Doses Of Glucagon Research Articles

Pharmacokinetics and pharmacodynamics of various glucagon dosages at different blood glucose levels.

To evaluate the pharmacokinetics and pharmacodynamics of different doses of glucagon administered subcutaneously (s.c.) at different blood glucose levels. This study was an open-label, randomized, three-period, cross-over experiment in 6 patients with type 1 diabetes. During each of the three periods, different blood glucose levels were established in four consecutive steps (8, 6, 4 and 2.8 mmol/l) and glucagon was given at each blood glucose level in doses from 0.11 to 0.44 mg and 0.33, 0.66 and 1 mg at the lowest glucose concentration. Maximum glucagon concentration and area under the curve increased with increasing glucagon dose. Maximum glucagon concentration was reached after 10-20 min. Glucagon raised blood glucose in a dose-dependent manner at different baseline blood glucose levels. The median glucose excursion ranged from 2.6 to 6.2 mmol/l. Time to maximum glucose concentration was dose-dependent for the glucagon doses at 2.8 mmol/l, with median values from 40 to 80 min. Glucagon administered s.c. produces a stable pharmacokinetic and pharmacodynamic response at lower doses than the usual rescue dose and across a range of hypo- to hyperglycaemic blood glucose levels. This supports the use of small glucagon doses in the artificial pancreas to correct and prevent hypoglycaemia.

Effect of Repeated Glucagon Doses on Hepatic Glycogen in Type 1 Diabetes: Implications for a Bihormonal Closed-Loop System

OBJECTIVETo evaluate subjects with type 1 diabetes for hepatic glycogen depletion after repeated doses of glucagon, simulating delivery in a bihormonal closed-loop system.RESEARCH DESIGN AND METHODSEleven adult subjects with type 1 diabetes participated. Subjects underwent estimation of hepatic glycogen using 13C MRS. MRS was performed at the following four time points: fasting and after a meal at baseline, and fasting and after a meal after eight doses of subcutaneously administered glucagon at a dose of 2 µg/kg, for a total mean dose of 1,126 µg over 16 h. The primary and secondary end points were, respectively, estimated hepatic glycogen by MRS and incremental area under the glucose curve for a 90-min interval after glucagon administration.RESULTSIn the eight subjects with complete data sets, estimated glycogen stores were similar at baseline and after repeated glucagon doses. In the fasting state, glycogen averaged 21 ± 3 g/L before glucagon administration and 25 ± 4 g/L after glucagon administration (mean ± SEM) (P = NS). In the fed state, glycogen averaged 40 ± 2 g/L before glucagon administration and 34 ± 4 g/L after glucagon administration (P = NS). With the use of an insulin action model, the rise in glucose after the last dose of glucagon was comparable to the rise after the first dose, as measured by the 90-min incremental area under the glucose curve.CONCLUSIONSIn adult subjects with well-controlled type 1 diabetes (mean A1C 7.2%), glycogen stores and the hyperglycemic response to glucagon administration are maintained even after receiving multiple doses of glucagon. This finding supports the safety of repeated glucagon delivery in the setting of a bihormonal closed-loop system.

Glucagon sensitivity and clearance in type 1 diabetes: insights from in vivo and in silico experiments.

Glucagon use in artificial pancreas for type 1 diabetes (T1D) is being explored for prevention and rescue from hypoglycemia. However, the relationship between glucagon stimulation of endogenous glucose production (EGP) viz., hepatic glucagon sensitivity, and prevailing glucose concentrations has not been examined. To test the hypothesis that glucagon sensitivity is increased at hypoglycemia vs. euglycemia, we studied 29 subjects with T1D randomized to a hypoglycemia or euglycemia clamp. Each subject was studied at three glucagon doses at euglycemia or hypoglycemia, with EGP measured by isotope dilution technique. The peak EGP increments and the integrated EGP response increased with increasing glucagon dose during euglycemia and hypoglycemia. However, the difference in dose response based on glycemia was not significant despite higher catecholamine concentrations in the hypoglycemia group. Knowledge of glucagon's effects on EGP was used to develop an in silico glucagon action model. The model-derived output fitted the obtained data at both euglycemia and hypoglycemia for all glucagon doses tested. Glucagon clearance did not differ between glucagon doses studied in both groups. Therefore, the glucagon controller of a dual hormone control system may not need to adjust glucagon sensitivity, and hence glucagon dosing, based on glucose concentrations during euglycemia and hypoglycemia.

Journal of Diabetes News

Journal of Diabetes News

Journal of Diabetes News

Journal of Diabetes News

The Health Service and Economic Impact of Glucagon Rescue Administration During Severe Hypoglycemic Events.

Hypoglycemia, which if left untreated, can be severe and result in seizures, unconsciousness, and coma, during which another person’s help is required to administer a rescue dose of glucagon. Injectable glucagon kits are difficult to use and require training to administer. This study aimed to quantify the economic impact of using glucagon kits on resource use and costs, and identify evidentiary gaps requiring future research. A conceptual model was developed illustrating the series of events resulting from a SHE: successful administration of glucagon, ambulance calls, transport to the ED, inpatient admission, and outpatient follow-up. A literature search was conducted to assess service use and costs associated with severe hypoglycemia events (SHE). English language articles were reviewed in PubMed, EMBASE and Cochrane databases. Resource use associated with SHE, as a function of successful administration of glucagon, has not been systematically evaluated in the literature. Uncertainty exists for the probability of receiving a glucagon prescription for diabetics and successful use of glucagon kits. Furthermore, based on successful administration of glucagon, the probability of ambulance calls, transports to the ED, inpatient admissions, and frequency of outpatient follow-up are lacking in the literature. Diabetes is a costly condition for payers, and a common complication is hypoglycemia. Glucagon kits are effective in stabilizing diabetics’ blood glucose levels during SHE; however, oftentimes physicians do not prescribe, patients do not fill, or caregivers do not successfully administer glucagon due to the complex administration procedures. As less complicated glucagon products are developed, their value propositions must be informed by the economic implications resulting from the complex administration requirements of current kits. However, the current literature does not systematically evaluate these implications. Consequently, future research is needed to quantify the impact of non-successful administration of glucagon rescue kits, as well as the extent of under-utilization.

Quantification of the glycemic response to microdoses of subcutaneous glucagon at varying insulin levels.

Glucagon delivery in closed-loop control of type 1 diabetes is effective in minimizing hypoglycemia. However, high insulin concentration lowers the hyperglycemic effect of glucagon, and small doses of glucagon in this setting are ineffective. There are no studies clearly defining the relationship between insulin levels, subcutaneous glucagon, and blood glucose. Using a euglycemic clamp technique in 11 subjects with type 1 diabetes, we examined endogenous glucose production (EGP) of glucagon (25, 75, 125, and 175 μg) at three insulin infusion rates (0.016, 0.032, and 0.05 units/kg/h) in a randomized, crossover study. Infused 6,6-dideuterated glucose was measured every 10 min, and EGP was determined using a validated glucoregulatory model. Area under the curve (AUC) for glucose production was the primary outcome, estimated over 60 min. At low insulin levels, EGP rose proportionately with glucagon dose, from 5 ± 68 to 112 ± 152 mg/kg (P = 0.038 linear trend), whereas at high levels, there was no increase in glucose output (19 ± 53 to 26 ± 38 mg/kg, P = NS). Peak glucagon serum levels and AUC correlated well with dose (r2 = 0.63, P < 0.001), as did insulin levels with insulin infusion rates (r2 = 0.59, P < 0.001). EGP increases steeply with glucagon doses between 25 and 175 μg at lower insulin infusion rates. However, high insulin infusion rates prevent these doses of glucagon from significantly increasing glucose output and may reduce glucagon effectiveness in preventing hypoglycemia when used in the artificial pancreas.

Factors affecting the success of glucagon delivered during an automated closed-loop system in type 1 diabetes

BackgroundIn bi-hormonal closed-loop systems for treatment of diabetes, glucagon sometimes fails to prevent hypoglycemia. We evaluated glucagon responses during several closed-loop studies to determine factors, such as gain factors, responsible for glucagon success and failure. MethodsWe extracted data from four closed-loop studies, examining blood glucose excursions over the 50min after each glucagon dose and defining hypoglycemic failure as glucose values<60 mg/dl. Secondly, we evaluated hyperglycemic excursions within the same period, where glucose was>180 mg/dl. We evaluated several factors for association with rates of hypoglycemic failure or hyperglycemic excursion. These factors included age, weight, HbA1c, duration of diabetes, gender, automation of glucagon delivery, glucagon dose, proportional and derivative errors (PE and DE), insulin on board (IOB), night vs. day delivery, and point sensor accuracy. ResultsWe analyzed a total of 251 glucagon deliveries during 59 closed-loop experiments performed on 48 subjects. Glucagon successfully maintained glucose within target (60–180 mg/dl) in 195 (78%) of instances with 40 (16%) hypoglycemic failures and 16 (6%) hyperglycemic excursions. A multivariate logistic regression model identified PE (p<0.001), DE (p<0.001), and IOB (p<0.001) as significant determinants of success in terms of avoiding hypoglycemia. Using a model of glucagon absorption and action, simulations suggested that the success rate for glucagon would be improved by giving an additional 0.8μg/kg. ConclusionWe conclude that glucagon fails to prevent hypoglycemia when it is given at a low glucose threshold and when glucose is falling steeply. We also confirm that high IOB significantly increases the risk for glucagon failures. Tuning of glucagon subsystem parameters may help reduce this risk.

The influence of glucagon on the concentration of triacylglycerols and cholesterol in the liver and kidney of mice

Abstract. The experiment was performed on sexually mature male Swiss mice to determine the effect of pharmacological doses of glucagon administered over a period of 4 or 8 days on the concentration of triacylglycerols and cholesterol in liver and kidneys of mice selected for fast rate of body weight gain and unselected ones, kept on a high-protein and low-protein diet. On the basis of the results obtained it was concluded that the selection and the diet, as well as glucagon injections, were lowering the content of triacylglycerols and cholesterol in the examined organs of mice, in many cases confirmed in a statistically significant way.

Pharmacokinetics Modeling of Exogenous Glucagon in Type 1 Diabetes Mellitus Patients

Insulin-induced hypoglycemia is as a critical barrier in the treatment of type 1 diabetes mellitus patients and may lead to unconsciousness, brain damage, or even death. Clinically, glucagon is used as a rescue drug to treat severe hypoglycemic episodes. More recently, in a bihormonal closed-loop glucose control, glucagon has been used subcutaneously along with insulin for protection against hypoglycemia. In this context, small doses of glucagon are frequently administered. The efficacy and safety of such systems, however, require precise information on the pharmacokinetics of the glucagon transport from the administrative site to the circulation, which is currently lacking. The goal of this work is to address this need by developing and validating a mathematical model of exogenous glucagon transport to the plasma. Eight pharmacokinetic models with various levels of complexity were fitted to nine clinical datasets. An optimal model was chosen in two consecutive steps. At Step 1, all models were screened for parameter identifiability (discarding the unidentifiable candidates). At Step 2, the remaining models are compared based on Bayesian information criterion. At Step 1, two models were removed for higher parameter fractional SDs. Another three were discarded for location of their optimal parameters on the parameter search boundaries. At Step 2, an optimal model was selected based on the Bayesian information criterion. It has a simple linear structure, assuming that glucagon is injected into one compartment, from where it enters a pool for a slower release into a third, plasma compartment. In the first and third compartments, glucagon is cleared at a rate proportional to its concentration. A linear kinetic model of glucagon intervention has been developed and validated. It is expected to provide guidance for glucagon delivery and the construction of preclinical simulation testing platforms.

The Future of Closed Loop

The Future of Closed Loop

Glucagon and insulin have opposite effects on tissue chromium distribution in an obese mouse model.

Previous studies have suggested that chromium (Cr) is an essential cofactor for normal carbohydrate metabolism and affects insulin sensitivity, especially in rodent models. Several factors, such as insulin challenge, high carbohydrate intake, and response to stress (e.g., in obesity), alter Cr excretion or distribution. Glucagon is known to regulate carbohydrate metabolism and hyperglucagonemia plays a role in the development of hyperglycemia in diabetic subjects. In the present study we investigated possible modulation of Cr levels by glucagon using an obese mouse model. Mice were kept on a high-fat diet and then used as an obesity model. These obese mice were injected with one dose of glucagon or insulin and Cr levels in their tissues were determined. In obese mice, glucagon challenge significantly increased Cr levels in bone but decreased them in the fat and liver. In contrast, insulin challenge significantly decreased Cr levels in bone but increased them in the fat, liver and muscle. The results show that glucagon and insulin have opposite effects on Cr levels in bone, fat, liver, and muscle.

Glucagon and GLP-1 inhibit food intake and increase c-fos expression in similar appetite regulating centres in the brainstem and amygdala

Glucagon and glucagon-like peptide-1 (GLP-1) are evolutionarily related anorectic hormones. Glucagon also increases energy expenditure. The combination of glucagon and GLP-1 could cause weight loss through a simultaneous reduction in food intake and increased energy expenditure. However, the effect of combined administration of glucagon and GLP-1 on food intake and neuronal activation has not previously been studied. Furthermore, the effect of glucagon on neuronal activation in appetite regulating centres has not been assessed. Characterisation of the effects of glucagon when administered singly and in combination with GLP-1 on neuronal activation will be important for determining the mechanism of action of related potential antiobesity therapies. To investigate the effects of peripherally administered GLP-1 and glucagon on food intake, neuronal activation and blood glucose in mice when administered individually and in combination. Food intake, blood glucose and c-fos expression in the hypothalamus, amygdala and brainstem were measured in response to GLP-1 and glucagon, alone and in combination. Peripherally administered GLP-1 and glucagon decreased food intake and increased c-fos expression in the brainstem and amygdala. Doses of GLP-1 and glucagon that individually did not significantly affect feeding, in combination were anorectic and stimulated neuronal activation in the area postrema (AP) and central nucleus of the amygdala. Combined administration of GLP-1 and glucagon prevented the acute hyperglycemic effect of glucagon alone. Anorectic doses of glucagon and GLP-1 induced similar patterns of c-fos expression. Combined administration of low dose GLP-1 and glucagon inhibited food intake and induced c-fos expression in the AP and amygdala. The combination of both hormones may offer the opportunity to utilise the beneficial effects of reduced food intake and increased energy expenditure, and may therefore be a potential treatment for obesity.

Stable Liquid Glucagon Formulations for Rescue Treatment and Bi-Hormonal Closed-Loop Pancreas

Small doses of glucagon given subcutaneously in the research setting by an automated system prevent most cases of hypoglycemia in persons with diabetes. However, glucagon is very unstable and cannot be kept in a portable pump. Glucagon rapidly forms amyloid fibrils, even within the first day after reconstitution. Aggregation eventually leads to insoluble gels, which occlude pump catheters. Fibrillation occurs rapidly at acid pH, but is absent or minimal at alkaline pH values of ~10. Glucagon also degrades over time; this problem is greater at alkaline pH. Several studies suggest that its primary degradative pathway is deamidation, which results in a conversion of asparagine to aspartic acid. A cell-based assay for glucagon bioactivity that assesses glucagon receptor (GluR) activation can screen promising glucagon formulations. However, mammalian hepatocytes are usually problematic as they can lose GluR expression during culture. Assays for cyclic AMP (cAMP) or its downstream effector, protein kinase A (PKA), in engineered cell systems, are more reliable and suitable for inexpensive, high-throughput assessment of bioactivity.

Response to: ‘Intravenous Fat Emulsion Therapy: Can It be Tried Without Sufficient First‐Line Treatment Modalities?’

We wish to thank Dr. Zamani for his comments and the opportunity to clarify the treatment of poisoned patients. While we agree that at this moment the use of intravenous fat emulsion (IFE) therapy for patients with life-threatening poisoning from cardiotoxic lipophilic drugs should be only considered after routine care is provided, we emphatically disagree with Dr. Zamani's definition of routine care. Although the use of calcium 1 and glucagon 2 is frequently recommended for calcium channel blocker and beta-adrenergic antagonist toxicity, there are no controlled trials that establish their optimal dosing. Furthermore, the use of either calcium and/or glucagon in bupropion toxicity is entirely unknown. The patient we described had failed acceptable initial doses of calcium and glucagon that would have been used for empiric treatment of cardiotoxic overdose and was receiving high doses of norepinephrine at the time IFE therapy was considered. Increasing norepinephrine further may have improved the blood pressure at the cost of end-organ vasoconstriction and subsequent ischaemia. Instead, we chose to administer IFE, based on published success 3 in hopes of sequestering a lipid-soluble toxin and obviating the need for another toxic drug (norepinephrine). Finally, most of the adverse effects associated with IFE, as noted in the article cited by Dr. Zamani, are with prolonged total parenteral nutrition and therefore cannot be extrapolated to short administration of lipid resuscitation therapy 4.

Design and Simulation of a High Precision Drug Delivery System

This work describes the design and simulation using Computational Fluid Dynamics (CFD) of a High Precision Drug Delivery System which is part of a bionic pancreas. The system interacts in a dynamic and intelligent way with other subsystems of the device, which includes a non-invasive monitor of glucose and the control algorithm for the entire system. P-MEM Microfabrication technology brings the opportunity to construct these devices in the scale of micrometers, in order to have a device with high portability, low power consumption, reliability and low cost. The system has the potential to deliver highly controlled doses of insulin and glucagon in order to achieve a high level of personalization of the therapy. This paper will discuss the design parameters of the device, velocity, pressure and dimensions. Velocity determines the possibility to create monodisperse microdroplets, and pressure the validity of the microfabrication process.

Use of Glucagon in Relieving Esophageal Food Bolus Impaction in the Era of Eosinophilic Esophagitis

Introduction: Esophageal food bolus impaction has an annual incidence of approximately 13 cases per 100,000 per year. To promote the spontaneous passage of the food bolus glucagon is often administered. Glucagon acts by relaxing the smooth musculature of the lower esophagus, thereby reducing the resting pressure of the lower esophageal sphincter. Studies have reported a response in up to one third of the cases who received glucagon, however conflicting data does exist. Eosinophilic esophagitis (EoE) is increasingly recognized as a cause of dysphagia. Food impaction is quite often the presenting symptom (56-86% of the cases). There is little to no data on the effectiveness of glucagon in relieving the esophageal foreign body obstruction in the setting EoE. Methods: Using the ICD codes and the emergency department database, a retrospective chart review of all the patients (≥ 18 years of age) presenting to the emergency department with symptoms of esophageal food bolus impaction from July 2004 to February 2010 was performed. Data collected included age, sex, food type, whether glucagon was given or not, dose of glucagon, response to glucagon, endoscopic findings, dilatation performed, biopsy results, and follow up. Response to glucagon was defined as symptomatic relief of obstruction after receiving glucagon. Endoscopic and pathology reports were reviewed electronically. Results: A total of 193 episodes of esophageal food bolus obstruction were identified during the study period. Glucagon was given in 107 episodes of which 35 had a response (33%). A total of 158 had an EGD performed either during the impaction event or at a later date. Biopsies were taken in 49 of the cases (25.4%). Out of 49 patients who had biopsies, 35 of them had received glucagon (13 with EoE, 22 without EoE). None of the 13 patients with EoE had responded to the glucagon (0%). Seven of 22 without evidence of EoE had responded to glucagon (31.8%, p-value 0.031). Conclusions: Our study shows that glucagon is effective in about one third of patients with esophageal food bolus impaction, which is consistent with historical data. Compared to patients without eosinophilic esophagitis, those with the condition appear to be even less likely to respond to glucagon.

Allergy Testing in Pediatric Eosinophilic Esophagitis – Identification of IgE and Delayed Hypersensitivity Food Reactions and Its Impact on Management

Introduction: Esophageal food bolus impaction has an annual incidence of approximately 13 cases per 100,000 per year. To promote the spontaneous passage of the food bolus glucagon is often administered. Glucagon acts by relaxing the smooth musculature of the lower esophagus, thereby reducing the resting pressure of the lower esophageal sphincter. Studies have reported a response in up to one third of the cases who received glucagon, however conflicting data does exist. Eosinophilic esophagitis (EoE) is increasingly recognized as a cause of dysphagia. Food impaction is quite often the presenting symptom (56-86% of the cases). There is little to no data on the effectiveness of glucagon in relieving the esophageal foreign body obstruction in the setting EoE. Methods: Using the ICD codes and the emergency department database, a retrospective chart review of all the patients (≥ 18 years of age) presenting to the emergency department with symptoms of esophageal food bolus impaction from July 2004 to February 2010 was performed. Data collected included age, sex, food type, whether glucagon was given or not, dose of glucagon, response to glucagon, endoscopic findings, dilatation performed, biopsy results, and follow up. Response to glucagon was defined as symptomatic relief of obstruction after receiving glucagon. Endoscopic and pathology reports were reviewed electronically. Results: A total of 193 episodes of esophageal food bolus obstruction were identified during the study period. Glucagon was given in 107 episodes of which 35 had a response (33%). A total of 158 had an EGD performed either during the impaction event or at a later date. Biopsies were taken in 49 of the cases (25.4%). Out of 49 patients who had biopsies, 35 of them had received glucagon (13 with EoE, 22 without EoE). None of the 13 patients with EoE had responded to the glucagon (0%). Seven of 22 without evidence of EoE had responded to glucagon (31.8%, p-value 0.031). Conclusions: Our study shows that glucagon is effective in about one third of patients with esophageal food bolus impaction, which is consistent with historical data. Compared to patients without eosinophilic esophagitis, those with the condition appear to be even less likely to respond to glucagon.

Glimepiride-Induced Hypoglycemia with Ciprofloxacin, Metronidazole, and Acute Kidney Injury

A 79-year-old white male presented to the emergency room with altered mental status and a blood glucose of 28 mg/dL. He was taking glimepiride 1 mg by mouth daily prior to admission and had recently been prescribed ciprofloxacin and metronidazole for diverticulitis. The patient was also found to have acute-on-chronic renal failure upon presentation. Escalated dextrose infusion with repeated doses of D50W and glucagon failed to sustain his blood glucose, which remained in the range of 30 to 50 mg/dL. Salvage treatment with intravenous octreotide was implemented successfully; only one dose of D50W was required after octreotide initiation and blood glucose normalized within several hours. In the presence of this patient's complex medication therapy, we explore the contributing causes of hypoglycemia. Fluoroquinolones are widely associated with dysglycemias, particularly in diabetic patients receiving hypoglycemic agents. Similarly, renal insufficiency has been implicated to precipitate hypoglycemia with sulfonylureas, with dosage adjustment being required almost class-wide. We also recognize a theoretical drug interaction mediated by metronidazole-induced CYP 2C9 inhibition of glimepiride metabolism. Sulfonylurea-induced hypoglycemia can be serious and refractory to traditional therapy and can be exacerbated by multiple factors, such as drug interactions or impaired renal function. In the era of complex medication therapy for patient populations with multiple disease states, we present a severe episode of glimepiride-induced hypoglycemia with multiple causative factors.

Factors Influencing the Effectiveness of Glucagon for Preventing Hypoglycemia

Administration of small, intermittent doses of glucagon during closed-loop insulin delivery markedly reduces the frequency of hypoglycemia. However, in some cases, hypoglycemia occurs despite administration of glucagon in this setting. Fourteen adult subjects with type 1 diabetes participated in 22 closed-loop studies, duration 21.5±2.0 h. The majority of subjects completed two studies, one with insulin + glucagon, given subcutaneously by algorithm during impending hypoglycemia, and one with insulin+placebo. The more accurate of two subcutaneous glucose sensors was used as the controller input. To better understand reasons for success or failure of glucagon to prevent hypoglycemia, each response to a glucagon dose over 0.5 µg/kg was analyzed (n=19 episodes). Hypoglycemia occurred in the hour after glucagon delivery in 37% of these episodes. In the failures, estimated insulin on board was significantly higher versus successes (5.8±0.5 versus 2.9±0.5 U, p<.001). Glucose at the time of glucagon delivery was significantly lower in failures versus successes (86±3 versus 95±3 mg/dl, p=.04). Sensor bias (glucose overestimation) was highly correlated with starting glucose (r=0.65, p=.002). Prior cumulative glucagon dose was not associated with success or failure. 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.