An insulin-dependent glucagon dosing regimen to optimally treat mild hypoglycemia in patients with T1D

A new article published in Journal of Basic & Clinical Pharmacology &Toxicology (September 2017) by Danish Diabetes Academy PhD fellow Ranjan Ajenthen, has proposed an insulin-dependent glucagon dosing regimen to optimally treat mild hypoglycemia in patients with type 1 diabetes. 

DOSING REGIMEN DEVELOPED FROM MATHEMATICAL SIMULATIONS

The glucagon dosing regimen was developed from mathematical simulations that used data from a previously published clinical study. In each simulation, one of ten different and individualised subcutaneous insulin boluses was administered to decrease plasma glucose from 7.0 to ≤3.9 mmol/l. When plasma glucose reached 3.9 mmol/l, one of 17 subcutaneous glucagon boluses was administered. Thus, a total of 510 study days was simulated on seven virtual patients with insulin pump treated type 1 diabetes. This design made it able to simulate large scale cross-over trials that were not feasible in real-life settings. The glucose response to glucagon was then assessed, and the optimal glucagon bolus to treat mild hypoglycaemia at varying insulin levels was chosen as the lowest dose that in most patients caused plasma glucose peak between 5.0 and 10.0 mmol/l and sustained plasma glucose above 3.9 mmol/l for two hours after the bolus.  

The results showed that:

1. The glucose response to glucagon declined with increasing insulin levels.
2. The glucagon dose to optimally treat mild hypoglycaemia depended exponentially on insulin levels, regardless of how insulin was estimated.
3. 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 insulin levels were 2.5-fold higher than baseline or when the insulin on board (a crude estimation used in recent insulin pumps) was 6% of the total daily insulin dose.  

MAYBE A FUTURE ALTERNATIVE TREATMENT TO ORAL CARBOHYDRATE FOR MILD INSULIN OVERDOSE

Although the proposed model-based glucagon regimen needs confirmation in clinical trials, this is, according to Ajenthen Ranjan, the first attempt to develop an insulin-dependent glucagon dosing regimen for treatment of insulin-induced mild hypoglycaemia in patients with type 1 diabetes.

The study may in the future be basis for a new treatment approach for type 1 diabetes as glucagon may be an alternative treatment to oral carbohydrate for mild insulin overdose. This dose finding study investigates the appropriate dose of glucagon to rescue patients from hypoglycemia to normal blood glucose range. Additionally, small doses of glucagon may prevent weight gain associated with extra calories from the carbohydrate rescues.

AUTHORS AND AFFILIATIONS

Ranjan A^1,2, Wendt SL^3,4, Schmidt S^1,2, Madsbad S^1,5, Holst JJ⁵, Madsen H⁴, Knudsen CB³, Jørgensen JB⁴, Nørgaard K¹.

¹Department of Endocrinology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
²Danish Diabetes Academy, Odense, Denmark
³Department of Bioanalysis and Pharmacokinetics, Zealand Pharma A/S, Glostrup, Denmark
⁴Department of Applied Mathematics and Computer Science, Technical University of Denmark, Kgs. Lyngby, Denmark
⁵NFF Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, denmark

Source: Journal of Basic & Clinical Pharmacology &Toxicology