Preserved glucose response to low-dose glucagon after exercise in insulin-pump-treated individuals with type 1 diabetes: a randomised crossover study
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.
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): HbA1c 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).
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.
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.
The study was funded by the Danish Diabetes Academy founded by Novo Nordisk foundation and by an unrestricted grant from Zealand Pharma
KeywordsExercise Glucagon Insulin pump-treated Type 1 diabetes
Continuous glucose monitor
General Practice Physical Activity Questionnaire
HR reserve calculated as 220 – age
HR at resting
HR during cycling calculated as 50% × (HRmax − HRrest) + HRrest
Predictive low glucose management
Visual analogue scale
The authors thank the study participants and acknowledge the laboratory assistance by A. Sloth Andersen (Department of Endocrinology Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark) and J. Bjerager and J. Laigard (medical students, University of Copenhagen). Furthermore, we thank L. Brus Albæk (Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark) for analysing the glucagon, R. Raml (Joanneum Research, Graz, Austria) for the aspart analysis, J. Nymann (Department of Biochemistry, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark) for analysing triacylglycerols and NEFA, and G. Kølander Hansen (Obesity Research, Novo Nordisk, Måløv, Denmark) for measuring plasma total ketones.
Some of the data were presented at the Advanced Technologies and Treatments for Diabetes (ATTD) meeting, Vienna Austria and the EASD meeting, Berlin, Germany, in 2018.
IIKS, AR, SS and KN conceived the idea and designed the study. IIKS performed the studies, analysed the data and wrote and edited the manuscript. AR performed some of the studies, analysed the data and reviewed and edited the manuscript. JJH and TRC provided data and reviewed, edited and approved the final manuscript. SS and KN reviewed, edited and approved the final manuscript. IIKS, AR and KN take full responsibility for the content of this article and are responsible for the integrity of the work as a whole. All authors made substantial contributions to conception and design of the study, acquisition of data or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content and all gave final approval of the version to be published.
This study was funded by the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation, and by an unrestricted grant from Zealand Pharma. Dexcom provided transmitters, receivers and sensors for the study. The Danish Diabetes Academy, Zealand Pharma and Dexcom hold no rights to the study results. The study sponsors were not involved in the design of the study, the collection, analysis, or interpretation of data, writing the report or the decision to submit the report for publication.
Duality of interest
None of the investigators has personal or financial interests in the conduct or the outcomes of the project. IIKS has received speaker grants from Roche Diabetes Care and Rubin Medical. SS has served on the continuous glucose monitoring advisory board of Roche Diabetes Care. JJH has consulted for Merck Sharp & Dome, Novo Nordisk and Roche. TRC works for Novo Nordisk A/S and own shares in Novo Nordisk A/S and Zealand Pharma A/S. KN serves as adviser to Medtronic, Abbott and Novo Nordisk A/S, owns shares in Novo Nordisk A/S, has received research grants from Novo Nordisk A/S and Roche Diabetes Care and has received fees for speaking from Medtronic, Roche Diabetes Care, Rubin Medical, Sanofi, Novo Nordisk A/S, Zealand Pharma and Bayer. AR declares that there is no duality of interest associated with his contribution to this manuscript.
- 3.Ploug T, Galbo H, Richter E (1984) Increased muscle glucose uptake during contractions: no need for insulin. Am J Phys 247(October):E726–E731Google Scholar
- 5.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–E509Google Scholar
- 8.Riddell MC, Gallen IW, Smart CE et al (2017) Review exercise management in type 1 diabetes: a consensus statement. Lancet Diabetes Endocrinol 8587:1–14Google Scholar
- 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
- 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 CrossRefPubMedGoogle Scholar
- 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 Google Scholar
- 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):307–315Google Scholar
- 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 133Google Scholar
- 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 CrossRefPubMedGoogle Scholar
- 34.Ranjan A (2018) Glucagon treatment in type 1 diabetes -with focus on restoring plasma glucose during mild hypoglycemia. Dan Med J 65:B5449Google Scholar
- 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 CrossRefPubMedPubMedCentralGoogle Scholar