Introduction to Appendix A

Unrestrained alpha-cell secretion of glucagon is thought to be a central factor in the pathogenesis of T1D.  To quote a 2016 review: “Hyperglucagonemia is present in every form of diabetes.  Glucagon is essential for hyperglycemia in T1D.” [1]

In addition to the canonical role of glucagon in glucose homeostasis, there is long established evidence that glucagon plays a role in energy homeostasis by enhancing satiety, increasing energy expenditures, and inducing thermogenesis. [2]  Alpha-cells are known to respond to nonglycemic plasma signals, e.g. arginine. [3]

It is the purpose of this paper to use correlation analysis to quantify the glycemic and nonglycemic glucagon diurnal patterns caused by postprandial glucose in populations of nondiabetic, healthy subjects.  It is well understood that there is regulatory linkage between circulating glucose and glucagon, so the cause-and-effect basis for the resulting correlation is established.  Our hypothesis is that there is, first, a dose-response of glucagon secretion to rising blood glucose, and that there are second, nonglycemic mediating effects on alpha-cell secretion that are independent of circulating glucose concentrations.

We do not consider comparable alpha-cell responses to hypoglycemia, since none of the underlying studies generated data in the hypoglycemic range.

The data is sourced from studies that were not designed specifically for the goals in this paper, so there are limitations to the analysis.  For example, the studies don’t permit considering short (several minutes) time lags in responses.  However, the results provide interesting perspective on average glucagon secretory patterns in the study populations, as well as offer insight into the separate glycemic and nonglycemic mediators of glucagon secretion.  They also permit quantifying the disturbances in postprandial alpha-cell secretion caused by T1D.

In this paper we use the term “model” to refer to the correlation equations and deviations therefrom derived from the clinical studies.  This approach differs from simulation modeling aimed at estimating the impact of multiple parameters interacting in dynamic systems (see, for example, Modelling the Effects of Glucagon During Glucose Tolerance Testing; Theoretical Biology and Medical Modelling, https://tbiomed.biomedcentral.com/ 2019.)  Our goal here is to mathematically describe the diurnal profiles from the top down – an approach that we term “empirical modeling” – in order to better understand the interactions among three plasma parameters, circulating glucose, insulin, and glucagon.  From our modeling we make observations about the endocrine factors that force alpha-cell secretion, and we illustrate an approach to modeling alpha-cell secretion that with appropriately designed clinical studies could be extended to hypoglycemia and amylin secretion.

Endnotes:

[1] -- Glucagon is the key factor in the development of diabetes; Diabetologia 59:1372-5 2016.

[2] -- Glucagon Control on Food Intake and Energy Balance; International Journal of Molecular Sciences 20:3904-16 2019.

[3] -- Arginine-Stimulated Acute Phase of Insulin and Glucagon Secretion in Diabetic Subjects; Journal of Clinical Investigation 58:565-70 1976.