Abstract
Recent estimates by the International Diabetes Federation suggest that the incidence of diabetes soared to an all-time high of 463 million in 2019, and the federation predicts that by 2045 the number of individuals afflicted with this disease will increase to 700 million. Therefore, efforts to understand the pathophysiology of diabetes are critical for moving toward the development of novel therapeutic strategies for this disease. Several contributors (oxidative stress, endoplasmic reticulum stress and others) have been proposed for the onset of metabolic dysfunction and demise of the islet β-cell leading to the pathogenesis of diabetes. Existing experimental evidence revealed sustained activation of PP2A and Rac1 in pancreatic β-cells exposed to metabolic stress (diabetogenic) conditions. Evidence in a variety of cell types implicates modulatory roles for specific signaling proteins (α4, SET, nm23-H1, Pak1) in the functional regulation of PP2A and Rac1. In this Commentary, I overviewed potential cross-talk between PP2A and Rac1 signaling modules in the onset of metabolic dysregulation of the islet β-cell leading to impaired glucose-stimulated insulin secretion (GSIS), loss of β-cell mass and the onset of diabetes. Potential knowledge gaps and future directions in this fertile area of islet biology are also highlighted. It is hoped that this Commentary will provide a basis for future studies toward a better understanding of roles of PP2A-Rac1 signaling module in pancreatic β-cell dysfunction, and identification of therapeutic targets for the treatment of islet β-cell dysfunction in diabetes.
Accepted Version
Published Version
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