| First Author | Wang C | Year | 2014 |
| Journal | Diabetes | Volume | 63 |
| Issue | 3 | Pages | 947-59 |
| PubMed ID | 24296716 | Mgi Jnum | J:209077 |
| Mgi Id | MGI:5565639 | Doi | 10.2337/db13-1096 |
| Citation | Wang C, et al. (2014) Hepatic overexpression of ATP synthase beta subunit activates PI3K/Akt pathway to ameliorate hyperglycemia of diabetic mice. Diabetes 63(3):947-59 |
| abstractText | ATP synthase beta subunit (ATPSbeta) had been previously shown to play an important role in controlling ATP synthesis in pancreatic beta-cells. This study aimed to investigate the role of ATPSbeta in regulation of hepatic ATP content and glucose metabolism in diabetic mice. ATPSbeta expression and ATP content were both reduced in the livers of type 1 and type 2 diabetic mice. Hepatic overexpression of ATPSbeta elevated cellular ATP content and ameliorated hyperglycemia of streptozocin-induced diabetic mice and db/db mice. ATPSbeta overexpression increased phosphorylated Akt (pAkt) levels and reduced PEPCK and G6pase expression levels in the livers. Consistently, ATPSbeta overexpression repressed hepatic glucose production in db/db mice. In cultured hepatocytes, ATPSbeta overexpression increased intracellular and extracellular ATP content, elevated the cytosolic free calcium level, and activated Akt independent of insulin. The ATPSbeta-induced increase in cytosolic free calcium and pAkt levels was attenuated by inhibition of P2 receptors. Notably, inhibition of calmodulin (CaM) completely abolished ATPSbeta-induced Akt activation in liver cells. Inhibition of P2 receptors or CaM blocked ATPSbeta-induced nuclear exclusion of forkhead box O1 in liver cells. In conclusion, a decrease in hepatic ATPSbeta expression in the liver, leading to the attenuation of ATP-P2 receptor-CaM-Akt pathway, may play an important role in the progression of diabetes. |
