Design principles of the paradoxical feedback between pancreatic alpha and beta cells

Immacolata Garzilli,Shalev Itzkovitz

doi:10.1038/s41598-018-29084-4

Abstract

Mammalian glucose homeostasis is controlled by the antagonistic hormones insulin and glucagon, secreted by pancreatic beta and alpha cells respectively. These two cell types are adjacently located in the islets of Langerhans and affect each others’ secretions in a paradoxical manner: while insulin inhibits glucagon secretion from alpha cells, glucagon seems to stimulate insulin secretion from beta cells. Here we ask what are the design principles of this negative feedback loop. We systematically simulate the dynamics of all possible islet inter-cellular connectivity patterns and analyze different performance criteria. We find that the observed circuit dampens overshoots of blood glucose levels after reversion of glucose drops. This feature is related to the temporal delay in the rise of insulin concentrations in peripheral tissues, compared to the immediate hormone action on the liver. In addition, we find that the circuit facilitates coordinate secretion of both hormones in response to protein meals. Our study highlights the advantages of a paradoxical paracrine feedback loop in maintaining metabolic homeostasis.

Highlights

Homeostasis is a specialized form of regulation that precisely maintains the function of a system at a set point[1]
Alpha and beta cells are spatially adjacent in the islets of Langerhans and each cell type expresses the receptors for its antagonistic hormone
To characterize the circuit underlying the control of blood glucose, we derived a mathematical model of 4 Ordinary Differential Equations (ODEs) that took into account experimental observations and hypotheses from literature

Summary

Introduction

Homeostasis is a specialized form of regulation that precisely maintains the function of a system at a set point[1]. Glucose homeostasis is controlled by two antagonistic hormones, insulin and glucagon, secreted by beta and alpha cells respectively. These two cell types are adjacently located in the islet of Langerhans[5]. Failure of beta cells to secrete insulin in diabetic patients results in uncontrolled fluctuations in blood glucose levels In addition to their action on blood glucose levels, glucagon and insulin are jointly secreted in response to protein intake[6,7]. A natural circuitry to implement the antagonistic secretion of insulin and glucagon would be a mutual inhibition (T2 topology, Fig. 1c)[17] This does not seem to be the case for the intra-islet interactions. When considering blood glucose levels, as low glucose levels would directly inhibit insulin secretion, yet indirectly stimulate it through its induction of glucagon (T1 topology, Fig. 1b,c)

Methods

Results

Conclusion