(515bn) Systems Level Approach Of Pancreatic Beta-Cell Function

Research over the past few decades in the area of diabetes has revealed that it is a multifactorial and polygenic disease manifested by defects in insulin production, action or both. Insulin production is regulated in pancreatic β-cells by an interplay between glucose metabolism and various signaling cascades. Understanding the action of individual components within the cell is not sufficient and hence there is a need for systems level modeling of these components and their interactions at the level of genes, proteins and metabolites. Unraveling the dynamic interactions among the underlying biological processes giving rise to physiological functions in pancreatic β-cells is vital to detect, prevent and find treatments for diabetes. In this study, we have constructed a systems level model of pancreatic β-cell insulin response. Within this framework three subsystems are linked: glucose metabolism, calcium signaling and insulin exocytosis. The model provides a relation between blood glucose levels and insulin release. On simulating low glucose conditions (2mM), we observe that insulin levels are minimal. However, when the glucose concentration was ramped up to 25 mM with time and brought down to 2 mM, the intracellular ATP concentrations increased resulting in depolarization of the membrane, increase in intracellular calcium levels and subsequent oscillations. The exocytosis model was built to mimic an initial, fast, transient phase of insulin secretion dependent on intracellular calcium and a slow, steady phase independent of calcium concentration and rather depending on the mobilization rate of insulin granules from the reserve pool to the readily releasable pool. The time profiles of insulin release and insulin secretion rates match the blood glucose levels. Although the blood glucose levels are brought back to 2 mM, intracellular ATP concentrations are still maintained and the calcium oscillations are sustained. In this model, the amount of insulin secreted in the beginning is controlled by the storage capacity of readily releasable pool and the calcium signal but once this pool is depleted, the mobilization rate becomes the rate limiting step for basal insulin secretion. Our results illustrate the experimentally observed matching of the insulin levels to the blood glucose concentrations in a quantitative manner from a systems perspective. The development is underway of transcriptional and translational modules for insulin and insulin signaling, which leads to other metabolic effects. Such modules will be integrated with the present model. The outcome of this study will facilitate the discovery of novel targets for therapeutic intervention and the identification of new biomarkers of abnormal β-cell function for diagnostic purposes.