Decoding the regulatory mechanism of glucose and insulin induced phosphatidylinositol 3,4,5-trisphosphate dynamics in β-cells†

In MIN6 pancreatic β-cells, glucose and insulin act in a synergistic manner to regulate the dynamics of Phosphatidylinositol (3,4,5)-trisphosphate (PIP₃). However, the precise regulatory mechanism behind such an experimentally observed synergy is poorly understood. In this article, we propose a phenomenological mathematical model for studying the glucose and insulin driven PIP₃ activation dynamics under various stimulatory conditions to unfold the mechanism responsible for the observed synergy. The modeling study reveals that the experimentally observed oscillation in PIP₃ dynamics with disparate time scales for different external glucose doses is mainly orchestrated by the complex dynamic regulation of cytosolic Ca²⁺ in β-cells. The model accounts for the dose-dependent activation of PIP₃ as a function of externally added insulin, and further shows that even in the absence of Ca²⁺ signaling, externally added glucose can still maintain a basal level of endogenous insulin secretion via the fatty acid metabolism pathway. Importantly, the model analysis suggests that the glucose mediated ROS (reactive oxygen species) activation often contributes considerably to the synergistic activation of PIP₃ by glucose and insulin in a context dependent manner. Under the physiological conditions that keep β-cells in an insulin responsive state, the effect of glucose induced ROS signaling plays a moderate role in PIP₃ activation. As β-cells approach an insulin resistant state, the glucose induced ROS signaling significantly affects the PIP₃ dynamics. Our findings provide a plausible mechanistic insight into the experimentally observed synergy, and can lead to novel therapeutic strategies.