Glycerol-3-phosphate phosphatase operates a glycerol shunt in pancreatic β-cells that controls insulin secretion and metabolic stress

Objective: The recently identified glycerol-3-phosphate (Gro3P) phosphatase (G3PP) in mammalian cells, encoded by the PGP gene, was shown to regulate glucose, lipid and energy metabolism by hydrolyzing Gro3P and to control glucose-stimulated insulin secretion (GSIS) in beta-cells, in vitro. However, whether G3PP regulates beta-cell function and insulin secretion in vivo is not known. Methods: We now examined the role of G3PP in the control of insulin secretion in vivo, beta-cell function and glucotoxicity in inducible beta-cell specific G3PP-KO (BKO) mice. Inducible BKO mice were generated by crossing floxed-G3PP mice with Mip-Cre-ERT (MCre) mice. All the in vivo studies were done using BKO and control mice fed normal diet and the ex vivo studies were done using pancreatic islets from these mice. Results: BKO mice, compared to MCre controls, showed increased body weight, adiposity, fed insulinemia, enhanced in vivo GSIS, reduced plasma triglycerides and mild glucose intolerance. Isolated BKO mouse islets incubated at high (16.7 mM), but not at low or intermediate glucose (3 and 8 mM), showed elevated GSIS, Gro3P content as well as increased levels of metabolites and signaling coupling factors known to reflect beta-cell activation for insulin secretion. BKO islets also showed reduced glycerol release and increased O-2 consumption and ATP production at high glucose only. BKO islets chronically exposed to elevated glucose levels showed increased apoptosis, reduced insulin content and decreased mRNA expression of 13-cell differentiation markers, Pdx-1, MafA and Ins-2. Conclusions: The results demonstrate that beta-cells are endowed with a "glycerol shunt ", operated by G3PP that regulates beta-cell metabolism, signaling and insulin secretion in vivo, primarily at elevated glucose concentrations. We propose that the glycerol shunt plays a role in preventing insulin hypersecretion and excess body weight gain and contributes to beta-cell mass preservation in the face of hyperglycemia. (C) 2022 The Authors. Published by Elsevier GmbH.