Rapid Correction of the Hypoglycemia State in Nonhuman Primates Using a Glucagon Long-Dissolving Microneedle Patch.

The timely administration of glucagon is a standard clinical practice for the treatment of severe hypoglycemia. However, the process involves cumbersome steps, including the reconstitution of labile glucagon and filling of the syringe, which cause considerable delays in emergency situations. Moreover, multiple dosages are often required to prevent the recurrence of the hypoglycemic episode because of the short half-life of glucagon in plasma. Herein, we develop a glucagon-loaded long-dissolving microneedle (GLMN) patch that exhibits the properties of fast onset and sustained activity for the effective treatment of severe hypoglycemia. Three types of MN patches were fabricated with different dimensions (long, medium, and short). The longer MN patch packaged a higher dosage of glucagon and exhibited supreme mechanical strength compared to the shorter one. Additionally, the longer MN patch could insert more deeply into the skin, resulting in higher permeability of glucagon across the skin tissue and more rapid systemic absorption as compared with the shorter MN patch. The GLMN patch was observed to reverse the effects of hypoglycemia within 15 min of application in animal models (specifically, rat and rhesus monkey models) and maintained long-term glycemic control, owing to highly efficient drug permeation and the drug reservoir effect of the MN base. The current study presents a promising strategy for the rapid reversal of severe hypoglycemia that exhibits the desirable properties of easy use, high efficiency, and sustained action.

Nasal Glucagon Is Easier to Use and More Preferred and Needs Less Effort to Administer Than Injectable Glucagon: User Perceptions of Glucagon Administration During Severe Hypoglycemia Simulation.

OBJECTIVE: To evaluate ease of use, user preference, and effort required to use nasal glucagon (NG) versus injectable glucagon needing reconstitution (IG) in simulations of severe hypoglycemia (SH)-a challenge for caregivers of a person with diabetes (PWD) in real-life. METHODS: In this randomized, crossover study, high-fidelity manikins placed in mock representative high-stress environments were used to simulate an SH rescue. Thirty-two trained (by PWDs) and 33 untrained participants attempted NG and IG administrations and then completed questionnaires regarding ease of use, preference, and workload for each device. RESULTS: More trained users agreed that NG was easy to use (87.1% vs 54.8%) and prepare (80.6% vs 51.6%) and had confidence to use NG correctly (93.5% vs 54.8%) than those who agreed the same for IG (P < .05). Untrained users reported similar differences, favoring NG in all parameters. In direct device comparison across all simulations, 80.6% of trained users and 93.5% of untrained users preferred NG over IG-a preference largely sustained regardless of the success or failure of administration. Among PWDs, 90.3% considered NG device as safer than IG during an SH event. In the assessment of workload required to administer glucagon, the weighted mean National Aeronautics and Space Administration Task Load Index scores were 37.8 for NG and 48.4 for IG (P = .0020). CONCLUSION: Participants in this study considered NG easier, more preferred, required less effort for administration, and more intuitive to use than reconstitutable IG, irrespective of whether there was prior training. NG improves the potential for successful administration of glucagon, better preparedness, and increased adoption of glucagon for SH rescue.

Impact of pharmacist outreach on glucagon prescribing.

BACKGROUND: Hypoglycemia is a major limiting factor in the glycemic management of diabetes. As a method of treating hypoglycemia, the American Diabetes Association recommends glucagon to be prescribed for all individuals at increased risk of clinically impactful hypoglycemia. Glucagon Emergency Kits have been shown to reduce emergency department visits and overall health care costs. Despite these known benefits, glucagon continues to be underprescribed. Previous pharmacist-led interventions embedded in a single clinic have been shown to positively affect the rate of glucagon prescribing in patients with diabetes. OBJECTIVE: This study aimed to compare the rate of glucagon prescribing between quality improvement remote pharmacist outreach to multiple primary care and endocrinology specialty clinics and the control group in 1 month following a pharmacist-led provider outreach. METHODS: This was a single-center, 2-arm study with a simple randomization design. RESULTS: On pharmacist outreach, 61 of 109 patients (56.0%) in the outreach group were prescribed a glucagon product within 1 month of their primary care provider (PCP) or endocrinology appointment compared with 1 of 113 (0.9%) of patients in the control group (P < 0.001). Glucagon prescribing occurred in 25 of 35 Black patients (71.4%) compared with 36 of 73 white patients (49.3%) in the outreach group. Glucagon prescribing was associated with race (P = 0.03; chi-square test). CONCLUSIONS: The pharmacist-led provider outreach before a PCP or endocrinology appointment has a positive and statistically significant impact on glucagon prescribing rates. The pharmacist outreach had a higher impact on Black patients than white patients, possibly because of a lower rate of glucagon prescribing in Black patients before the outreach.

Evaluation of the cost and medical resource use outcomes associated with nasal glucagon versus injectable glucagon for treatment of severe hypoglycemia in people with diabetes in Canada: a modeling analysis.

OBJECTIVES: Treatments for severe hypoglycemia aim to restore blood glucose through successful administration of rescue therapy, and choosing the most effective and cost-effective option will improve outcomes for patients and may reduce costs for healthcare payers. The present analysis aimed to compare costs and use of medical services with nasal glucagon and injectable glucagon in people with type 1 and 2 diabetes in Canada when used to treat severe hypoglycemic events when impaired consciousness precludes treatment with oral carbohydrates using an economic model, based on differences in the frequency of successful administration of the two interventions. METHODS: A decision tree model was prepared in Microsoft Excel to project outcomes with nasal glucagon and injectable glucagon. The model structure reflected real-world decision-making and treatment outcomes, based on Canada-specific sources. The model captured the use of glucagon, emergency medical services (EMS), emergency room, inpatient stay, and follow-up care. Costs were accounted for in 2019 Canadian dollars (CAD). RESULTS: Nasal glucagon was associated with reduced use of all medical services compared with injectable glucagon. EMS call outs were projected to be reduced by 45%, emergency room treatments by 52%, and inpatient stays by 13%. Use of nasal glucagon was associated with reduced direct, indirect, and combined costs of CAD 1,249, CAD 460, and CAD 1,709 per severe hypoglycemic event, respectively, due to avoided EMS call outs and hospital costs, resulting from a higher proportion of successful administrations. CONCLUSIONS: When a patient with type 1 or type 2 diabetes is being treated for a severe hypoglycemic event when impaired consciousness precludes treatment with oral carbohydrate, use of nasal glucagon was projected to be dominant versus injectable glucagon in Canada reducing costs and use of medical services.

Hypoglycemia requiring paramedic assistance among adults in southwestern Ontario, Canada: a population-based retrospective cohort study.

BACKGROUND: People with diabetes mellitus commonly experience hypoglycemia, but they may not necessarily present to hospital after severe hypoglycemia requiring paramedic assistance. We sought to describe the incidence and characteristics of calls for hypoglycemia requiring paramedic assistance among adults in southwestern Ontario, Canada, and to determine predictors of hospital transport. METHODS: This population-based retrospective cohort study used data extracted from ambulance call reports (ACRs) of 8 paramedic services of the Southwest Ontario Regional Base Hospital Program from January 2008 to June 2014. We described calls in which treatment for hypoglycemia was administered, summarized the incidence of hypoglycemia calls and performed logistic regression to determine predictors of hospital transport. RESULTS: Out of 470 467 ACRs during the study period, 9185 paramedic calls occurred in which hypoglycemia treatment was administered to an adult (mean age 60.2 yr, 56.8% male, 81.1% with documented diabetes). Refusal of hospital transport occurred in 2243 (24.4%) of calls. Documented diabetes diagnosis (adjusted odds ratio [OR] 0.82, 95% confidence interval [CI] 0.69-0.96), higher capillary blood glucose (adjusted OR 0.31, 95% CI 0.22-0.44) and overnight calls (adjusted OR 0.80, 95% CI 0.72-0.91) were associated with lower odds of hospital transport. Higher-acuity calls (adjusted OR 2.05, 95% CI 1.58-2.66) were associated with higher odds of transport. The estimated annual incidence rate of hypoglycemia requiring paramedic assistance was 108 per 10 000 people with diabetes per year. INTERPRETATION: Hypoglycemia requiring paramedic assistance in southwestern Ontario is common, and close to 25% of calls do not result in hospital transport. Physicians managing diabetes care may be unaware of patients' hypoglycemia requiring paramedic care, suggesting a potential gap in follow-up care; we suggest that paramedics play an important role in identifying those at high recurrence risk and communicating with their care providers.

New Fast Acting Glucagon for Recovery from Hypoglycemia, a Life-Threatening Situation: Nasal Powder and Injected Stable Solutions.

The goal of diabetes care is to achieve and maintain good glycemic control over time, so as to prevent or delay the development of micro- and macrovascular complications in type 1 (T1D) and type 2 diabetes (T2D). However, numerous barriers hinder the achievement of this goal, first of all the frequent episodes of hypoglycemia typical in patients treated with insulin as T1D patients, or sulphonylureas as T2D patients. The prevention strategy and treatment of hypoglycemia are important for the well-being of patients with diabetes. Hypoglycemia is strongly associated with an increased risk of cardiovascular disease in diabetic patients, due probably to the release of inflammatory markers and prothrombotic effects triggered by hypoglycemia. Treatment of hypoglycemia is traditionally based on administration of carbohydrates or of glucagon via intramuscular (IM) or subcutaneous injection (SC). The injection of traditional glucagon is cumbersome, such that glucagon is an under-utilized drug. In 1983, it was shown for the first time that intranasal (IN) glucagon increases blood glucose levels in healthy volunteers, and in 1989-1992 that IN glucagon is similar to IM glucagon in resolving hypoglycemia in normal volunteers and in patients with diabetes, both adults and children. IN glucagon was developed in 2010 and continued in 2015; in 2019 IN glucagon obtained approval in the US, Canada, and Europe for severe hypoglycemia in children and adults. In the 2010s, two ready-to-use injectable formulations, a stable non-aqueous glucagon solution and the glucagon analog dasiglucagon, were developed, showing an efficacy similar to traditional glucagon, and approved in the US in 2020 and in 2021, respectively, for severe hypoglycemia in adults and in children. Fast-acting glucagon (nasal administration and injected solutions) appears to represent a major breakthrough in the treatment of severe hypoglycemia in insulin-treated patients with diabetes, both adults and children. It is anticipated that the availability of fast-acting glucagon will expand the use of glucagon, improve overall metabolic control, and prevent hypoglycemia-related complications, in particular cardiovascular complications and cognitive impairment.

Glucagon as a Therapeutic Approach to Severe Hypoglycemia: After 100 Years, Is It Still the Antidote of Insulin?

Hypoglycemia represents a dark and tormented side of diabetes mellitus therapy. Patients treated with insulin or drug inducing hypoglycemia, consider hypoglycemia as a harmful element, which leads to their resistance and lack of acceptance of the pathology and relative therapies. Severe hypoglycemia, in itself, is a risk for patients and relatives. The possibility to have novel strategies and scientific knowledge concerning hypoglycemia could represent an enormous benefit. Novel available glucagon formulations, even now, allow clinicians to deal with hypoglycemia differently with respect to past years. Novel scientific evidence leads to advances concerning physiopathological mechanisms that regulated glycemic homeostasis. In this review, we will try to show some of the important aspects of this field.

Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening.

Allosteric modulators have emerged with many potential pharmacological advantages as they do not compete the binding of agonist or antagonist to the orthosteric sites but ultimately affect downstream signaling. To identify allosteric modulators targeting an extra-helical binding site of the glucagon-like peptide-1 receptor (GLP-1R) within the membrane environment, the following two computational approaches were applied: structure-based virtual screening with consideration of lipid contacts and ligand-based virtual screening with the maintenance of specific allosteric pocket residue interactions. Verified by radiolabeled ligand binding and cAMP accumulation experiments, two negative allosteric modulators and seven positive allosteric modulators were discovered using structure-based and ligand-based virtual screening methods, respectively. The computational approach presented here could possibly be used to discover allosteric modulators of other G protein-coupled receptors.

Glucagon delivery - An overview of current and future devices.

Glucagon is crucial in the treatment of Type 1 diabetes mellitus due to the prevalence of hypoglycemia in patients with this disorder. Hypoglycemia can be life-threatening, leading to loss of consciousness, and requiring emergency glucagon to reverse the effects. Emergency kits are difficult to use, requiring reconstitution of glucagon, which itself is not stable for lengthy periods. Approaches have aimed to improve stability which has allowed for use in pens or pumps. Glucagon can now also be delivered intranasally. This review discusses the history of glucagon, its current delivery methods as well as some modern approaches being introduced.

Dasiglucagon: an effective medicine for severe hypoglycemia.

PURPOSE: Patients with type 1 diabetes mellitus (T1DM) receiving insulin therapy commonly suffer from insulin-mediated hypoglycemia and require glucagon for glycemic control to achieve normal plasma glucose (PG) levels. Severe hypoglycemia will endanger the life of patients and require intervention. Stable glucagon analog dasiglucagon was approved for the treatment of patients with severe hypoglycemia and is administered via Zegalogue autoinjector/Zegalogue prefilled syringe. The main purpose of this review article is to review the basic properties and clinical effects of dasiglucagon. METHOD: We search related literature on CNKI, Web of Science and PubMed by keywords dasiglucagon, hypoglycemia, type 1 diabetes, glucagon. Carry out a careful review of the included literature. Dasiglucagon information on clinicaltrials.gov and https://www.fda.gov/ has been adopted. RESULTS AND CONCLUSION: Dasiglucagon is a novel peptide analog of human glucagon, which can effectively rescue insulin-induced severe hypoglycemia in patients with T1DM and rapidly increase glycemic levels in a small dose under normal and hypoglycemic conditions. It has been proven that dasiglucagon has definite stability and solubility in aqueous formulations. Dasiglucagon has a higher absorption rate and longer plasma elimination half-life than traditional reconstituted glucagon. In three randomized, double-blind, placebo-controlled trials in children aged 6 to 17 years and adults with T1DM the median time to glycemic recovery in 10 min after dasiglucagon administration was significantly faster than placebo and 99% of patients recovered within 15 min after subcutaneous injection of dasiglucagon in the key phase 3 clinical trial. The most common adverse reactions in these phase 3 trials were vomiting, nausea, diarrhea, headache, and injection site pain.

Dual-hormone artificial pancreas for management of type 1 diabetes: Recent progress and future directions.

Over the last few years, technological advances have led to tremendous improvement in the management of type 1 diabetes (T1D). Artificial pancreas systems have been shown to improve glucose control compared with conventional insulin pump therapy. However, clinically significant hypoglycemic and hyperglycemic episodes still occur with the artificial pancreas. Postprandial glucose excursions and exercise-induced hypoglycemia represent major hurdles in improving glucose control and glucose variability in many patients with T1D. In this regard, dual-hormone artificial pancreas systems delivering other hormones in addition to insulin (glucagon or amylin) may better reproduce the physiology of the endocrine pancreas and have been suggested as an alternative tool to overcome these limitations in clinical practice. In addition, novel ultra-rapid-acting insulin analogs with a more physiological time-action profile are currently under investigation for use in artificial pancreas devices, aiming to address the unmet need for further improvements in postprandial glucose control. This review article aims to discuss the current progress and future outlook in the development of novel ultra-rapid insulin analogs and dual-hormone closed-loop systems, which offer the next steps to fully closing the loop in the artificial pancreas.

Glucagon Reduces Neutrophil Migration and Increases Susceptibility to Sepsis in Diabetic Mice.

Sepsis is one of the most common comorbidities observed in diabetic patients, associated with a deficient innate immune response. Recently, we have shown that glucagon possesses anti-inflammatory properties. In this study, we investigated if hyperglucagonemia triggered by diabetes might reduce the migration of neutrophils, increasing sepsis susceptibility. 21 days after diabetes induction by intravenous injection of alloxan, we induced moderate sepsis in Swiss-Webster mice through cecum ligation and puncture (CLP). The glucagon receptor (GcgR) antagonist des-his1-[Glu9]-glucagon amide was injected intraperitoneally 24h and 1h before CLP. We also tested the effect of glucagon on CXCL1/KC-induced neutrophil migration to the peritoneal cavity in mice. Neutrophil chemotaxis in vitro was tested using transwell plates, and the expression of total PKA and phospho-PKA was evaluated by western blot. GcgR antagonist restored neutrophil migration, reduced CFU numbers in the peritoneal cavity and improved survival rate of diabetic mice after CLP procedure, however, the treatment did no alter hyperglycemia, CXCL1/KC plasma levels and blood neutrophilia. In addition, glucagon inhibited CXCL1/KC-induced neutrophil migration to the peritoneal cavity of non-diabetic mice. Glucagon also decreased the chemotaxis of neutrophils triggered by CXCL1/KC, PAF, or fMLP in vitro. The inhibitory action of glucagon occurred in parallel with the reduction of CXCL1/KC-induced actin polymerization in neutrophils in vitro, but not CD11a and CD11b translocation to cell surface. The suppressor effect of glucagon on CXCL1/KC-induced neutrophil chemotaxis in vitro was reversed by pre-treatment with GcgR antagonist and adenylyl cyclase or PKA inhibitors. Glucagon also increased PKA phosphorylation directly in neutrophils in vitro. Furthermore, glucagon impaired zymosan-A-induced ROS production by neutrophils in vitro. Human neutrophil chemotaxis and adherence to endothelial cells in vitro were inhibited by glucagon treatment. According to our results, this inhibition was independent of CD11a and CD11b translocation to neutrophil surface or neutrophil release of CXCL8/IL-8. Altogether, our results suggest that glucagon may be involved in the reduction of neutrophil migration and increased susceptibility to sepsis in diabetic mice. This work collaborates with better understanding of the increased susceptibility and worsening of sepsis in diabetics, which can contribute to the development of new effective therapeutic strategies for diabetic septic patients.

Pharmacokinetics of Intraperitoneally Delivered Glucagon in Pigs: A Hypothesis of First Pass Metabolism.

BACKGROUND AND OBJECTIVE: Artificial pancreases administering low-dose glucagon in addition to insulin have the scope to improve glucose control in patients with diabetes mellitus type 1. If such a device were to deliver both hormones intraperitoneally, it would mimic normal physiology, which may be beneficial. However, the pharmacokinetic properties of glucagon after intraperitoneal administration are not well known. Hence, the current study aims to evaluate the relationship between the amount of intraperitoneally delivered glucagon and pharmacokinetic variables in a pig model. METHODS: Pharmacokinetic data was retrieved from experiments on 19 anaesthetised pigs and analysed post hoc. The animals received a single intraperitoneal bolus of glucagon ranging from 0.30 to 4.46 µg/kg. Plasma glucagon was measured every 2-10 min for 50 min. RESULTS: Peak plasma concentration and area under the time-plasma concentration curve of glucagon correlated positively with the administered dose, and larger boluses provided a relatively greater increase. The mean (standard deviation) time to maximum glucagon concentration in plasma was 11 (5) min, and the mean elimination half-life of glucagon in plasma was 19 (7) min. CONCLUSIONS: Maximum plasma concentration and area under the time-plasma concentration curve of glucagon increase nonlinearly in relation to the intraperitoneally administered glucagon dose. We hypothesise that the results are compatible with a satiable first-pass metabolism in the liver. Time to maximum glucagon concentration in plasma and the elimination half-life of glucagon in plasma seem independent of the drug dose.

Dasiglucagon, a next-generation ready-to-use glucagon analog, for treatment of severe hypoglycemia in children and adolescents with type 1 diabetes: Results of a phase 3, randomized controlled trial.

BACKGROUND: Dasiglucagon, a next-generation, ready-to-use aqueous glucagon analog formulation, has been developed to treat severe hypoglycemia in individuals with diabetes. OBJECTIVE: The aim of this trial was to evaluate the safety and efficacy of dasiglucagon in pediatric individuals with type 1 diabetes (T1DM). Participants were children and adolescents (6-17 years) with T1DM. METHODS: In this randomized double-blind trial, 42 participants were randomly allocated (2:1:1) to a single subcutaneous (SC) injection of dasiglucagon (0.6 mg), placebo, or reconstituted glucagon (GlucaGen; dosed per label) during insulin-induced hypoglycemia. The primary endpoint was time to plasma glucose (PG) recovery (first PG increase ≥20 mg/dL after treatment initiation without rescue intravenous glucose). The primary comparison was dasiglucagon vs. placebo; glucagon acted as a reference. RESULTS: The median time (95% confidence interval) to PG recovery following SC injection was 10 min (8-12) for dasiglucagon vs. 30 min (20 to -) for placebo (P < .001); the median time for glucagon was 10 min (8-12), which did not include the time taken to reconstitute the lyophilized powder. PG recovery was achieved in all participants in the dasiglucagon and glucagon groups within 20 min of dosing compared to 2 out of 11 patients (18%) with placebo. The most frequent adverse events were nausea and vomiting, as expected with glucagon treatment. CONCLUSIONS: Consistent with adult phase 3 trials, dasiglucagon rapidly and effectively restored PG levels following insulin-induced hypoglycemia in children and adolescents with T1DM, with an overall safety profile similar to glucagon.

Dasiglucagon: First Approval.

Dasiglucagon (Zegalogue®) is an antihypoglycaemic agent being developed by Zealand Pharma for the treatment of hypoglycaemia, type 1 diabetes mellitus (T1DM) management and congenital hyperinsulinism. In March 2021, dasiglucagon received its first approval in the USA for the treatment of severe hypoglycaemia in paediatric and adult patients with diabetes aged 6 years and above. Dasiglucagon, a glucagon analogue, is available as a single-dose autoinjector or prefilled syringe for subcutaneous injection. This article summarizes the milestones in the development of dasiglucagon leading to this first approval for hypoglycaemia.

Prolonged Glucagon Infusion Does Not Affect Energy Expenditure in Individuals with Overweight/Obesity: A Randomized Trial.

OBJECTIVE: The aim of this study was to determine the effects of prolonged (72 hours) glucagon administration at a low dose (LD) (12.5 ng/kg/min) and high dose (HD) (25 ng/kg/min) on energy expenditure (EE) in healthy individuals with overweight or obesity. METHODS: Thirty-one healthy participants with overweight or obesity (BMI of 27-45 kg/m2 , 26-55 years old, 23 females) were randomized into LD, HD, or placebo groups and underwent 72-hour intravenous infusion of glucagon. Whole-room calorimetry was used to assess EE and substrate use during five overnight stays (2 days at baseline, 3 days of infusion) and during two 24-hour stays (baseline vs. day 3). Blood was sampled at regular intervals throughout the inpatient stay and analyzed for glucagon and biomarkers of metabolism. RESULTS: HD infusion elevated plasma glucagon levels compared with the placebo and LD infusion (P < 0.001). Sleeping, basal, and 24-hour EE was not significantly different among groups at any time point. Those receiving HD had significantly higher basal fat oxidation (Fat Ox) at days 2 and 3 than those receiving the placebo (P < 0.05); however, no differences in 24-hour Fat Ox were observed among groups (baseline vs. day 3). CONCLUSIONS: An HD plasma glucagon infusion over 72 hours does not increase any aspects of EE in healthy individuals with overweight or obesity.

Optimization of Truncated Glucagon Peptides to Achieve Selective, High Potency, Full Antagonists.

Antagonism of glucagon's biological action is a proven strategy for decreasing glucose in diabetic animals and patients. To achieve full, potent, and selective suppression, we chemically optimized N-terminally truncated glucagon fragments for the identification and establishment of the minimum sequence peptide, [Glu9]glucagon(6-29) amide (11) as a full antagonist in cellular signaling and receptor binding (IC50 = 36 nM). Substitution of Phe6 with l-3-phenyllactic acid (Pla) produced [Pla6, Glu9]glucagon(6-29) amide (21), resulting in a 3-fold improvement in receptor binding (IC50 = 12 nM) and enhanced antagonist potency. Further substitution of Glu9 and Asn28 with aspartic acid yielded [Pla6, Asp28]glucagon amide (26), which demonstrated a further increase in inhibitory potency (IC50 = 9 nM), and improved aqueous solubility. Peptide 26 and a palmitoylated analogue, [Pla6, Lys10(γGluγGlu-C16), Asp28]glucagon(6-29) amide (31), displayed sustained duration in vivo action that successfully reversed glucagon-induced glucose elevation in mice.

An Evaluation of Glucagon Injection Anxiety and Its Association with the Fear of Hypoglycemia among the Parents of Children with Type 1 Diabetes

Objective: Hypoglycemia is a common acute complication of type 1 diabetes (T1D), which may cause seizure, loss of consciousness, and temporary motor or sensory impairment. Glucagon administration is an effective way of treating severe hypoglycemia, especially in a free-living setting. Nonetheless, families have difficulties in managing severe hypoglycemia due to their anxiety and challenges with current glucagon administration techniques. The aim of the current study was to explore the associations between parental fear of hypoglycemia (FoH) and their general anxiety level, and in particular, their attitudes towards and thoughts on glucagon administration. Methods: Parents of children with T1D completed questionnaires assessing background and clinical information, FoH, generalized anxiety disorder (GAD) and parental anxiety for glucagon administration (PAGA). Results: Sixty-eight parents participated. Positive correlations were found between parental GAD-7 score and both FoH and the number of night-time blood glucose measurements and there was a negative correlation with the child's age. Parents mean self-evaluation score of their competence in glucagon administration was 6 (standard deviation±2.9) on a scale of 0 to 10. Unsurprisingly, this score was negatively correlated with the PAGA scores. There was no significant difference between children using continuous glucose monitoring system and self-monitoring of blood glucose in terms of parental FoH, anxiety and misconceptions about glucagon administration. Conclusion: The results showed that parents of children with T1D had anxiety and fear connected with hypoglycemia and glucagon administration. Structured and practical training should be implemented to increase parents' self-confidence including annual refresher training for home glucagon administration.