Mechanisms of glucose sensing in the pancreatic β-cell: A computational systems-based analysis

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.