Diabetes debate: Triglycerides form in liver despite insulin resistance

Solving one of the great mysteries of type 2 diabetes, a team of Yale researchers found that triglycerides, a type of fat in the blood and liver, are produced in the liver independent of insulin action in the liver.

In type 2 diabetics, insulin fails to suppress blood sugar production by the liver while paradoxically allowing the production of hepatic triglycerides. This combination results in multiple health risks, including high blood sugar and fatty liver disease. For years, to gain insight into this phenomenon, researchers focused on the role of altered insulin action in the liver in the production of triglycerides. However, Yale researchers tested a theory that triglycerides formed in the liver were more dependent on the delivery of fatty acids to the liver than on insulin action.

In their study, the Yale team — led by Gerald I. Shulman, the George R. Cowgill professor of medicine and cellular & molecular physiology — developed a novel method to measure the rate of triglyceride production from fatty acids in three types of animals: normal rats, insulin-resistant rats fed a high-fat diet, and rats with genetically modified insulin receptors. They found that in all of the animals tested increased triglyceride production was primarily dependent on fatty acid delivery and not on insulin action in the liver.

The findings also explain the long-standing paradox of why insulin therapy does not exacerbate, but instead reduces, fatty liver disease in patients with type 2 diabetes. “These results provide new insights into the pathogenesis of non-alcoholic liver disease and provides new approaches to treat fatty liver disease, which is now the most common liver disease in the world,” said Shulman.

Shulman and his team plan to apply similar methodology to translate their findings to insulin-resistant patients with type 2 diabetes, hyperlipidemia, and fatty liver disease.

The study was published online in the Proceedings of the National Academy of Sciences

Other Yale authors include Daniel F. Vatner, Sachin K. Majumdar Naoki Kumashiro, Max C. Petersen, Yasmeen Rahimi, Arijeet K. Gattu, Mitchell Bears, João-Paulo G. Camporez, Gary W. Cline, Michael J. Jurczak, and Varman T. Samuel.

This work was partially funded by the Yale Clinical and Translational Science Award (CTSA) grant from the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health. It was also supported by U.S. Public Health Service Grants R01 DK-40936, R24 DK-085836, T32 DK-007058, U24 DK-59635, and P30 DK-45735, an American Diabetes Association Mentor-Based Postdoctoral Fellowship award, and the Novo Nordisk Foundation Center for Basic Metabolic Research.