. Laguna Sanz AJ, Mulla CM, Fowler KM, Cloutier E, Goldfine AB, Newswanger B, et al. Design and clinical evaluation of a novel low-glucose prediction algorithm with mini-dose stable glucagon delivery in post-bariatric hypoglycemia. Diabetes Technol Ther. 2018;20(2):127–39. https://doi.org/10.1089/dia.2017.0298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

Michael R. Rickels is supported in part by Public Health Service Research Grant R01 DK091331. Diva D. De Leon is supported in part by Public Health Service Research Grants R01 DK056268 and R01 DK098517.

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Authors and Affiliations

  1. Division of Endocrinology and Diabetes, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Colin P. Hawkes & Diva D. De Leon

  2. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Colin P. Hawkes, Diva D. De Leon & Michael R. Rickels

  3. Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, 12-134 Smilow Center for Translational Research, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA

    Diva D. De Leon & Michael R. Rickels

  4. Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Michael R. Rickels

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  1. Colin P. Hawkes
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Correspondence to Michael R. Rickels.

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Conflict of Interest

Colin P. Hawkes declares that he has no conflict of interest.

Diva D. De Leon reports grants from National Institute of Health, during the conduct of the study, grants and personal fees from Zealand Pharma A/S, grants and personal fees from Crinetics, personal fees from Soleno Therapeutics, non-financial support from Dexcom, personal fees from Novartis Pharmaceuticals, personal fees from NovoNordisk, personal fees from Xoma Corporation, personal fees from ProSciento, other from Merck, outside the submitted work.

Michael R. Rickels reports grants from National Institutes of Health, during the conduct of the study, grants and personal fees from Xeris Pharmaceuticals and personal fees from Hua Medicine, outside the submitted work.

Human and Animal Rights and Informed Consent

All procedures performed in studies conducted by the authors involving human participants were in accordance with the ethical standards of the University of Pennsylvania or Children’s Hospital of Philadelphia Institutional Review Boards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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This article is part of the Topical Collection on Therapies and New Technologies in the Treatment of Diabetes

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Hawkes, C.P., De Leon, D.D. & Rickels, M.R. Novel Preparations of Glucagon for the Prevention and Treatment of Hypoglycemia. Curr Diab Rep 19, 97 (2019). https://doi.org/10.1007/s11892-019-1216-4

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