Researchers from the University of Texas Southwestern Medical Center are working to help the 25 million Americans with type 2 diabetes. Led by Dr. Anil Agarwal, the team of scientists identified that phosphatidic acids (a type of lipid molecule) enhance glucose production in the liver and increase blood glucose. “The study published in The Journal of Biological Chemistry establishes a role for phosphatidic acids in enhancing glucose production by the liver and identifies enzymes involved in the synthesis of phosphatidic acids as potential drug targets,” said Dr. Agarwal. The thought is that if phosphatidic acids increase glucose production, inhibiting the lipids may reduce glucose production by the liver.
The scientists made their observation and tested their theory using a mouse model of lipodystrophy, a rare metabolic disease where patients often develop diabetes and accumulate fat in the liver. The model was created by knocking out the gene AGPAT2, which is involved in the synthesis of phophatidic acid and triglycerides. This caused an imbalance in the mice’s ability to properly regulate lipids and glucose. “We expected the levels of phosphatidic acids to go down. However, in examining the livers of these lipodystrophic mice, we unexpectedly found high levels of this lipid class,” Dr. Agarwal said. This surprise finding was due to an increase in diacylglycerol kinase and phopholipase D, two enzymes in the liver. Another finding was an increase in glucose production in the liver as a result of abnormal insulin signaling and unrestricted production of phosphatidic acid.
Knowledge of the involvement of phosphatidic acids in glucose metabolism could lead to new treatments for diabetes. Lead author Dr. Shireesha Sankella, a postdoctoral researcher in the Division of Nutrition and Metabolic Diseases, plans to test diacylglycerol kinase and phospholipase D inhibitors in cells and in vivo to better understand the molecular mechanism for enhanced liver glucose production. Another branch of research may look at the role of phosphatidic acids in metabolic pathways that give cancer cells energy. These may be future works of Drs. Agarwal and Sankella, as well as fellow authors Dr. Abhimanyu Garg and Dr. Jay Horton.