Mini-Dose Glucagon as a Novel Approach to Prevent Exercise-Induced Hypoglycemia in Type 1 Diabetes

Rickels, Michael R.; DuBose, Stephanie N.; Toschi, Elena; Beck, Roy W.; Verdejo, Alandra; Wolpert, Howard; Cummins, Martin J.; Newswanger, Brett; Riddell, Michael C.; Peleckis, Amy J.; Evangelisti, M. I.; Dalton-Bakes, Cornelia; Fuller, Carissa; Wolpsert, Howard; Middelbeek, Roeland; Jye, Louis Seow Cherng; Shahar, Jacqueline; Slyne, Christine; Edwards, Stephanie S.; Castillo, Astrid Atakov; Prestrelski, Steve

doi:10.2337/dc18-0051

Cited by 66 publications

(48 citation statements)

References 25 publications

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“…clamp method could have avoided this bias [34]. Recently, results were published from a study in a similar group of individuals performing 45 min of exercise at four different sessions under conditions of: (1) no intervention; (2) 50% basal insulin reduction; (3) 40 g oral glucose tablets; or (4) after injections of 150 μg glucagon [15]. In contrast to our study, the investigators found that none of the participants receiving glucagon before exercise experienced hypoglycaemia.…”

Section: Discussionmentioning

confidence: 99%

“…A recently published study found that an injection of 150 μg glucagon may be more effective than insulin reduction for preventing exercise-induced hypoglycaemia and may also result in less post-intervention hyperglycaemia (i.e. less time spent in hyperglycaemia and fewer hyperglycaemic episodes) than ingestion of carbohydrates [15]. Currently, the use of low doses of glucagon to manage mild hypoglycaemia is not recommended by official guidelines for type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2019

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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/m 2 (21-30 kg/m 2 ); 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 NCT02882737Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4807-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Therefore, mini dose glucagon has been proposed as a novel approach to prevent exercise-induced hypoglycemia in T1DM patients. This approach has been demonstrated by Michael et al [34]. In their study, 15 adults with T1DM were treated with continuous subcutaneous insulin infusion and exercised while fasting in the morning at about 25% VO 2 max for 45 minutes under the condition of no intervention (control), 50% basal insulin reduction, 40-g oral glucose tablets, or 150 μg subcutaneous glucagon (MDG).…”

Section: Mini Dose Glucagonmentioning

confidence: 99%

The hypoglycemia associated autonomic failure triggered by exercise in the patients with “brittle” diabetes and the strategy for prevention

Mao

Zhou

et al. 2019

Endocr J

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Exercise is a fundamental component of diabetes management. However, choosing inappropriate type or timing of exercise is associated with mild or severe hypoglycemia either during exercise or several hours after exercise. Several studies have shown that impaired counterregulatory responses triggers hypoglycemia. Therefore, in this investigation, we explored the appropriate intensity and time of exercise in patients with diabetes. The mechanisms of counterregulatory responses and hypoglycemia associated autonomic failure (HAAF), as well as the strategies for preventing episodes of hypoglycemia after exercise were also investigated. In this study, we obtained the following results: 1) High intensity interval exercise is more suitable for diabetic patients. 2) Morning exercise reduces nocturnal hypoglycemia risks compared with midday, afternoon and evening exercise. 3) Hypoglycemia can be prevented by dietary approach, reduction or suspension of insulin dose, use of mini dose glucagon, caffeine, mitigation methods, prediction algorithm, autonomic feedback controlled close-loop insulin delivery, real time continuous glucose monitoring. Based on these results we concluded that exercise may cause severe hypoglycemia or induce blunted response in patients with diabetes. For Diabetes Mellitus (DM) patients, the intensity and time of exercise influence the occurrence of hypoglycemia. This review summarizes the clinical characteristics of different types of exercises and time of exercise that can be potentially used to educate and guide patients regarding the role of exercise in standard of care.

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“…One option for further improvement might be dual‐hormone artificial pancreas (DHAP) systems which, in addition to insulin, use glucagon to counteract the effect of excessive insulin . The administration of mini‐doses of glucagon in a DHAP system has been shown to be more effective in preventing hypoglycaemia than the suspension of insulin delivery alone, particularly in situations of rapidly decreasing glucose levels, such as late postprandial hypoglycaemia or physical activity . As currently available glucagon formulations show limited stability, daily glucagon renewal is required, making the use of DHAP systems cumbersome .…”

Section: Introductionmentioning

confidence: 99%

“…delivery alone, particularly in situations of rapidly decreasing glucose levels, such as late postprandial hypoglycaemia or physical activity. [4][5][6][7][8][9] As currently available glucagon formulations show limited stability, daily glucagon renewal is required, making the use of DHAP systems cumbersome. [10][11][12] Because of this practical limitation, mainly shortterm efficacy and safety have been demonstrated to date.…”

mentioning

confidence: 99%

Low doses of dasiglucagon consistently increase plasma glucose levels from hypoglycaemia and euglycaemia in people with type 1 diabetes mellitus

Hövelmann

Olsen

Mouritzen

et al. 2018

Diabetes Obesity Metabolism

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Aim To characterize the pharmacokinetic and pharmacodynamic properties of dasiglucagon, a novel, stable and liquid formulated glucagon analogue, during hypoglycaemic and euglycaemic conditions in adult patients with type 1 diabetes mellitus. Research Design and Methods In this randomized double‐blind trial, 17 patients received four single subcutaneous doses (0.03, 0.08, 0.2 and 0.6 mg) of dasiglucagon (4 mg/mL formulation) under euglycaemic (plasma glucose [PG] 5.6 mmol/L [100 mg/dL]) or hypoglycaemic (PG 3.1‐3.7 mmol/L [56‐66 mg/dL]) conditions. For comparison, three doses (0.03, 0.08 and 0.2 mg) of a commercial glucagon formulation (Eli Lilly) were investigated at euglycaemia. Results Dasiglucagon led to a dose‐dependent and rapid increase in PG levels across all doses tested (mean increases 30 minutes post‐dosing of 2.2 to 4.4 mmol/L [39‐80 mg/dL] from euglycaemia and 1.3 to 5.2 mmol/L [24‐94 mg/dL] from hypoglycaemia), which was higher than the rises elicited by similar doses of commercial glucagon (1.7‐3.9 mmol/L [30‐71 mg/dL]). The median time (range) to an increase in PG of >1.1 mmol/L (20 mg/dL) was <20 (18‐19.5) minutes with 0.03 mg dasiglucagon and, with higher doses, the median times ranged from 9 to 15 minutes (commercial glucagon 13‐14 minutes). In hypoglycaemia, 0.03 and 0.08 mg dasiglucagon re‐established normoglycaemia (PG ≥3.9 mmol/L [70 mg/dL]) within median times of 14 and 10 minutes, respectively. Nausea and vomiting occurred more frequently with dasiglucagon than with commercial glucagon at identical doses which might be attributable to dasiglucagon's higher potency. Conclusion Dasiglucagon rapidly increased PG at doses of 0.03 to 0.6 mg in a dose‐dependent manner and, therefore, is a good candidate for use in dual‐hormone artificial pancreas systems.

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Mini-Dose Glucagon as a Novel Approach to Prevent Exercise-Induced Hypoglycemia in Type 1 Diabetes

Abstract: MDG may be more effective than insulin reduction for preventing exercise-induced hypoglycemia and may result in less postintervention hyperglycemia than ingestion of carbohydrate.

Cited by 66 publications

References 25 publications

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

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

The hypoglycemia associated autonomic failure triggered by exercise in the patients with “brittle” diabetes and the strategy for prevention

Low doses of dasiglucagon consistently increase plasma glucose levels from hypoglycaemia and euglycaemia in people with type 1 diabetes mellitus

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