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Diabetologia

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01-04-2019 | Insulins | Article

Preserved glucose response to low-dose glucagon after exercise in insulin-pump-treated individuals with type 1 diabetes: a randomised crossover study

Authors: Isabelle I. K. Steineck, Ajenthen Ranjan, Signe Schmidt, Trine R. Clausen, Jens J. Holst, Kirsten Nørgaard

Published in: Diabetologia | Issue 4/2019

Abstract

Aims/hypothesis

This study aimed to compare the increase in plasma glucose after a subcutaneous injection of 200 μg glucagon given after 45 min of cycling with resting (study 1) and to investigate the effects of glucagon when injected before compared with after 45 min of cycling (study 2). We hypothesised that: (1) the glucose response to glucagon would be similar after cycling and resting; and (2) giving glucagon before the activity would prevent the exercise-induced fall in blood glucose during exercise and for 2 h afterwards.

Methods

Fourteen insulin-pump-treated individuals with type 1 diabetes completed three visits in a randomised, placebo-controlled, participant-blinded crossover study. They were allocated by sealed envelopes. Baseline values were (mean and range): HbA_1c 54 mmol/mol (43–65 mmol/mol) or 7.1% (6.1–8.1%); age 45 years (23–66 years); BMI 26 kg/m² (21–30 kg/m²); and diabetes duration 26 years (8–51 years). At each visit, participants consumed a standardised breakfast 2 h prior to 45 min of cycling or resting. A subcutaneous injection of 200 μg glucagon was given before or after cycling or after resting. The glucose response to glucagon was compared after cycling vs resting (study 1) and before vs after cycling (study 2).

Results

The glucose response to glucagon was higher after cycling compared with after resting (mean ± SD incremental peak: 2.6 ± 1.7 vs 1.8 ± 2.0 mmol/l, p = 0.02). As expected, plasma glucose decreased during cycling (−3.1 ± 2.8 mmol/l) but less so when glucagon was given before cycling (−0.9 ± 2.8 mmol/l, p = 0.002). The number of individuals reaching glucose values ≤3.9 mmol/l was the same on the 3 days.

Conclusions/interpretation

Moderate cycling for 45 min did not impair the glucose response to glucagon compared with the glucose response after resting. The glucose fall during cycling was diminished by a pre-exercise injection of 200 μg glucagon; however, no significant difference was seen in the number of events of hypoglycaemia.

Trial registration

Clinicaltrials.gov NCT02882737

Funding

The study was funded by the Danish Diabetes Academy founded by Novo Nordisk foundation and by an unrestricted grant from Zealand Pharma

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Bolli GB, Dimitriadis GD, Pehling GB et al (1984) Abnormal glucose counterregulation after subcutaneous insulin in insulin-dependent diabetes mellitus. N Engl J Med 310(26):1706–1711. https://doi.org/10.1056/NEJM198406283102605 CrossRefPubMed

Reddy R, El Youssef J, Winters-Stone K et al (2018) The impact of exercise on sleep in adults with type 1 diabetes. Diabetes Obes Metab 20(2):443–447. https://doi.org/10.1111/dom.13065 CrossRefPubMed

Ploug T, Galbo H, Richter E (1984) Increased muscle glucose uptake during contractions: no need for insulin. Am J Phys 247(October):E726–E731

Tansey MJ, Tsalikian E, Beck RW et al (2006) The effects of aerobic exercise on glucose and counterregulatory hormone concentrations in children with type 1 diabetes. Diabetes Care 29:20–25CrossRef

Wasserman DH, Williams PE, Lacy DB, Goldstein RE, Cherrington AD (1989) Exercise-induced fall in insulin and hepatic carbohydrate metabolism during muscular work. Am J Phys 256:E500–E509

Mallad A, Hinshaw L, Schiavon M et al (2015) Exercise effects on postprandial glucose metabolism in type 1 diabetes: a triple-tracer approach. Am J Physiol Endocrinol Metab 308(12):E1106–E1115. https://doi.org/10.1152/ajpendo.00014.2015 CrossRefPubMedPubMedCentral

Cryer PE (2009) Exercise-related hypoglycemia-associated autonomic failure in diabetes. Diabetes 58(9):1951–1952. https://doi.org/10.2337/db09-0834 CrossRefPubMedPubMedCentral

Riddell MC, Gallen IW, Smart CE et al (2017) Review exercise management in type 1 diabetes: a consensus statement. Lancet Diabetes Endocrinol 8587:1–14

Pinsker JE, Kraus A, Gianferante D et al (2016) Techniques for exercise preparation and management in adults with type 1 diabetes. Can J Diabetes 40(6):503–508. https://doi.org/10.1016/j.jcjd.2016.04.010 CrossRefPubMed

10.

Zaharieva DP, Riddell MC (2017) Insulin management strategies for exercise in diabetes. Can J Diabetes 41(5):507–516. https://doi.org/10.1016/j.jcjd.2017.07.004 CrossRefPubMed

11.

Collier A, Steedman DJ, Patrick AW et al (1987) Comparison of intravenous glucagon and dextrose in treatment of severe hypoglycemia in an accident and emergency department. Diabetes Care 10(6):712–715. https://doi.org/10.2337/diacare.10.6.712 CrossRefPubMed

12.

Haymond MW, Redondo MJ, McKay S et al (2016) Nonaqueous, mini-dose glucagon for treatment of mild hypoglycemia in adults with type 1 diabetes: a dose-seeking study. Diabetes Care 39(3):465–468. https://doi.org/10.2337/dc15-2124 CrossRefPubMedPubMedCentral

13.

Ranjan A, Schmidt S, Madsbad S, Holst JJ, 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(4):410–418. https://doi.org/10.1111/dom.12627 CrossRefPubMed

14.

Haymond MW, Schreiner B (2001) Mini-dose glucagon rescue for hypoglycemia in children with type 1 diabetes. Diabetes Care 24(4):643–645. https://doi.org/10.2337/diacare.24.4.643 CrossRefPubMed

15.

Rickels M, Dubose S, Wolpert H et al (2018) Mini-dose glucagon as a novel approach to prevent exercise-induced hypoglycemia in type 1 diabetes. Diabetes Care 41(9):1909–1916. https://doi.org/10.2337/dc18-0051 CrossRefPubMed

16.

Hövelmann U, Bysted BV, Mouritzen U et al. (2017) Pharmacokinetic and pharmacodynamic characteristics of dasiglucagon, a novel soluble and stable glucagon analog. Diabetes Care: 41:531–537. https://doi.org/10.2337/dc17-1402

17.

Sherr JL, Ruedy KJ, Foster NC et al (2016) Glucagon nasal powder: a promising alternative to intramuscular glucagon in youth with type 1 diabetes. Diabetes Care 39(4):555–562. https://doi.org/10.2337/dc15-1606 CrossRefPubMedPubMedCentral

18.

Ranjan A, Schmidt S, Damm-Frydenberg C et al (2017) Low-carbohydrate diet impairs the effect of glucagon in the treatment of insulin-induced mild hypoglycemia: a randomized crossover study. Diabetes Care 40(1):132–135. https://doi.org/10.2337/dc16-1472 CrossRefPubMed

19.

Ranjan A, Nørgaard K, Tetzschner R et al (2018) Effects of preceding ethanol intake on glucose response to low-dose glucagon in individuals with type 1 diabetes: a randomized, placebo-controlled, crossover study. Diabetes Care 41(4):797–806. https://doi.org/10.2337/dc17-1458 CrossRefPubMed

20.

Gold AE, MacLeod KM, Frier BM (1994) Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia. Diabetes Care 17(7):697–703. https://doi.org/10.2337/diacare.17.7.697 CrossRefPubMed

21.

Pedersen-Bjergaard U, Pramming S, Heller SR et al (2004) Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection. Diabetes Metab Res Rev 20(6):479–486. https://doi.org/10.1002/dmrr.482 CrossRefPubMed

22.

Høi-Hansen T, Pedersen-Bjergaard U, Thorsteinsson B (2010) Classification of hypoglycemia awareness in people with type 1 diabetes in clinical practice. J Diabetes Complicat 24(6):392–397. https://doi.org/10.1016/j.jdiacomp.2009.07.006 CrossRefPubMed

23.

Scheen AJ, Castillo MJ, Lefèbvre PJ (1996) Assessment of residual insulin secretion in diabetic patients using the intravenous glucagon stimulatory test: methodological aspects and clinical applications. Diabetes Metab 22(6):397–406PubMed

24.

UK Department of Health and Social Care (2013) The General Practice Physical Activity Questionnaire (GPPAQ) report. Department of Health, London, p 2006 Available from: www.gov.uk/government/publications/general-practice-physical-activity-questionnaire-gppaq

25.

Walsh J, Roberts R, Bailey T (2011) Guidelines for optimal bolus calculator settings in adults. J Diabetes Sci Technol 5(1):129–135. https://doi.org/10.1177/193229681100500118 CrossRefPubMedPubMedCentral

26.

Karvonen MJ, Kentala E, Mustala O (1957) The effects of training on heart rate; a longitudinal study. Ann Med Exp Biol Fenn 35(3):307–315PubMed

27.

Gerich JE, Woerle HJ, Meyer C, Stumvoll M (2001) Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 24(2):382–391. https://doi.org/10.2337/diacare.24.2.382 CrossRef

28.

Petersen KF, Price TB, Bergeron R (2004) Regulation of net hepatic glycogenolysis and gluconeogenesis during exercise: impact of type 1 diabetes. J Clin Endocrinol Metab 89(9):4656–4664. https://doi.org/10.1210/jc.2004-0408 CrossRefPubMedPubMedCentral

29.

Greenhaff PL, Hultman E, Harris RC (2004) Carbohydrate metabolism. In: Poortmans JR (ed) Principles of exercise biochemistry, 3rd, rev ed. Med Sport Sci. Basel, Karger, vol 46, Brussels, pp 133

30.

Bélanger P, Couturier K, Latour MG, Lavoie JM (2000) Effects of supranormal liver glycogen content on hyperglucagonemia-induced liver glycogen breakdown. Eur J Appl Physiol 83:328–335CrossRef

31.

Lavoie C (2005) Glucagon receptors: effect of exercise and fasting. Can J Appl Physiol 30(3):313–327. https://doi.org/10.1139/h05-124 CrossRefPubMed

32.

Melançon A, Gagnon V, Milot M et al (2013) Liver glucagon receptors (GluR): effect of exercise and fasting on binding characteristics, GluR-mRNA, and GluR protein content in rats. Horm Metab Res 45(10):716–721. https://doi.org/10.1055/s-0033-1349853 CrossRefPubMed

33.

Schmidt S, Finan DA, Duun-Henriksen AK et al (2012) Effects of everyday life events on glucose, insulin, and glucagon dynamics in continuous subcutaneous insulin infusion-treated type 1 diabetes: collection of clinical data for glucose modeling. Diabetes Technol Ther 14(3):210–217. https://doi.org/10.1089/dia.2011.0101 CrossRefPubMed

34.

Ranjan A (2018) Glucagon treatment in type 1 diabetes -with focus on restoring plasma glucose during mild hypoglycemia. Dan Med J 65:B5449

35.

Brazeau A-S, Rabasa-Lhoret R, Strychar I, Mircescu H (2008) Barriers to physical activity among patients with type 1 diabetes. Diabetes Care 31(11):2108–2109. https://doi.org/10.2337/dc08-0720 CrossRefPubMedPubMedCentral

36.

Zaharieva D, Yavelberg L, Jamnik V, Cinar A, Turksoy K, Riddell MC (2017) The effects of basal insulin suspension at the start of exercise on blood glucose levels during continuous versus circuit-based exercise in individuals with type 1 diabetes on continuous subcutaneous insulin infusion. Diabetes Technol Ther 19(6):370–378. https://doi.org/10.1089/dia.2017.0010 CrossRefPubMedPubMedCentral

37.

Steineck I, Ranjan A, Nørgaard K, Schmidt S (2017) Sensor-augmented insulin pumps and hypoglycemia prevention in type 1 diabetes. J Diabetes Sci Technol 11(1):50–58. https://doi.org/10.1177/1932296816672689 CrossRefPubMed

38.

Russell SJ, El-Khatib FH, Sinha M et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes. N Engl J Med 371(4):313–325. https://doi.org/10.1056/NEJMoa1314474 CrossRefPubMedPubMedCentral

Title: Preserved glucose response to low-dose glucagon after exercise in insulin-pump-treated individuals with type 1 diabetes: a randomised crossover study
Authors: Isabelle I. K. Steineck
Ajenthen Ranjan
Signe Schmidt
Trine R. Clausen
Jens J. Holst
Kirsten Nørgaard
Publication date: 01-04-2019
Publisher: Springer Berlin Heidelberg
Keywords: Insulins
Hypoglycemia
Insulins
Type 1 Diabetes
Published in: Diabetologia / Issue 4/2019
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-018-4807-8

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Preserved glucose response to low-dose glucagon after exercise in insulin-pump-treated individuals with type 1 diabetes: a randomised crossover study

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Trial registration

Funding

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Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Trial registration

Funding

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