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

Mackenzie Dalton, Emmanuel Asante-Asamani, James Greene
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Abstract

The dynamics of insulin and glucose are tightly regulated. 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 cannot utilize glucose, their primary source of energy. 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. We construct a three-compartment mechanistic model that includes insulin, glucose, and glucagon, which is then validated by fitting to publicly available from an intravenous glucose tolerance test (IVGTT). After model validation, we investigate how removing glucose feedback from insulin secretion, as seen in insulin-dependent diabetes, disrupts the regulation of glucose and glucagon. To do this, we simulate the model (a) when insulin secretion is reduced to mimic an insufficient dose of insulin, (b) when the peak of insulin action is delayed mimicking a dosing delay of insulin, and (c) when both occur simultaneously. Lastly, we test different half-lives of insulin to evaluate how an increased half-life of manufactured insulin may further disrupt the system. We find that when insulin secretion is decreased, glucagon still responds to high glucose levels by decreasing glucagon production. This suggests that in cases of type 2 diabetes, where glucagon secretion is elevated despite high levels of glucose, a lack of insulin response may not be the sole cause for glucagon dysfunction. We also find that delaying insulin secretion increases the risk of a hypoglycemic event through a suppression of glucagon production. Initially, the spike in glucose causes glucagon secretion to be reduced; this is then followed by the delay in insulin peak which then continues to suppress glucagon despite blood glucose levels falling, leading to a lack of response by glucagon and a subsequent hypoglycemic event. Furthermore, we find that a higher half-life of insulin causes it to remain longer in the blood stream, inhibiting glucagon's response to severely low glucose levels (glucose levels less than 3.9 mmol/L). This sheds light on why patients taking exogenous insulin, which has a longer half-life than endogenous insulin, may have difficulty recovering from hypoglycemic events. Hence, our model suggests that keeping the half-life of exogenous insulin below 10 minutes and administering it immediately after meals could help reduce the risk of hypoglycemic events in patients with type 1 or insulin dependent diabetes. Overall, we highlight how a disruption in the feedback between insulin and glucose not only alters blood glucose levels, but also glucagon response, which may lead to further disruption of the system.
评估胰高血糖素在胰岛素-葡萄糖调节系统中的重要性:机制建模方法
胰岛素和葡萄糖的动态变化受到严格调控。胰腺的朗格汉斯胰岛含有β细胞和α细胞,它们分别产生胰岛素和胰高血糖素。胰岛素是人体内唯一能降低血糖水平的激素,它就像一把钥匙,让葡萄糖进入细胞。没有胰岛素,细胞就无法利用葡萄糖这一主要能量来源。与此相反,胰高血糖素是一种通过促进肝脏中糖原的分解来提高血糖水平的激素。将血糖维持在安全范围内至关重要,因为过高或过低的血糖水平都可能危及生命(分别为高血糖和低血糖),而这两种激素共同作用以实现这一平衡。在这项研究中,我们旨在强调胰高血糖素在胰岛素-葡萄糖调节系统中的重要性。我们构建了一个包括胰岛素、葡萄糖和胰高血糖素的三室机理模型,然后通过拟合静脉葡萄糖耐量试验(IVGTT)的公开数据对该模型进行了验证。模型验证后,我们研究了胰岛素依赖型糖尿病患者从胰岛素分泌中移除葡萄糖反馈是如何扰乱葡萄糖和胰高血糖素的调节的。为此,我们模拟了以下情况下的模型:(a)胰岛素分泌减少以模拟胰岛素剂量不足;(b)胰岛素作用峰值延迟以模拟胰岛素剂量延迟;以及(c)两者同时发生。最后,我们测试了胰岛素的不同半衰期,以评估人造胰岛素半衰期的延长会如何进一步破坏该系统。我们发现,当胰岛素分泌减少时,胰高血糖素仍会通过减少胰高血糖素的分泌来应对高血糖水平。这表明,在 2 型糖尿病病例中,尽管葡萄糖水平较高,但胰高血糖素分泌仍会升高,胰岛素反应不足可能不是导致胰高血糖素功能障碍的唯一原因。我们还发现,通过抑制胰高血糖素的分泌,延迟胰岛素分泌会增加低血糖事件的风险。起初,葡萄糖飙升导致胰高血糖素分泌减少;随后,胰岛素峰值延迟,尽管血糖水平下降,但胰高血糖素继续受到抑制,导致胰高血糖素缺乏反应,继而引发低血糖事件。此外,我们还发现,胰岛素的半衰期较长,会使其在血流中停留更长时间,从而抑制胰高血糖素对严重低血糖水平(血糖水平低于 3.9 mmol/L)的反应。这就揭示了为什么服用外源性胰岛素的患者难以从低血糖事件中恢复,因为外源性胰岛素的半衰期比内源性胰岛素长。因此,我们的模型表明,将外源性胰岛素的半衰期控制在 10 分钟以下并在餐后立即给药,有助于降低 1 型糖尿病或胰岛素依赖型糖尿病患者发生低血糖的风险。总之,我们强调了胰岛素和葡萄糖之间反馈的中断不仅会改变血糖水平,还会改变胰高血糖素的反应,这可能会导致该系统的进一步中断。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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