(M-023) Evaluating the Importance of Glucagon in the Insulin-Glucose Regulatory System: A Mechanistic Modeling Approach

James Greene, PhD – Assistant Professor of Mathematics, Clarkson University; Emmanuel Asante-Asamani, PhD – Assistant Professor of Mathematics, Clarkson University

The results in this abstract have been previously presented in part at MCCNNY, Clarkson University, March 2, 2024 and at the QSP Summit, Boston, May, 1 2024 and published in the conference proceedings as abstract N/A (No conference proceedings were found).

Objectives: Insulin-glucose dynamics are a tightly regulated system in the body. The pancreatic islets of Langerhans contain both beta and alpha cells which produce insulin and glucagon, respectively. Insulin is the only hormone in the body that lowers blood glucose levels by acting like a key for glucose to enter cells. Without insulin, cells in the body cannot utilize glucose, the primary source of energy for cells. In contrast, glucagon functions as a hormone which elevates blood glucose levels by promoting the breakdown of glycogen in the liver. Maintaining blood glucose within a safe range is vital since both excessively high and low levels can be life-threatening (hyperglycemia and hypoglycemia, respectively), and these two hormones work together to achieve this balance. In this work we aim to underscore the significance of glucagon in the insulin-glucose regulatory system.

Methods: We construct a three-compartment mechanistic model that includes insulin, glucose, and glucagon. We then validate our model by fitting it to publicly available insulin, glucose, and glucagon data from pigs subjected to an intravenous glucose tolerance test (IVGTT) [1]. After model validation, we investigated how removing glucose feedback from insulin secretion, as seen in insulin-dependent diabetes, disrupts the regulation of glucose and glucagon. We simulated the model when insulin secretion is reduced to mimic an insufficient dose of insulin, when the peak of insulin action is delayed mimicking a dosing delay of insulin, and when both occur simultaneously. We also tested different half-lives of insulin to evaluate how the longer half-lives of manufactured insulin compared with endogenous insulin may further disrupt the system.

Results: We found that when insulin secretion is decreased, glucagon still responds to high glucose levels by decreasing glucagon production, suggesting that in cases where glucagon secretion is elevated despite high levels of glucose, lack of insulin response is not entirely to blame. We also found that delaying insulin secretion increases the risk of a hypoglycemic event through a delayed suppression of glucagon production. Lastly, we found that the higher the half-life of insulin the more it inhibits glucagon's response to severely low glucose levels. This sheds light on why patients taking exogenous insulin, which has a greater half-life than endogenous insulin, may have difficulty recovering from hypoglycemic events.

Conclusions: Our work highlights the importance of glucagon in regulating blood glucose levels and shows how a disruption in the feedback between insulin and glucose does not only alter blood glucose levels but also glucagon response.

Citations: [1] Manell, E., Hedenqvist, P., Svensson, A., & Jensen-Waern, M. (2016). Establishment of a Refined Oral Glucose Tolerance Test in Pigs, and Assessment of Insulin, Glucagon and Glucagon-Like Peptide-1 Responses. PLOS ONE, 11(2), e0148896. https://doi.org/10.1371/journal.pone.0148896