Hyperglycemic Stress Induces Expression, Degradation, and Nuclear Association of Rho GDP Dissociation Inhibitor 2 (RhoGDIβ) in Pancreatic β-Cells

Small G proteins (e.g., Rac1) play critical regulatory roles in islet beta-cell function in health (physiological insulin secretion) and in metabolic stress (cell dysfunction and demise). Multiple regulatory factors for these G proteins, such as GDP dissociation inhibitors (GDIs), have been implicated in the functional regulation of these G proteins. The current set of investigations is aimed at understanding impact of chronic hyperglycemic stress on the expression and subcellular distribution of three known isoforms of RhoGDIs (RhoGDI alpha, RhoGDI beta, and RhoGDI gamma) in insulin-secreting beta-cells. The data accrued in these studies revealed that the expression of RhoGDI beta, but not RhoGDI alpha or RhoGDI gamma, is increased in INS-1 832/13 cells, rat islets, and human islets. Hyperglycemic stress also promoted the cleavage of RhoGDI beta, leading to its translocation to the nuclear compartment. We also report that RhoGDI alpha, but not RhoGDI gamma, is associated with the nuclear compartment. However, unlike RhoGDI beta, hyperglycemic conditions exerted no effects on RhoGDI alpha's association with nuclear fraction. Based on these observations, and our earlier findings of the translocation of Rac1 to the nuclear compartment under the duress of metabolic stress, we conclude that the RhoGDI beta-Rac1 signaling module promotes signals from the cytosolic to the nucleus, culminating in accelerated beta-cell dysfunction under metabolic stress.