Relationship between Optimum Mini-doses of Glucagon and Insulin Levels when Treating Mild Hypoglycaemia in Patients with Type 1 Diabetes - A Simulation Study

Ajenthen Ranjan, Sabrina Lyngbye Wendt, Signe Schmidt, Sten Madsbad, Jens J Holst, Henrik Madsen, Carsten B Knudsen, John Bagterp Jørgensen, Kirsten Nørgaard

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Hypoglycaemia remains the main limiting factor in type 1 diabetes management. We developed an insulin-dependent glucagon dosing regimen for treatment of mild hypoglycaemia based on simulations. A validated glucose-insulin-glucagon model was used to describe seven virtual patients with insulin pump-treated type 1 diabetes. In each simulation, one of ten different and individualized subcutaneous insulin boluses was administered to decrease plasma glucose (PG) from 7.0 to ≤3.9 mmol/l. Insulin levels were estimated as ratio of actual to baseline serum insulin concentration (se/ba-insulin), insulin on board (IOB) or percentage of IOB to total daily insulin dose (IOB/TDD). Insulin bolus sizes were chosen to provide pre-defined insulin levels when PG reached 3.9 mmol/l, where one of 17 subcutaneous glucagon boluses was administered. Optimum glucagon bolus to treat mild hypoglycaemia at varying insulin levels was the lowest dose that in most patients caused PG peak between 5.0 and 10.0 mmol/l and sustained PG ≥ 3.9 mmol/l for 2 hr after the bolus. PG response to glucagon declined with increasing insulin levels. The glucagon dose to optimally treat mild hypoglycaemia depended exponentially on insulin levels, regardless of how insulin was estimated. A 125-μg glucagon dose was needed to optimally treat mild hypoglycaemia when insulin levels were equal to baseline levels. In contrast, glucagon doses >500 μg were needed when se/ba-insulin >2.5, IOB >2.0 U or IOB/TDD >6%. Although the proposed model-based glucagon regimen needs confirmation in clinical trials, this is the first attempt to develop an insulin-dependent glucagon dosing regimen for treatment of insulin-induced mild hypoglycaemia in patients with type 1 diabetes.
Original languageEnglish
JournalBasic & Clinical Pharmacology & Toxicology
Volume122
Issue number3
Pages (from-to)322-330
ISSN1742-7835
DOIs
Publication statusPublished - 2017

Cite this

Ranjan, Ajenthen ; Wendt, Sabrina Lyngbye ; Schmidt, Signe ; Madsbad, Sten ; Holst, Jens J ; Madsen, Henrik ; Knudsen, Carsten B ; Jørgensen, John Bagterp ; Nørgaard, Kirsten. / Relationship between Optimum Mini-doses of Glucagon and Insulin Levels when Treating Mild Hypoglycaemia in Patients with Type 1 Diabetes - A Simulation Study. In: Basic & Clinical Pharmacology & Toxicology. 2017 ; Vol. 122, No. 3. pp. 322-330.
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abstract = "Hypoglycaemia remains the main limiting factor in type 1 diabetes management. We developed an insulin-dependent glucagon dosing regimen for treatment of mild hypoglycaemia based on simulations. A validated glucose-insulin-glucagon model was used to describe seven virtual patients with insulin pump-treated type 1 diabetes. In each simulation, one of ten different and individualized subcutaneous insulin boluses was administered to decrease plasma glucose (PG) from 7.0 to ≤3.9 mmol/l. Insulin levels were estimated as ratio of actual to baseline serum insulin concentration (se/ba-insulin), insulin on board (IOB) or percentage of IOB to total daily insulin dose (IOB/TDD). Insulin bolus sizes were chosen to provide pre-defined insulin levels when PG reached 3.9 mmol/l, where one of 17 subcutaneous glucagon boluses was administered. Optimum glucagon bolus to treat mild hypoglycaemia at varying insulin levels was the lowest dose that in most patients caused PG peak between 5.0 and 10.0 mmol/l and sustained PG ≥ 3.9 mmol/l for 2 hr after the bolus. PG response to glucagon declined with increasing insulin levels. The glucagon dose to optimally treat mild hypoglycaemia depended exponentially on insulin levels, regardless of how insulin was estimated. A 125-μg glucagon dose was needed to optimally treat mild hypoglycaemia when insulin levels were equal to baseline levels. In contrast, glucagon doses >500 μg were needed when se/ba-insulin >2.5, IOB >2.0 U or IOB/TDD >6{\%}. Although the proposed model-based glucagon regimen needs confirmation in clinical trials, this is the first attempt to develop an insulin-dependent glucagon dosing regimen for treatment of insulin-induced mild hypoglycaemia in patients with type 1 diabetes.",
author = "Ajenthen Ranjan and Wendt, {Sabrina Lyngbye} and Signe Schmidt and Sten Madsbad and Holst, {Jens J} and Henrik Madsen and Knudsen, {Carsten B} and J{\o}rgensen, {John Bagterp} and Kirsten N{\o}rgaard",
year = "2017",
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Relationship between Optimum Mini-doses of Glucagon and Insulin Levels when Treating Mild Hypoglycaemia in Patients with Type 1 Diabetes - A Simulation Study. / Ranjan, Ajenthen; Wendt, Sabrina Lyngbye; Schmidt, Signe; Madsbad, Sten; Holst, Jens J; Madsen, Henrik; Knudsen, Carsten B; Jørgensen, John Bagterp; Nørgaard, Kirsten.

In: Basic & Clinical Pharmacology & Toxicology, Vol. 122, No. 3, 2017, p. 322-330.

Research output: Contribution to journalJournal articleResearchpeer-review

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AU - Ranjan, Ajenthen

AU - Wendt, Sabrina Lyngbye

AU - Schmidt, Signe

AU - Madsbad, Sten

AU - Holst, Jens J

AU - Madsen, Henrik

AU - Knudsen, Carsten B

AU - Jørgensen, John Bagterp

AU - Nørgaard, Kirsten

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N2 - Hypoglycaemia remains the main limiting factor in type 1 diabetes management. We developed an insulin-dependent glucagon dosing regimen for treatment of mild hypoglycaemia based on simulations. A validated glucose-insulin-glucagon model was used to describe seven virtual patients with insulin pump-treated type 1 diabetes. In each simulation, one of ten different and individualized subcutaneous insulin boluses was administered to decrease plasma glucose (PG) from 7.0 to ≤3.9 mmol/l. Insulin levels were estimated as ratio of actual to baseline serum insulin concentration (se/ba-insulin), insulin on board (IOB) or percentage of IOB to total daily insulin dose (IOB/TDD). Insulin bolus sizes were chosen to provide pre-defined insulin levels when PG reached 3.9 mmol/l, where one of 17 subcutaneous glucagon boluses was administered. Optimum glucagon bolus to treat mild hypoglycaemia at varying insulin levels was the lowest dose that in most patients caused PG peak between 5.0 and 10.0 mmol/l and sustained PG ≥ 3.9 mmol/l for 2 hr after the bolus. PG response to glucagon declined with increasing insulin levels. The glucagon dose to optimally treat mild hypoglycaemia depended exponentially on insulin levels, regardless of how insulin was estimated. A 125-μg glucagon dose was needed to optimally treat mild hypoglycaemia when insulin levels were equal to baseline levels. In contrast, glucagon doses >500 μg were needed when se/ba-insulin >2.5, IOB >2.0 U or IOB/TDD >6%. Although the proposed model-based glucagon regimen needs confirmation in clinical trials, this is the first attempt to develop an insulin-dependent glucagon dosing regimen for treatment of insulin-induced mild hypoglycaemia in patients with type 1 diabetes.

AB - Hypoglycaemia remains the main limiting factor in type 1 diabetes management. We developed an insulin-dependent glucagon dosing regimen for treatment of mild hypoglycaemia based on simulations. A validated glucose-insulin-glucagon model was used to describe seven virtual patients with insulin pump-treated type 1 diabetes. In each simulation, one of ten different and individualized subcutaneous insulin boluses was administered to decrease plasma glucose (PG) from 7.0 to ≤3.9 mmol/l. Insulin levels were estimated as ratio of actual to baseline serum insulin concentration (se/ba-insulin), insulin on board (IOB) or percentage of IOB to total daily insulin dose (IOB/TDD). Insulin bolus sizes were chosen to provide pre-defined insulin levels when PG reached 3.9 mmol/l, where one of 17 subcutaneous glucagon boluses was administered. Optimum glucagon bolus to treat mild hypoglycaemia at varying insulin levels was the lowest dose that in most patients caused PG peak between 5.0 and 10.0 mmol/l and sustained PG ≥ 3.9 mmol/l for 2 hr after the bolus. PG response to glucagon declined with increasing insulin levels. The glucagon dose to optimally treat mild hypoglycaemia depended exponentially on insulin levels, regardless of how insulin was estimated. A 125-μg glucagon dose was needed to optimally treat mild hypoglycaemia when insulin levels were equal to baseline levels. In contrast, glucagon doses >500 μg were needed when se/ba-insulin >2.5, IOB >2.0 U or IOB/TDD >6%. Although the proposed model-based glucagon regimen needs confirmation in clinical trials, this is the first attempt to develop an insulin-dependent glucagon dosing regimen for treatment of insulin-induced mild hypoglycaemia in patients with type 1 diabetes.

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JO - Basic & Clinical Pharmacology & Toxicology

JF - Basic & Clinical Pharmacology & Toxicology

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