title: Mechanisms of glucose sensing in the pancreatic β-cell: A computational systems-based analysis.
abstract: Pancreatic β-cells respond to rising blood glucose by increasing oxidative metabolism, leading to an increased ATP/ADP ratio in the cytoplasm with a subsequent influx of calcium and the eventual secretion of insulin. The mechanisms of glucose sensing in the pancreatic β-cell involve the coupling of cytoplasmic and mitochondrial processes. Our analysis, based on mathematical models of data from multiple sources has implications for β-cell function and the treatment of type 2 diabetes (Fridlyand and Philipson, 2010). This β-cell glucose response model correctly predicts changes in the ATP/ADP ratio, cytoplasmic and mitochondrial calcium levels, and other metabolic parameters in response to alterations in substrate delivery at steady-state and during cytoplasmic calcium oscillations. Here we consider how peculiarities of β-cell pathways that result in dysfunction can be a consequence of specific mechanisms of glucose sensitivity, using our computational systems-based analysis. We found that the mitochondrial membrane potential must be relatively low in β-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 cellular respiratory activity. Our analysis additionally demonstrates how activity of lactate dehydrogenase, uncoupling proteins, and the redox shuttles all working in concert can regulate β-cell function. We further show that a decreased mitochondrial membrane potential may lead to a low rate of production of reactive oxygen species in β-cells under physiological conditions. This computational systems analysis aids in providing a more complete understanding of the complex process of β-cell glucose sensing.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA. lfridlia@medicine.bsd.uchicago.edu
authors.forename: Leonid E
authors.initials: LE
authors.lastname: Fridlyand
authors.forename: Louis H
authors.initials: LH
authors.lastname: Phillipson
mesh_terms: D001786:Blood Glucose / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology; D008954:Models, Biological
chemical_list: D001786:Blood Glucose; D002118:Calcium