Abstract
Previous work has shown that reduced expression of PLCXD3, a member of the phosphoinositide-specific phospholipases (PI-PLC) family, impaired insulin secretion with an unclear mechanism. In the current study, we aim to investigate the mechanism underlying this effect using human islets and rat INS-1 (832/13) cells. Microarray and RNA sequencing data showed that PLCXD3 is among the highly expressed PI-PLCs in human islets and INS-1 (832/13) cells. Expression of PLCXD3 was reduced in human diabetic islets, correlated positively with Insulin and GLP1R expression and inversely with the donor's body mass index (BMI) and glycated hemoglobin (HbA1c). Expression silencing of PLCXD3 in INS-1 (832/13) cells was found to reduce glucose-stimulated insulin secretion (GSIS) and insulin content. In addition, the expression of Insulin, NEUROD1, GLUT2, GCK, INSR, IRS2, and AKT was downregulated. Cell viability and apoptosis rate were unaffected. In conclusion, our data suggest that low expression of PLCXD3 in pancreatic β-cells associates with downregulation of the key insulin signaling and insulin biosynthesis genes as well as reduction in glucose sensing.
Highlights
Phosphoinositide-specific phospholipase C (PI-PLC) is an enzyme that hydrolyzes the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) to inositol-1,4,5-trisphosphate (IP3) and diacylglycerol in response to external stimuli such as hormones, neurotransmitter, and growth factors [1]
Various studies have linked the PI-PLC with the regulation of insulin secretion and pancreatic β-cell function, where calcium influx was shown to activate PI-PLC in a positive feedback manner resulting in exocytosis [4,5,6]
We reported lower expression of phosphatidylinositol-specific phospholipase C X-domain containing 3 (PLCXD3) in diabetic islets compared to healthy islets, where its expression was correlated with insulin secretion and glycated hemoglobin (HbA1c) [11]
Summary
Phosphoinositide-specific phospholipase C (PI-PLC) is an enzyme that hydrolyzes the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) to inositol-1,4,5-trisphosphate (IP3) and diacylglycerol in response to external stimuli such as hormones, neurotransmitter, and growth factors [1]. There are six different subtypes of PI-PLCs (β, γ, δ, ε, ζ, and η) that have been identified and isolated from different tissues in humans, including brain, heart, spleen, thymus, and hematopoietic cells [2]. All PI-PLC subtypes hold distinct tissue distribution patterns with a distinctive function in regulating cell metabolism [3]. Little is known about the expression of PI-PLC subtypes. It has been previously reported that rodent pancreatic islets contain the three major PLC subtypes classes (β1, γ1, and δ1). Various studies have linked the PI-PLC with the regulation of insulin secretion and pancreatic β-cell function, where calcium influx was shown to activate PI-PLC in a positive feedback manner resulting in exocytosis [4,5,6]
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