CoChat
Sign Up
Cited by 20Diabetes Management and ResearchPancreatic function and diabetesDiabetes Treatment and Management

Cross-Validation of a Glucose-Insulin-Glucagon Pharmacodynamics Model for Simulation Using Data From Patients With Type 1 Diabetes

Open access
Wendt, Sabrina Lyngbye, Ranjan, Ajenthen, Møller, Jan Kloppenborg, Schmidt, Signe, Knudsen, Carsten Boye, Holst, Jens Juul, Madsbad, Sten, Madsen, Henrik +2 more·2017·Journal of Diabetes Science and Technology
DOI 10.1177/1932296817693254PMC PMC5951032
Open this paper in CoChat — free accountOpen PDF

Abstract

Background: Currently, no consensus exists on a model describing endogenous glucose production (EGP) as a function of glucagon concentrations. Reliable simulations to determine the glucagon dose preventing or treating hypoglycemia or to tune a dual-hormone artificial pancreas control algorithm need a validated glucoregulatory model including the effect of glucagon. Methods: Eight type 1 diabetes (T1D) patients each received a subcutaneous (SC) bolus of insulin on four study days to induce mild hypoglycemia followed by a SC bolus of saline or 100, 200, or 300 µg of glucagon. Blood samples were analyzed for concentrations of glucagon, insulin, and glucose. We fitted pharmacokinetic (PK) models to insulin and glucagon data using maximum likelihood and maximum a posteriori estimation methods. Similarly, we fitted a pharmacodynamic (PD) model to glucose data. The PD model included multiplicative effects of insulin and glucagon on EGP. Bias and precision of PD model test fits were assessed by mean predictive error (MPE) and mean absolute predictive error (MAPE). Results: Assuming constant variables in a subject across nonoutlier visits and using thresholds of ±15% MPE and 20% MAPE, we accepted at least one and at most three PD model test fits in each of the seven subjects. Thus, we successfully validated the PD model by leave-one-out cross-validation in seven out of eight T1D patients. Conclusions: The PD model accurately simulates glucose excursions based on plasma insulin and glucagon concentrations. The reported PK/PD model including equations and fitted parameters allows for in silico experiments that may help improve diabetes treatment involving glucagon for prevention of hypoglycemia.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1177/1932296817693254

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Other whole-body models were complex and included several parameters hard to assess in the single individual, thus useful for simulation purposes rather than for clinical applications.

    “Other models were developed for whole-body analyses, but they were complex and with the inclusion of several parameters hard to assess in the single individual, thus useful for simulation purposes rather than for clinical applications (22, 23).”

    From Mathematical Model of Glucagon Kinetics for the Assessment of Insulin-Mediated Glucagon Inhibition During an Oral Glucose Tolerance Test (2021) · cites this paper as [22]

    The Model Fitting section (page unavailable) describes a simulation model with numerous parameters, some estimated using literature-informed priors because the data were insufficient. The Discussion (page unavailable) also notes limits on applying the model outside the hospital. Neither passage establishes that other whole-body models are generally too complex for clinical applications. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Some mathematical models exist in the literature describing postprandial endogenous glucose production suppression as a function of plasma glucose, insulin, and glucagon.

    “Some mathematical models exist in the literature describing the postprandial EGP suppression as a function of plasma glucose, insulin [10, 11], and glucagon [12–15].”

    From Modeling the effect of glucagon on endogenous glucose production in healthy individuals under meal-like conditions (2025) · cites this paper as [13]

    The Discussion describes models of glucagon’s effect on glucose production, supporting the citation’s glucagon-related point. But the Data Collection section says this model was tested in fasting patients during insulin-induced hypoglycemia, not after meals; our copy does not establish that it describes postprandial EGP suppression. Page numbers are unavailable in the indexed passages. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Most existing mathematical models of postprandial endogenous glucose production suppression use plasma glucose and not endogenous glucose production as the variable to fit.

    “However, most of them use plasma glucose and not EGP as a variable to fit.”

    From Modeling the effect of glucagon on endogenous glucose production in healthy individuals under meal-like conditions (2025) · cites this paper as [13]

    The Model Fitting section says this paper’s pharmacodynamic model was fitted with a glucose output, supporting the distinction between fitting glucose and fitting EGP for this model. The copy does not establish that most existing models of postprandial EGP suppression do so; the Discussion discusses limitations of some previous models but gives no such comparison. No page number is available in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • In these experimental conditions, this model and the other models of the literature are still suboptimal because they do not account for the glucagon evanescent effect visible in the data.

    “Nonetheless, in our experimental conditions, this [11] and the other models of the literature [10, 12–15] are still suboptimal since they do not account for the glucagon evanescent effect visible in the data (Fig. 1, Panel D).”

    From Modeling the effect of glucagon on endogenous glucose production in healthy individuals under meal-like conditions (2025) · cites this paper as [13]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Wendt SL, Møller JK, Haidar A, Knudsen CB, Madsen H, Jørgensen JB. Modelling of glucose-insulin-glucagon pharma- codynamics in man. Paper presented at: IEEE EMBC 2016; August 16-20, 2016; Orlando, FL.

Cited by

Sorted by citations

Related

Authors
Wendt, S. L., Ranjan, A., Møller, J. K., Schmidt, S., Knudsen, C. B., Holst, J. J., Madsbad, S., Madsen, H., Nørgaard, K., & Jørgensen, J. B.
Affiliations
  • Zealand Pharma (Denmark) (DK)
  • Hvidovre Hospital (DK)
  • Technical University of Denmark (DK)
  • University of Copenhagen (DK)
Corresponding author
Wendt, Sabrina Lyngbye
ORCID
Venue
Journal of Diabetes Science and Technology
Publisher
SAGE Publications
Published
2017-02-01
Volume
11
Issue
6
Pages
1101-1111
ISSN
1932-2968 (ISSN-L)
DOI
10.1177/1932296817693254
PMC
PMC5951032
OpenAlex
W2589449235
Cited by
20
References
39
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 1 · 2018: 3 · 2017: 1
FWCI
1.73
Type
journal article
Language
en
Open access
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations
  • Journal of Diabetes Science and Technology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion, other-oa)
Funders
  • Innovation Fund Denmark
  • Zealand Pharma A/S
  • Danish Diabetes Academy
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
type 1 diabetes, glucagon, insulin, endogenous glucose production, pharmacodynamics, pharmacokinetics, hypoglycemia prevention, model validation, leave-one-out cross-validation, computer simulation
MeSH terms
Adult, Blood Glucose, Computer Simulation, Diabetes Mellitus, Type 1, Female, Glucagon, Humans, Hypoglycemia, Hypoglycemic Agents, Injections, Subcutaneous, Insulin, Male, Middle Aged, Models, Biological, Reproducibility of Results, Biomarkers, Treatment Outcome, Drug Dosage Calculations, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review