PI4KIIα regulates insulin secretion and glucose homeostasis via a PKD-dependent pathway

Insulin release by pancreatic β cells plays a key role in regulating blood glucose levels in humans, and to understand the mechanism for insulin secretion may reveal therapeutic strategies for diabetes. We found that PI4KⅡα transgenic (TG) mice have abnormal glucose tolerance and higher serum glucose levels than wild-type mice. Glucose-stimulated insulin secretion was significantly reduced in both PI4KⅡα TG mice and PI4KⅡα-overexpressing pancreatic β cell lines. A proximity-based biotin labeling technique, BioID, was used to identify proteins that interact with PI4KⅡα, and the results revealed that PI4KⅡα interacts with PKD and negatively regulates its activity. The effect of PI4KⅡα on insulin secretion was completely rescued by altering PKD activity. PI4KⅡα overexpression also worsened glucose tolerance in streptozotocin/high-fat diet-induced diabetic mice by impairing insulin secretion. Our study has shed new light on PI4KⅡα function and mechanism in diabetes and identified PI4KⅡα as an important regulator of insulin secretion.