Doses Of Glucagon Research Articles

In silico validation of a customizable fully-autonomous artificial pancreas with coordinated insulin, glucagon and rescue carbohydrates

Artificial pancreas systems should be designed considering different patient profiles, which is challenging from a control theory perspective. In this paper, a flexible-hybrid dual-hormone control algorithm for an artificial pancreas is proposed. The algorithm handles announced/unannounced meals by means of a non-interacting feedforward scheme that safely incorporates prandial boluses. Also, a coordination strategy is employed to distribute the counter-regulatory actions, which can be delivered as a continuous glucagon infusion via an automated pump, as an oral rescue carbohydrate recommendation, or as a rescue glucagon dose recommendation to be administrated through a glucagon pen. The different configurations of the proposed controller were evaluated in silico using a 14-day virtual scenario with random meal intakes and exercise sessions, achieving above 80% time-in-range and low time spent in hypoglycemia.

Analysis on the contribution of glucagon receptors to glucose dynamics in type 1 diabetes

The glucagon effect is understudied in type 1 diabetes (T1D) simulators, without a clear consensus on the pharmacodynamics of glucagon over glucose. Glucagon receptors dynamics could present a significant contribution to T1D simulators, making them more physiologically accurate without an excessive increase in complexity. This work analyzes the receptors model contributions to glucose dynamics using a model proposed in previous work. Then, the model is assessed from two different perspectives: (1) A clinical dataset of the influence of diet (high or low carbohydrate content) on two consecutive glucagon doses (100 and 500 μg) is used to identify the model parameters and (2) three other glucagon action models from the literature are also identified to serve as comparators. Different identification methods are used to adapt to the distinctive features of the dataset. The root mean square error (RMSE) and the Akaike Information Criterion (AIC) were the discerning metrics used to compare the models fittings. Results show that the receptors model offers the lowest RMSE and AIC in contrast to the comparators. This model will hence be helpful in the development of accurate T1D simulators.

Population pharmacokinetics and pharmacodynamics of nasal glucagon in patients with type 1 or 2 diabetes.

The objective was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of glucagon after injectable or nasal administration and confirm the appropriate therapeutic dose of nasal glucagon (NG) for adult patients. Six clinical studies with PK and five clinical studies with PD (glucose) data were included in the analysis. Doses ranging from 0.5 to 6 mg NG, and 0.5 to 1 mg injectable glucagon were studied. A total of 6284 glucagon and 7130 glucose concentrations from 265 individuals (patients and healthy participants) were available. Population PK/PD modeling was performed using NONMEM. Glucagon exposure and glucose response were simulated for patients administered various doses of NG to confirm the optimal dose. Glucagon PK was well-described with a single compartment disposition with first-order absorption and elimination processes. Bioavailability of NG relative to injectable glucagon was 16%. Exposure-response modeling revealed that lower baseline glucose was associated with higher maximum drug effect. The carry-over effect from prior insulin administration was incorporated into the model through a time-dependent increase in elimination rate of glucose. Simulations showed that more than 99% of hypoglycemic adult patients would experience treatment success, defined as an increase in blood glucose to ≥70 mg/dL or an increase of ≥20 mg/dL from nadir within 30 min after administration of NG 3 mg. The population PK/PD model adequately described the PK and PD profiles of glucagon after nasal administration. Modeling and simulations confirmed that NG 3 mg is the most appropriate dose for rescue treatment during hypoglycemia emergencies.

High Doses of Exogenous Glucagon Stimulate Insulin Secretion and Reduce Insulin Clearance in Healthy Humans.

Glucagon is generally defined as a counter-regulatory hormone with a primary role to raise blood glucose concentrations by increasing endogenous glucose production (EGP) in response to hypoglycemia. However, glucagon has long been known to stimulate insulin release, and recent preclinical findings support a paracrine action of glucagon directly on islet β-cells that augments secretion. In mice, the insulinotropic effect of glucagon is glucose dependent and not present during basal euglycemia. To test the hypothesis that the relative effects of glucagon on hepatic and islet function were also varied with blood glucose, a group of healthy subjects received glucagon (100 ng/kg) during fasting glycemia or experimental hyperglycemia (~150 mg/dl) on two separate days. During fasting euglycemia, administration of glucagon caused blood glucose to rise due to increased EGP, with a delayed increase of insulin secretion. When given during experimental hyperglycemia, glucagon caused a rapid, 3-fold increase in insulin secretion, as well as a more gradual increase in EGP. Under both conditions, insulin clearance was decreased in response to glucagon infusion. The insulinotropic action of glucagon, which is proportional to elevated levels of blood glucose, suggests distinct physiologic roles in the fasting and prandial states.

Glucagon Prescribing and Costs Among U.S. Adults With Diabetes, 2011-2021.

To characterize contemporary trends in glucagon fill rates and expenditures in a nationwide cohort of adults with diabetes overall and by key demographic and clinical characteristics. In this retrospective cohort study, we examined 1) glucagon fill rates per 1,000 person-years and 2) patient out-of-pocket and health plan costs per filled glucagon dose among adults with diabetes included in OptumLabs Data Warehouse between 1 January 2011 and 31 March 2021. The study population comprised 2,814,464 adults with diabetes with a mean age of 62.8 (SD 13.2) years. The overall glucagon fill rate decreased from 2.91 to 2.28 per 1,000 person-years (-22%) over the study period. In groups at high risk for severe hypoglycemia, glucagon fill rates increased from 22.46 to 36.76 per 1,000 person-years (64%) among patients with type 1 diabetes, 11.64 to 16.63 per 1,000 person-years (43%) among those treated with short-acting insulin, and 16.08 to 20.12 per 1,000 person-years (25%) among those with a history of severe hypoglycemia. White patients, women, individuals with high income, and commercially insured patients had higher glucagon fill rates compared with minority patients, males, individuals with low income, and Medicare Advantage patients, respectively. Total cost per dosing unit increased from $157.97 to $275.32 (74%) among commercial insurance beneficiaries and from $150.37 to $293.57 (95%) among Medicare Advantage beneficiaries. Glucagon fill rates are concerningly low and declined between 2011 and 2021 but increased in appropriate subgroups with type 1 diabetes, using short-acting insulin, or with a history of severe hypoglycemia. Fill rates were disproportionately low among minority patients and individuals with low income.

Validation of a model of glucagon action including glucagon receptor dynamics under consecutive doses in low and high-carb diets

Accurate mathematical models are needed to simulate and validate dual-hormone control algorithms for Artificial pancreas systems. Glucagon receptors are a key component for glucagon to have effect on glucose. However, they are not usually taken into consideration in the development of models for type 1 diabetes (T1D). In previous work, a model proposal integrating glucagon receptor dynamics into endogenous glucose production (EGP) was successfully validated under single glucagon boluses. In this work, this model is further validated using a dataset of clinical data where two glucagon doses (100 and 500 µg) are consecutively administered to 10 patients with T1D in two different settings: low and high-carb diets (total of 20 datasets). The model performance is compared to three other EGP models from literature under different identification criteria. The receptors model achieved the lowest root mean squared error regardless of the diet and the individualization method.

S2352 No Soup for You: The Case of an Intramucosal Hematoma Found During Endoscopy for an Esophageal Food Impaction

Introduction: Esophageal food impaction (EFI) is third most common gastrointestinal emergency, which is commonly associated with obstructive lesions such as peptic strictures and Schatzki rings, eosinophilic esophagitis and rarely motility disorders. Endoscopic therapy is the mainstay option for the management of EFI if medical therapy fails. The most commonly impacted foods include beef, chicken, pork, and undercooked vegetables with liquids rarely causing an impaction. Complications from a prolonged EFI can result in mucosal disruption to an esophageal perforation. We present an unusual case of an esophageal intramucosal hematoma found in a during endoscopic retrieval of an esophageal impaction. Case Description/Methods: An 80-year-old male presented with a 2-hour history of foreign body sensation in his throat that began while eating hamburger meat and soup with potatoes. He began coughing up a large amount of mucus at symptom onset and was unable to finish his meal. He has been unable to swallow solids or liquids. History was significant for esophageal peptic strictures in the past requiring dilations. After 2 doses of glucagon failed to help pass the bolus, the patient underwent endoscopic removal of the esophageal food impaction. During the procedure, food was found in the middle and lower thirds of the esophagus and was subsequently removed with suction cap and rat toothed forceps. The esophagus was tortious and was noted to have decreased and abnormal movement throughout with a moderate stenosis found at the gastroesophageal junction. The middle and lower third of the esophagus had localized severe erythema, suspicious for the presence of intramucosal hemorrhage (Figure). The patient tolerated a diet after endoscopy and discharged home. Discussion: Esophageal food impactions are uncommon and are commonly associated with stricture and rings. Complications from a prolonged food impaction include mucosal disruption however findings of an intramucosal hematoma are rare. Intramucosal hematoma present with chest pain, dysphagia, and hematemesis. This patient presented with dysphagia however had no other pain or episodes of hematemesis. In this patient it is unclear whether his presentation was due to an acute EFI causing an intramucosal hematoma or whether the ingestion of soup caused an intramucosal hematoma resulting in an EFI. Nevertheless, one should take caution during endoscopic evaluation for patients who presented with an EFI.Figure 1.: Localized severe erythema suspicious for intramucosal hemorrhage. (1a., 1b., 1c.), Lower third of the esophagus. (1d.)- Gastroesophageal junction.

Metabolic acidosis during continuous glucagon therapy for neonatal hypoglycemia.

Refractory neonatal hypoglycemia may be treated with glucagon infusions, which have been associated with thrombocytopenia and hyponatremia. After anecdotally noting metabolic acidosis during glucagon therapy in our hospital, an outcome not previously reported in the literature, we aimed to quantify occurrence of metabolic acidosis (base excess >-6) as well as thrombocytopenia and hyponatremia during treatment with glucagon. We performed a single-centre retrospective case series. Descriptive statistics were used and subgroups compared with Chi-Square, Fisher's Exact Test, and Mann-Whitney U testing. Sixty-two infants (mean birth gestational age 37.2 weeks, 64.5% male) were treated with continuous glucagon infusions for median 10 days during the study period. 41.2% were preterm, 21.0% were small for gestational age, and 30.6% were infants of diabetic mothers. Metabolic acidosis was seen in 59.6% and was more common in infants who were not born to diabetic mothers (75% versus 24% in infants of diabetic mothers, P<0.001). Infants with versus without metabolic acidosis had lower birth weights (median 2,743 g versus 3,854 g, P<0.01) and were treated with higher doses of glucagon (0.02 versus 0.01 mg/kg/h, P<0.01) for a longer duration (12.4 versus 5.9 days, P<0.01). Thrombocytopenia was diagnosed in 51.9% of patients. In addition to thrombocytopenia, metabolic acidosis of unclear etiology appears to be very common with glucagon infusions for neonatal hypoglycemia, especially in lower birth weight infants or those born to mothers without diabetes. Further research is needed to elucidate causation and potential mechanisms.

276-OR: Impaired Glucagon-Mediated Suppression of VLDL-TG Secretion in Individuals with MAFLD

Background: Individuals with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) have both elevated triglyceride and glucagon levels, although glucagon suppresses the very-low-density lipoprotein-triglyceride (VLDL-TG) secretion in lean individuals. Therefore, we hypothesized that the glucagon-mediated suppression of VLDL-TG secretion is impaired in MAFLD, with greater impairment in individuals with steatohepatitis (MASH) than individuals with simple steatosis (MAFL) . Methods: 28 participants were included in the study (seven overweight control subjects (CON) , patients with MAFL, and with MASH) . We performed a somatostatin-clamp with replacement doses of growth hormone, insulin (0.2 mU/kg/min) and glucagon to suppress endogenous hormone production. Participants were studied during low-dose glucagon infusion (0.65 ng/kg/min, t=0─270 min, LowG) followed by a high-dose glucagon infusion (1.5 ng/kg/min, t=270─450 min, HighG) . We used 14C-labeled VLDL-TG and 3H-labeled glucose tracers to evaluate VLDL-TG secretion and endogenous glucose production (EGP) . Results: HighG suppressed VLDL-TG secretion compared to LowG in all groups, but with a greater reduction in VLDL-TG secretion in CON than in the MAFLD groups (CON 36% (±SD 19%) ; MAFL 10% (±SD 8%) ; MASH 13% (±SD 16%) , p&amp;lt;0.01) . Thus, the suppression was similarly mitigated in both MAFLD groups. This led to insignificant reductions in plasma VLDL-TG, TG and VLDL-TG oxidation rates in the CON group, in contrast to stable or increasing values in the MAFLD groups (CON vs. MAFLD delta-values, p&amp;lt;0.01, p=0.02 and p=0.04) , respectively) . EGP was similar in all groups throughout the LowG period and rose similarly when increasing glucagon infusion rate. Conclusions: Patients with MAFLD, MAFL as well as MASH, have an impaired glucagon-mediated suppression of VLDL-TG secretion which is a probable contributing factor to the dyslipidemia and the increased cardiovascular risk observed in individuals with MAFLD. NCT04042142 Disclosure S.Heebøll: None. J.R.Risikesan: None. H.Gronbaek: Other Relationship; ARLA, Research Support; AbbVie Inc., Intercept Pharmaceuticals, Inc., Speaker's Bureau; AstraZeneca, Novartis AG. E.Søndergaard: None. S.Nielsen: None. Funding Independent Research Fund Denmark (9039-00177B and -00278B) and Aase og Ejnar Danielsens Fond

New Options to Simplify the Treatment of Severe Hypoglycemia in Long-Term Care

New Options to Simplify the Treatment of Severe Hypoglycemia in Long-Term Care

Effect of Landiolol Hydrochloride on Hemodynamics in a Histamine-Induced Shock Model.

Background and ObjectiveAnaphylactic shock is a serious adverse drug reaction that can occur in response to contrast media used during coronary computed tomography angiography. The imaging quality of coronary computed tomography angiography is improved by β-blockers, which decrease heart rate. In this study, we sought to analyze anaphylactic shock treatment in patients receiving short-acting β1-blockers.MethodsWe examined the influence of epinephrine and glucagon on hemodynamics during β-blocker treatment, using a dog histamine shock model; the β1-blocker landiolol hydrochloride was used. The effects of these drugs were assessed by recording changes relative to established baselines. ResultsHistamine and landiolol decreased mean blood pressure. Histamine exerted no apparent effect on heart rate, whereas landiolol decreased heart rate. Further, landiolol reduced histamine-mediated increases in the force of cardiac contraction. Increasing the doses of epinephrine and glucagon ameliorated anaphylactic shock-induced deterioration in hemodynamic parameters in subjects receiving landiolol.ConclusionsIn patients receiving landiolol for coronary computed tomography angiography, deterioration in hemodynamic parameters due to anaphylactic shock can be mitigated by increasing the doses of epinephrine and glucagon. Clinicians should thus prepare appropriate amounts of epinephrine and glucagon prior to coronary computed tomography angiography.

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

Background and ObjectiveArtificial 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.MethodsPharmacokinetic 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.ResultsPeak 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.ConclusionsMaximum 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.

Role of Octreotide in Sulfonylurea-Induced Hypoglycemia

Introduction: The most common adverse effect associated with sulfonylurea ingestion is hypoglycemia. Sulfonylureas have very narrow therapeutic indices with a prolonged half-life in End-Stage renal Disease (ESRD). As per literature review, insulin and oral sulfonylureas are responsible for 13.9% and 10.7% of emergency hospitalizations respectively. It is, however, not surprising that intentional or unintentional overdose with these agents can lead to prolonged hypoglycemia which can prove to be fatal. Case Report:76-year-old female presented to the Emergency Department (ED) with complaints of generalized weakness since the past three days. Her past medical history was significant for ESRD, Hypertension and Non-Insulin Dependent Diabetes Mellitus type II (home regimen of glipizide 10 mg daily). On physical exam, she was tachypneic and appeared lethargic. Her neurological exam was intact, and she was oriented to time, place and person. Her labs were significant for BUN of 77 mg/dL (5–20 mg/dL), Creatinine of 9.94 mg/dL (<1.3mg/dL) and blood glucose of 89 mg/dL (70-140mg/dL). Liver and thyroid function tests were normal. Computed Tomography scan of the head was unremarkable. In the ED, she received 5 mg of glipizide after which she became more confused and lethargic. Her blood glucose level was 21mg/dL thus she received seven pushes of intravenous (IV) dextrose (25g each), two doses of intramuscular glucagon (1mg each) and was started on a continuous infusion of dextrose (D10) at 75cc/hour. Her blood glucose levels continued to remain low with a repeat value of 34 mg/dL and her mental status continued to worsen. Labs checked at that time were significant for a C-Peptide level of 22.13ng/ml (1.00–4.00ng/ml) and an insulin level of 43.7uU/ml (<20uU/ml) suggesting it to be sulfonylurea toxicity. Sulfonylurea level could not be checked due to laboratory limitations. She was started on subcutaneous octreotide 30 mcgs every 6 hours as per endocrinology recommendations. Her blood glucose started to improve, and her mental status returned to baseline. Per oral food intake was resumed, she remained euglycemic and octreotide was discontinued. Conclusion: Octreotide is a synthetic octapeptide analogue of somatostatin which can effectively suppress insulin secretion. Glucose, on the other hand, would stimulate insulin release and cause rebound hypoglycemia. Boyle et al, showed that octreotide was superior to diazoxide and glucose in preventing sulfonylurea-induced hypoglycemia. Therefore, we as clinicians should be able to quickly recognize sulfonylurea toxicity as the cause of hypoglycemia and attempt to administer octreotide as soon as possible. This in turn would help decrease length of hospital stay and avoid the detrimental effects of hypoglycemia like seizures, coma and death especially in older individuals.

Liraglutide and Dulaglutide Have Comparable HbA1c Reduction in Emirati Patients with T2DM

Glucagon like peptide-1 is responsible for the incretin effect after a meal or an oral glucose load. Patients with type 2 diabetes mellitus have impairment of secretion and action of glucagon like peptide-1. This impairment can be overcome through pharmacological doses of glucagon like peptide-1 analogues. Aim of the Study: This study aimed at evaluation of the effect of treatment with glucagon like peptide-1 analogues; liraglutide and dulaglutide, in Emirati patients with type 2 diabetes mellitus. Glycemic control was the primary end point while the secondary end point was the effect on body mass index, blood pressure, heart rate, serum creatinine, lipid profile and estimated glomerular filtration rate. Patients & Methods: This is a retrospective study including 54 patients with type 2 diabetes mellitus. Patients used Liraglutide or Dulaglutide as add on therapy to oral antidiabetic medications for one year. Thirty-four patients used liraglutide 1.8 mg once daily and 20 patients used dulaglutide 1.5 mg once weekly. All patients were older than 18 years and had estimated glomerular filtration rate (>90 ml/min/1.73 m2). Body mass index, sitting blood pressure and heart rate were collected. Fasting plasma glucose, HbA1c, lipid panel and other biochemical parameters were also collected. Data were analysed before and at 6 and 12 months of glucagon like peptide-1 analogue treatment. Results: At 12 months of treatment, liraglutide significantly reduced fasting plasma glucose (11.3 ± 4 vs 7 ± 1.7, p

High-Dose Glucagon Has Hemodynamic Effects Regardless of Cardiac Beta-Adrenoceptor Blockade: A Randomized Clinical Trial.

BackgroundIntravenous high‐dose glucagon is a recommended antidote against beta‐blocker poisonings, but clinical effects are unclear. We therefore investigated hemodynamic effects and safety of high‐dose glucagon with and without concomitant beta‐blockade.Methods and ResultsIn a randomized crossover study, 10 healthy men received combinations of esmolol (1.25 mg/kg bolus+0.75 mg/kg/min infusion), glucagon (50 µg/kg), and identical volumes of saline placebo on 5 separate days in random order (saline+saline; esmolol+saline; esmolol+glucagon bolus; saline+glucagon infusion; saline+glucagon bolus). On individual days, esmolol/saline was infused from −15 to 30 minutes. Glucagon/saline was administered from 0 minutes as a 2‐minute intravenous bolus or as a 30‐minute infusion (same total glucagon dose). End points were hemodynamic and adverse effects of glucagon compared with saline. Compared with saline, glucagon bolus increased mean heart rate by 13.0 beats per minute (95% CI, 8.0–18.0; P<0.001), systolic blood pressure by 15.6 mm Hg (95% CI, 8.0–23.2; P=0.002), diastolic blood pressure by 9.4 mm Hg (95% CI, 6.3–12.6; P<0.001), and cardiac output by 18.0 % (95% CI, 9.7–26.9; P=0.003) at the 5‐minute time point on days without beta‐blockade. Similar effects of glucagon bolus occurred on days with beta‐blockade and between 15 and 30 minutes during infusion. Hemodynamic effects of glucagon thus reflected pharmacologic glucagon plasma concentrations. Glucagon‐induced nausea occurred in 80% of participants despite ondansetron pretreatment.ConclusionsHigh‐dose glucagon boluses had significant hemodynamic effects regardless of beta‐blockade. A glucagon infusion had comparable and apparently longer‐lasting effects compared with bolus, indicating that infusion may be preferable to bolus injections.Registration InformationURL: https://www.clinicaltrials.gov; Unique identifier: NCT03533179.

Glucagon for hypoglycaemia treatment in type 1 diabetes.

To achieve strict glycaemic control and avoid chronic diabetes complications, individuals with type 1 diabetes (T1D) are recommended to follow an intensive insulin regimen. However, the risk and fear of hypoglycaemia often prevent individuals from achieving the treatment goals. Apart from early insulin suspension in insulin pump users, carbohydrate ingestion is the only option for preventing and treating non-severe hypoglycaemic events. These rescue treatments may give extra calories and cause overweight. As an alternative, the use of low-dose glucagon to counter hypoglycaemia has been proposed as a tool to raise glucose concentrations without adding extra calories. Previously, the commercially available glucagon formulations required reconstitution from powder to a solution before being injected subcutaneously or intramuscularly-making it practical only for treating severe hypoglycaemia. Several companies have developed more stable formulations that do not require the time-consuming reconstitution process before use. As well as treating severe hypoglycaemia, non-severe and impending hypoglycaemia can also be treated with lower doses of glucagon. Once available, low-dose glucagon can be either delivered manually, as an injection, or automatically, by an infusion pump. This review focuses on the role and perspectives of using glucagon to treat and prevent hypoglycaemia in T1D.

Glucagon stimulation test to assess growth hormone status in Prader\u2013Willi syndrome

PurposeGrowth hormone deficiency (GHD) must be confirmed before starting treatment in adults with Prader-Willi syndrome (PWS). Most studies use the growth-hormone-releasing hormone plus arginine (GHRH-arginine) test. No data are available on the glucagon stimulation test (GST) in PWS. We compared the utility of fixed-dose (1 mg) GST versus GHRH-arginine test in diagnosing GHD.MethodsAdults and late adolescents with PWS underwent both tests on separate days. In the GHRH-arginine test, GHD was defined according to body mass index. In the GST, two cutoffs were analyzed: peak GH concentration < 3 ng/mL and < 1 ng/mL. For analyses, patients were divided into two groups according to body weight (≤ 90 kg and > 90 kg).ResultsWe analyzed 34 patients: 22 weighing ≤ 90 kg and 12 weighing > 90 kg. In patients weighing ≤ 90 kg, the two tests were concordant in 16 (72.72%) patients (k = 0.476, p = 0.009 with GST cutoff < 3 ng/mL, and k = 0.450, p = 0.035 with GST cutoff < 1 ng/mL). In patients weighing > 90 kg, the two tests were not concordant with GST cutoff < 3 ng/mL, but were concordant in 11 (91.6%) patients (k = 0.833, p = 0.003) with GST cutoff < 1 ng/mL. GH peaks on the two tests correlated (r = 0.725, p = 0.008).ConclusionFixed-dose (1 mg) GST using a peak GH cutoff of < 3 ng/mL or < 1 ng/mL promises to be useful for screening for GHD in adults and late adolescents with PWS. However, in those weighing > 90 kg, the < 1 ng/mL cutoff seems better. Larger studies are necessary to establish definitive glucagon doses and cutoffs, especially in extremely obese patients.

Acute Effects of Glucagon on Reproductive Hormone Secretion in Healthy Men.

ContextGlucagon increases energy expenditure; consequently, glucagon receptor agonists are in development for the treatment of obesity. Obesity negatively affects the reproductive axis, and hypogonadism itself can exacerbate weight gain. Therefore, knowledge of the effects of glucagon receptor agonism on reproductive hormones is important for developing therapeutics for obesity; but reports in the literature about the effects of glucagon receptor agonism on the reproductive axis are conflicting.ObjectiveThe objective of this work is to investigate the effect of glucagon administration on reproductive hormone secretion in healthy young men.DesignA single-blinded, randomized, placebo-controlled crossover study was conducted.SettingThe setting of this study was the Clinical Research Facility, Imperial College Healthcare NHS Trust.ParticipantsEighteen healthy eugonadal men (mean ± SEM: age 25.1 ± 1.0 years; body mass index 22.5 ± 0.4 kg/m2; testosterone 21.2 ± 1.2 nmol/L) participated in this study.InterventionAn 8-hour intravenous infusion of 2 pmol/kg/min glucagon or rate-matched vehicle infusion was administered.Main Outcome MeasuresLuteinizing hormone (LH) pulsatility; LH, follicle-stimulating hormone (FSH), and testosterone levels were measured.ResultsAlthough glucagon administration induced metabolic effects (insulin area under the curve: vehicle 1065 ± 292 min.µU/mL vs glucagon 2098 ± 358 min.µU/mL, P < .001), it did not affect LH pulsatility (number of LH pulses/500 min: vehicle 4.7 ± 0.4, glucagon 4.2 ± 0.4, P = .22). Additionally, there were no significant differences in circulating LH, FSH, or testosterone levels during glucagon administration compared with vehicle administration.ConclusionsAcute administration of a metabolically active dose of glucagon does not alter reproductive hormone secretion in healthy men. These data are important for the continued development of glucagon-based treatments for obesity.

Parallel Control of an Artificial Pancreas with Coordinated Insulin, Glucagon, and Rescue Carbohydrate Control Actions.

An artificial pancreas with insulin and glucagon delivery has the potential to reduce the risk of hypo- and hyperglycemia in people with type 1 diabetes. However, a maximum dose of glucagon of 1 mg/d is recommended, potentially still requiring rescue carbohydrates in some situations. This work presents a parallel control structure with intrinsic insulin, glucagon, and rescue carbohydrates coordination to overcome glucagon limitations when needed. The coordinated controller that combines insulin, glucagon, and rescue carbohydrate suggestions (DH-CC-CHO) was compared with the insulin and glucagon delivery coordinated controller (DH-CC). The impact of carbohydrate quantization for practical delivery was also assessed. An in silico study using the UVA-Padova simulator, extended to include exercise and various sources of variability, was performed. DH-CC and DH-CC-CHO performed similarly with regard to mean glucose (126.25 [123.43; 130.73] vs 127.92 [123.99; 132.97] mg/dL, P = .088), time in range (93.04 [90.00; 95.92] vs 92.91 [90.05; 95.75]%, P = .508), time above 180 mg/dL (4.94 [2.72; 7.53] vs 4.99 [2.93; 7.24]%, P = .966), time below 70 mg/dL (0.61 [0.09; 1.75] vs 0.96 [0.23; 2.17]%, P = .1364), insulin delivery (43.50 [38.68; 51.75] vs 42.86 [38.58; 51.36] U/d, P = .383), and glucagon delivery (0.75 [0.40; 1.83] vs 0.76 [0.43; 0.99] mg/d, P = .407). Time below 54 mg/dL was different (0.00 [0.00; 0.05] vs 0.00 [0.00; 0.16]%, P = .036), although non-clinically significant. This was due to the carbs quantization effect in a specific patient, as no statistical difference was found when carbs were not quantized (0.00 [0.00; 0.05] vs 0.00 [0.00; 0.00]%, P = .265). The new strategy of automatic rescue carbohydrates suggestion in coordination with insulin and glucagon delivery to overcome constraints on daily glucagon delivery was successfully evaluated in an in silico proof of concept.

Human factors studies of a prefilled syringe with stable liquid glucagon in a simulated severe hypoglycemia rescue situation

ABSTRACTBackground: Two human factors studies evaluated whether a stable liquid formulation of glucagon in a prefilled syringe (G-PFS) could be safely and effectively administered and evaluated the effectiveness of the product label guide and instructions-for-use (IFU).Research design and methods: In a formative study, 11 participants received orientation with the G-PFS instructional materials and performed a single unaided rescue attempt. In the validation study, 75 adult and adolescent participants received training or familiarized themselves with the G-PFS IFU, Label Guide, and device. All participants returned 1 week later to perform a single unaided rescue attempt of a simulated person with diabetes suffering from an emergency severe hypoglycemic event.Results: The formative study resulted in a 100% success rate across all rescue dose attempts. The validation study resulted in 74/75 (99%) of participants successfully using the G-PFS to administer the full glucagon rescue dose, and validated that intended users could learn from, comprehend, and recall the G-PFS instructions to successfully use the product.Conclusion: The G-PFS provides a familiar, easy-to-use alternative to currently marketed lyophilized glucagon kits for treating severe hypoglycemia. The G-PFS IFU and Label Guide enable even untrained users to successfully administer a full rescue dose of stable liquid glucagon.