Factors Influencing the Effectiveness of Glucagon for Preventing Hypoglycemia

Abstract

Glucagon may fail to prevent hypoglycemia when insulin on board is high or when glucagon delivery is delayed due to overestimation of glucose by the sensor. Improvements in sensor accuracy and delivery of larger or earlier glucagon doses when insulin on board is high may further reduce the frequency of hypoglycemia.

Glucagon responses to exercise-induced hypoglycaemia are improved by somatostatin receptor type 2 antagonism in a rat model of diabetes

“…Although hepatic glucagon resistance is also a possibility, a recent study by Castle et al [40] showed that hepatic glucagon resistance does not occur in humans with type 1 diabetes, even after multiple exposures to exogenous glucagon. In our study, high prevailing insulin concentrations likely promoted increased glucose disposal during muscular exercise [41], thus limiting the effectiveness of glucagon at increasing hepatic glucose production, as is seen in patients with type 1 diabetes on bi-hormonal pump therapy who still develop hypoglycaemia with glucagon administration at rest [42,43] One alternative explanation for the failure to protect against hypoglycaemia in this study might be that glucagon concentrations, although increased with SSTR2a treatment, could not be sustained as the glucose was reaching its nadir (Fig. 4).…”

A Controlled Study of the Effectiveness of an Adaptive Closed-Loop Algorithm to Minimize Corticosteroid-Induced Stress Hyperglycemia in Type 1 Diabetes

“…Since glucose tended to be high as a result of the corticosteroid administration, glucagon was not used as often as in our earlier study. 7,31 Over the course of the 28 experiments, glucagon was administered 70 times and the duration of administration was typically 5 or 10 min at a mean rate of 16 μg per minute. When the hour after glucagon administration was examined for efficacy, glucose did not fall to <70 mg/dl in 80% of cases and did not fall to <60 mg/dl in 86% of cases.…”

“…This change was instituted after we observed impaired efficacy of glucagon when IOB was high in a previous study. 31 For each closed-loop study, subjects arrived at the research unit after fasting overnight. Meals were given 1, 5, 10, 25, and 29 h after beginning the study (breakfast, lunch, dinner, breakfast, and lunch).…”

Glucagon for hypoglycemic episodes in insulin-treated diabetic patients: a systematic review and meta-analysis with a comparison of glucagon with dextrose and of different glucagon formulations

“…Measure of efficacy was the number/percentage of patients/subjects not responding to glucagon according to criteria pre-defined by the authors of each paper. All the data are tabulated in Tables 1 and 2. Sixteen studies fulfilled the inclusion criteria [33,42,44,[50][51][52][53][54][55][56][57][58][59][60][61][62]. Details of data source and searches, study selection, data extraction and quality assessment, data synthesis, ER emergency room, SH severe hypoglycemia, IV intravenous, IM intramuscular; AEs adverse events, FDA food and drugs administration, EMS emergency medical services, and NEMSIS national emergency medical services information system and analysis have already been published [12].…”

“…In contrast, Mulhauser et al [51] reported four cases of failure among 53 diabetic patients treated with IM glucagon in the pre-hospital setting. Similarly, Slama et al [52] observed a 14 % ''non responder'' rate among 20 children affected by type 1 diabetes mellitus during incident episodes of severe hypoglycemia; in experiments with a bi-hormonal artificial endocrine pancreas, Castle et al [53] showed that glucagon administration failed to prevent hypoglycemia in 7 out of 19 episodes in diabetic subjects, and it was observed that circulating insulin levels at the start of glucagon delivery were significantly higher in failures compared to successes. Again, data from the National EMS Information System (NEMSIS) regarding the pre-hospital EMS response to diabetic emergencies in the United States indicated that, in 2011, glucagon was administered 18,483 times in runs listed in the dataset, with 436 times requiring a repeat dose [54]; the Food and Drug Administration (FDA), and Health Canada, reported 82 and 8 failures out of a total of 568 reports from 2011 to 2012 and of 20 reports from 1997 to 2012, respectively [55,56].…”