Mini-dose glucagon might be a better option for treating exercise-induced hypoglycemia than carbohydrate ingestion or insulin dose reduction.
Exercise is a critical component in the management of diabetes, regardless of type. Exercise can be beneficial in its ability to maintain an ideal body composition, achieve glycemic control, maintain appropriate lipid levels, and promote wellness overall. Previous studies have concluded that exercise in people with type 1 diabetes can reduce insulin doses, HbA1c, and cardiovascular complications (e.g. hypertension). patients often do not implement this practice.
Despite its many benefits, exercise for people who have type 1 diabetes pose some problems, such as hypoglycemia. Aerobic exercise often causes low blood glucose. The American Diabetes Association recommends self-monitoring of blood glucose in patients with intensive insulin regimens prior to exercise, education in hypoglycemia-causing scenarios, reductions in insulin dosage, and education of procedures to combat hypoglycemia. Current methods of treating hypoglycemia depend on the patient’s ability to ingest glucose and their level of consciousness; typically, patients who are conscious are recommended to consume glucose/carbohydrates while those who are unconscious or incapable of oral consumption are advised to use caregiver-administered glucagon.
Recently, a non-aqueous liquid glucagon was developed at various doses of 75µg, 150µg, and 300µg. A previous study found 150µg non-aqueous liquid glucagon, or mini-dose glucagon (MDG), is as effective as oral glucose tablets at restoring normoglycemia.
The primary outcome of this study aimed to determine if MDG, administered prior to exercise, could prevent post-exercise hypoglycemia in patients with type 1 diabetes. This treatment was compared with no intervention, glucose tablet use, and basal insulin dose reduction.
From June 2016 to February 2017, 15 participants, fitting the following inclusion criteria, were enrolled: 18-64 years old, at least 2 years of type 1 diabetes, received continuous subcutaneous insulin by pump, exercised regularly, maintained a BMI <30 kg/m2. Participants followed specific pre-exercise requirements (i.e. overnight fast for at least 8 hours, plasma glucose 100-140 mg/dL, avoidance of vigorous exercise 24 hours prior to sessions) and replaced subcutaneous glucose sensors for continuous glucose monitoring prior to sessions. Participants were blinded and randomly placed into one of four groups: 1) no intervention (control), 2) basal rate reduction by 50%, which was returned to normal 45 minutes post-exercise, 3) 40g of oral glucose, 4) subcutaneous injection of 150µg glucagon. Blood samples and subsequent blood glucose levels were obtained pre- and post-exercise at scheduled intervals.
The primary outcome, MDG compared to each group, was analyzed with linear mixed model with repeated measures. Secondary outcomes include hypoglycemic (<70mg/dL) or hyperglycemic (≥250mg/dL) occurrences during exercise or recovery, glucose levels, percentage of time spent at various glucose levels, and number of events with glucose <54mg/dL and <70mg/dL for 15 minutes.
Analysis showed that prior to exercise, plasma glucose, glucagon, and insulin concentrations were similar in both control and treatment groups. During exercise, the plasma glucose concentration for both insulin reduction and control groups decreased while MDG and glucose tablet groups increased (p < 0.001) (refer to Table 1).
|Table 1: Plasma Glucose & Plasma Glucagon Results|
|Time||Group||Plasma Glucose (mg/dL)A||Plasma Glucose (mg/dL)B|
|At end of exerciseA
After early recoveryB
|Control||86 ± 30||90 ± 34|
|Insulin||85 ± 25||92 ± 34|
|Glucose||174 ± 59||222 ± 66|
|MDG||161 ± 39||163 ± 49|
|Time||Group||Plasma Glucagon (pg/mL)|
|Control||55 ± 12|
|Insulin||53 ± 9|
|Glucose||61 ± 21|
|MDG||424 ± 201|
During exercise, plasma glucagon concentrations remained similar while the MDG group showed increased concentrations (see Table 1). The levels remained elevated even 30 minutes after exercise sessions were ended (p < 0.001). During exercise and early recovery, insulin levels remained similar for each of the groups. Post-meal results included plasma glucose concentrations that became similar for each group, plasma glucagon concentrations for the MDG group that declined until levels were nearly equal with the other groups, and plasma insulin levels that increased for all four groups. Furthermore, hypo- and hyperglycemia occurrences were documented for each group (see Table 2). Incidents of nausea and vomiting were documented; no subjects reported nausea during exercise, however, two subjects reported nausea after their post-exercise meal.
|Table 2: Number of Hypo- and Hyperglycemic Events|
|Time||Group||Number of Events|
|During exercise &
|Time||Group||Number of Events|
|During exercise & Post-exercise||Control||0|
The evidence suggests that MDG is a viable alternative for the treatment of exercise-induced hypoglycemia. The results showed that MDG is superior to no intervention and insulin dose reduction at preventing hypoglycemia. Furthermore, previous studies have shown that MDG is as effective as glucose tablets. Still, this study has shown that glucose tablets, while effective, will more likely produce hyperglycemia compared to MDG. Though nausea is a concern due to the nature of glucagon, this study concluded that the timing of the post-exercise meal led to nausea rather than treatment with MDG. Nausea may be prevented by postponing the meal after MDG administration.
Despite showing some significant results, there remains questions about the study methods, particularly with the basal insulin reduction and the timing of glucose tablet ingestion. Regarding insulin dose reduction, the study chose a 50% insulin reduction 5 minutes before exercise sessions, a common recommendation. However, this group still experienced more hypoglycemic events compared to the glucose tablet and MDG group. This consequence indicates the possible need for greater reductions in insulin dose, however further studies are needed to confirm this. Another area of concern was the choice to administer 20g of glucose 5 minutes before exercise and 20g of glucose 30 minutes after exercise. It is possible hyperglycemia resulted because of the timing, but additional studies are needed to determine if 20g of glucose 5 minutes prior is sufficient in preventing hypoglycemia. Overall, additional long-term studies are needed to determine if MDG is truly a good option to treat exercise-induced hypoglycemia.
- Low dose, non-aqueous liquid glucagon (or mini-dose glucagon) was found to be as effective in the prevention of exercise induced hypoglycemia as standard glucagon.
- Mini-dose glucagon may be an option for carbohydrate ingestion as this method can result in hyperglycemia.
- According to this study, insulin reduction and no treatment prior to exercise can cause hypoglycemia, while treatment with mini-dose glucagon did not cause hypoglycemia.
Rickels, M.R., DuBose, S.N., Toschi, E., Beck, R.W., Verdejo, A.S., Wolpert, H., Cummins, M.J., Newswanger, B., and Riddell, M.C. Mini-Dose Glucagon as a Novel Approach to Prevent Exercise-Induced Hypoglycemia in Type 1 Diabetes. Diabetes Care. 2018. https://doi.org/10.2337/dc18-0051.
Riddell, M., Gallen, I., Smart, C., Taplin, C., Adolfsson, P., Lumb, A., Kowalski, A., Rabasa-Lhoret, R., McCrimmon, R., Hume, C., et al. Exercise Management in type 1 diabetes: a consensus statement. The Lancet: Diabetes & Endocrinology. 5.5 (2017): 377-390. https://doi.org/10.1016/S2213-8587(17)30014-1.
American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in Diabetes-2018. Diabetes Care. 41.Supplement 1 (2018): S55-S64.
Kaytie A. Weierstahl, Pharm.D. Candidate, LECOM School of Pharmacy