Glucose sensing in the pancreatic beta cell: a computational systems analysis

Abstract

BackgroundPancreatic beta-cells respond to rising blood glucose by increasing oxidative metabolism, leading to an increased ATP/ADP ratio in the cytoplasm. This leads to a closure of KATP channels, depolarization of the plasma membrane, influx of calcium and the eventual secretion of insulin. Such mechanism suggests that beta-cell metabolism should have a functional regulation specific to secretion, as opposed to coupling to contraction. The goal of this work is to uncover contributions of the cytoplasmic and mitochondrial processes in this secretory coupling mechanism using mathematical modeling in a systems biology approach.MethodsWe describe a mathematical model of beta-cell sensitivity to glucose. The cytoplasmic part of the model includes equations describing glucokinase, glycolysis, pyruvate reduction, NADH and ATP production and consumption. The mitochondrial part begins with production of NADH, which is regulated by pyruvate dehydrogenase. NADH is used in the electron transport chain to establish a proton motive force, driving the F1F0 ATPase. Redox shuttles and mitochondrial Ca2+ handling were also modeled.ResultsThe model correctly predicts changes in the ATP/ADP ratio, Ca2+ and other metabolic parameters in response to changes in substrate delivery at steady-state and during cytoplasmic Ca2+ oscillations. Our analysis of the model simulations suggests that the mitochondrial membrane potential should be relatively lower in beta cells compared with other cell types to permit precise mitochondrial regulation of the cytoplasmic ATP/ADP ratio. This key difference may follow from a relative reduction in respiratory activity. The model demonstrates how activity of lactate dehydrogenase, uncoupling proteins and the redox shuttles can regulate beta-cell function in concert; that independent oscillations of cytoplasmic Ca2+ can lead to slow coupled metabolic oscillations; and that the relatively low production rate of reactive oxygen species in beta-cells under physiological conditions is a consequence of the relatively decreased mitochondrial membrane potential.ConclusionThis comprehensive model predicts a special role for mitochondrial control mechanisms in insulin secretion and ROS generation in the beta cell. The model can be used for testing and generating control hypotheses and will help to provide a more complete understanding of beta-cell glucose-sensing central to the physiology and pathology of pancreatic β-cells.

The Pancreatic β-Cell: A Bioenergetic Perspective

“…A comprehensive and critical nonmathematical overview of the multiple experi-mental and theoretical models that have been advanced to interpret the complex pattern of ␤-cell firing (e.g., Refs. 44,45,121,159,293,391,534) has recently been published (151). The most comprehensive current mathematical construction, the Dual Oscillator Model, proposes interactions between three modules: glycolysis, the mitochondrion, and the plasma membrane (46,349,534).…”

Mechanisms of glucose sensing in the pancreatic β-cell

“…Kinetic analysis of our model 17 reveals that decreased Ψ m into the range lower than 150 mV can be simulated by decreased respiratory activity per unit of ATPase activity. This suggests that mitochondrial glucose sensitivity in β-cells can be a result of decreased respiratory activity compared with F1F0 ATPase activity.…”

“…However, this also gives β-cells the ability to adaptively regulate the ATP/ADP ratio in response to changes in glucose concentration (reviewed in ref. 17).…”

Regulation of Ca2+release through inositol 1,4,5-trisphosphate receptors by adenine nucleotides in parotid acinar cells

“…Because the levels of free ADP are very difficult to measure and are seldom reported, it is, however, difficult to predict whether regulation by ADP is physiologically important. Nevertheless as the ratio of ATP/ADP changes during oxidative phosphorylation (21) and also during periods of high metabolic demand, it is likely that the degree of regulation will be determined by the ratio of nucleotides locally present at release sites at a particular time.…”