(58h) A Computational Model of the Interplay of Pancreatic Islet Beta-Cells and Alpha-Cells on the Secretion of Insulin and Glucagon

The pancreatic islets of Langerhans are central to blood glucose homeostasis through the release of hormones, mainly insulin and glucagon. Insulin-producing β-cells are the predominant islet species, while the glucagon-secreting α-cells make up most of the remaining cells [1]. While blood glucose acts as the primary signal for these cells, the secreted moieties also influence intra-islet hormonal responses creating a multi-layered signaling landscape. Here, we set out to elucidate the interactions among α- and β-cells and their effects on hormone secretion upon exposure to various physiological levels of glucose. A mathematical framework was developed based on first principles and in conjunction with experimental data utilizing human and rodent islet cells. The model is aligned with results obtained in vivo as well as in vitro, where islet paracrine interactions can be isolated.

The network was considered comprising insulin, glucagon, and glucose among α- and β-cells which make almost 90% of the islet cells. The model development was divided in two parts: First, the steady-state behavior of the system was captured. Second, a transient, kinetic model was constructed describing how the system approaches steady state. The kinetic model was further developed containing a section describing the secretion of insulin and glucagon and another representing the transduction of glucose/glucagon and glucose/insulin signals. The constructed model entails 32 parameters, and their values were determined based on data from perifusion and static experiments using mouse and human islet cells.

Parameter estimation led to a reasonable agreement between the in silico results and measured secretion levels for insulin and glucagon. Importantly, the predicted glucagon response exhibited a U-shape with increasing glucose concentration that differs from the prevailing view of glucagon as solely a counterregulatory hormone that prevents hypoglycemia. Moreover, we examined the importance of conditions including the number of islets employed and mode (static or dynamic) of assays involving the determination of insulin and glucagon. While our framework was developed using in vitro data, we successfully simulated the release of insulin and glucagon from whole pancreas. The basal insulin and glucagon secretion rates were predicted to be 3x10^-3 mg/min and 5x10^-6 mg/min, respectively. The insulin secretion rate agrees well with a value close to 10^-3 mg/min observed both in vitro and in vivo [2]. The same modality was employed to estimate the release rate of glucagon in type 1 diabetes. The calculated glucagon secretion rate was 1.5x10^-4 mg/min resulting in glucagon concentration significantly greater than in the normal pancreas. This finding is aligned with the documented hyperglucagonemia experienced by diabetes patients [3].

The framework described in this study was developed from first principles and captures known qualitative interactions between glucagon and β-cells, and insulin and α-cells. Importantly, our findings highlight insulin action as a source of the discrepancy between glucagon secretion from whole islets and isolated α-cells. This further supports the notion that the hyperglucagonemia seen in diabetes (types 1 and 2) is linked to a failure of insulin (due to b-cell ablation) to inhibit α-cell activity. Overall, our study shines light on the physiological role of α-cells in normal glucose homeostasis or from the perspective of aberrant pancreatic function.

References

[1] T. Moede, et. al. Alpha cell regulation of beta cell function. Diabetologia, 63: 2064-75, 2020.

[2] S. van Vliet, et al. Obesity is associated with increased basal and postprandial beta-cell insulin secretion even in the absence of insulin resistance. Diabetes, 69: 2112-19, 2020.

[3] R.J. Brown, et al. Too much glucagon, too little insulin: time course of pancreatic islet dysfunction in new-onset type 1 diabetes. Diabetes Care, 31: 1403-4, 2008.