Mathematical Modeling of Interacting Glucose-Sensing Mechanisms and Electrical Activity Underlying Glucagon-Like Peptide 1 Secretion.

Michela Riz,Morten Gram Pedersen

doi:10.1371/journal.pcbi.1004600

Abstract

Intestinal L-cells sense glucose and other nutrients, and in response release glucagon-like peptide 1 (GLP-1), peptide YY and other hormones with anti-diabetic and weight-reducing effects. The stimulus-secretion pathway in L-cells is still poorly understood, although it is known that GLP-1 secreting cells use sodium-glucose co-transporters (SGLT) and ATP-sensitive K+-channels (K(ATP)-channels) to sense intestinal glucose levels. Electrical activity then transduces glucose sensing to Ca2+-stimulated exocytosis. This particular glucose-sensing arrangement with glucose triggering both a depolarizing SGLT current as well as leading to closure of the hyperpolarizing K(ATP) current is of more general interest for our understanding of glucose-sensing cells. To dissect the interactions of these two glucose-sensing mechanisms, we build a mathematical model of electrical activity underlying GLP-1 secretion. Two sets of model parameters are presented: one set represents primary mouse colonic L-cells; the other set is based on data from the GLP-1 secreting GLUTag cell line. The model is then used to obtain insight into the differences in glucose-sensing between primary L-cells and GLUTag cells. Our results illuminate how the two glucose-sensing mechanisms interact, and suggest that the depolarizing effect of SGLT currents is modulated by K(ATP)-channel activity. Based on our simulations, we propose that primary L-cells encode the glucose signal as changes in action potential amplitude, whereas GLUTag cells rely mainly on frequency modulation. The model should be useful for further basic, pharmacological and theoretical investigations of the cellular signals underlying endogenous GLP-1 and peptide YY release.

Highlights

Glucose sensing by a variety of specialized cells located, for example, in the pancreas [1], the brain [2] and the ingestive tract [3], plays a crucial role in the control of body weight and blood glucose levels, and dysfunctional glucose sensing is involved in the development of obesity and diabetes [2]
We propose that primary L-cells encode the glucose signal as changes in action potential amplitude, whereas GLUTag cells rely mainly on frequency modulation
Endocrine cells releasing hormones with a role in metabolism typically possess a refined molecular system for nutrient sensing, which allows them to respond in an appropriate manner to changes in e.g. glucose levels

Summary

Introduction

Glucose sensing by a variety of specialized cells located, for example, in the pancreas [1], the brain [2] and the ingestive tract [3], plays a crucial role in the control of body weight and blood glucose levels, and dysfunctional glucose sensing is involved in the development of obesity and diabetes [2]. The prototype mechanism operating in pancreatic β-cells involves glucose-uptake by GLUT transporters and closure of ATP-sensitive potassium (K(ATP)-) channels, which leads to cell depolarization and action potential firing with subsequent insulin release [1]. SGLTs are involved in glucose sensing in the hypothalamus [10], and play a role in pancreatic α-cells [11] in addition to K (ATP)-channels [1]. Glucagon-like peptide 1 (GLP-1) is an insulinotropic hormone released from intestinal Lcells in response to food ingestion [12]. It is, together with other hormones, responsible for the so-called incretin effect, i.e., the fact that glucose ingested orally elicits a greater insulin response than glucose administered intravenously, even when glucose concentrations in plasma are matched. GLP-1 inhibits glucagon secretion, slows gastric emptying, regulates appetite and food intake, stimulates β-cell neogenesis and proliferation, and promotes β-cell survival both in vitro and in vivo [12], and deficient incretin signalling has been suggested to be a major reason of insufficient insulin release and excessive glucagon release in type-2 diabetics [13]

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Discussion

Conclusion