Glucose metabolism-related protein 1 (GMRP1) regulates pancreatic beta cell proliferation and apoptosis via activation of Akt signalling pathway in rats and mice.

AIMS/HYPOTHESIS:We attempted to elucidate the impacts on and possible mechanisms by which glucose metabolism-related protein 1 (GMRP1) affects beta cell survival. METHODS:Adenovirus-mediated GMRP1 overproduction and siRNA-mediated knockdown were performed in INS-1E cells and rat islets, after which cell proliferation or apoptosis were determined, and phosphorylation of Akt and BCL2-associated agonist of cell death (BAD) investigated. INS-1E cells and rat islets were cultured at 5.6 (low) or 25 mmol/l (high) glucose for 24 or 48 h, and cell proliferation or apoptosis and GMRP1 levels were investigated. INS-1E cells were treated for 24 h with 0, 10, 50 and 100 nmol/l insulin, and GMRP1 levels were determined. After INS-1E cells were transfected with siRNA for 72 h, high glucose-induced cell proliferation and insulin-stimulated Akt phosphorylation were investigated. Glucose-infused rat models were established and beta cell proliferation and mass were evaluated. Levels of GMRP1, and phosphorylation of Akt and BAD were determined in glucose-infused islets. The GMRP1-mediated Akt pathway was also investigated in db/db mice. RESULTS:Overproduction of GMRP1 promoted beta cell proliferation via increased phosphorylation of Akt. Knockdown of Gmrp1 (also known as Btbd10) reduced phosphorylation of Akt with enhanced beta cell apoptosis. High glucose increased GMRP1 levels and cell proliferation in INS-1E cells and islet cells. Knockdown of Gmrp1 decreased high glucose-induced cell proliferation and insulin-stimulated Akt phosphorylation. Increased GMRP1 levels were involved in the enhancement of beta cell proliferation and mass in glucose-infused islets. Decreased GMRP1 levels may participate in beta cell apoptosis of db/db mice. CONCLUSIONS/INTERPRETATION:GMRP1 regulates pancreatic beta cell proliferation and apoptosis via activation of Akt signalling pathway.

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