The researchers have zeroed in on a molecular link between nonalcoholic fatty liver disease and liver insulin resistance in type 2 diabetes. The findings, reported in the journal Cell Metabolism, will help pave the way for new drugs to combat type 2 diabetes and other related metabolic disorders, the authors said.

Nonalcoholic fatty liver disease -- the most common form of chronic liver disease in the United States -- is marked by a dangerous accumulation of fat in the liver. The disease, which can be caused by excess calorie intake, is strongly associated with a host of metabolic disorders, including obesity, high triglyceride levels, and insulin resistance, a hallmark of type 2 diabetes.

But the precise molecular connection between fatty liver disease and liver insulin resistance has been hotly debated. Scientists have identified two separate lipids -- diacylglycerols and ceramides -- as potential links between fatty liver disease and liver insulin resistance. Scientists developed a way to measure the effects of both lipids within cells of the liver, which plays a central role in glucose regulation and metabolism.

They found that rats accumulating diacylglycerols in the liver developed liver insulin resistance. In the liver, the accumulation of plasma membrane diacylglycerols caused insulin resistance by triggering interaction between a protein anchored to the plasma membrane and the insulin receptor that is essential in regulating metabolism, they report.

The authors show that acute knockdown (KD) of diacylglycerol acyltransferase-2 in liver induced hepatic insulin reistance (HIR) in rats. This was due to PM sn-1,2-DAG accumulation, which promoted PKCϵ activation and insulin receptor kinase (IRK)-T1160 phosphorylation, resulting in decreased IRK-Y1162 phosphorylation. Liver plasma membrane sn-1,2-DAG content and IRK-T1160 phosphorylation were also higher in humans with HIR.

In rats, liver-specific PKCϵ KD ameliorated high-fat diet-induced HIR by lowering IRK-T1160 phosphorylation, while liver-specific overexpression of constitutively active PKCϵ-induced HIR by promoting IRK-T1160 phosphorylation. 

The molecular pathway identified in the current study has been explored by the lab as a possible regulator in a host of metabolic disorders. The lab is already developing a drug that targets this pathway in hopes it can combat insulin resistance and related metabolic disorders in multiple organs and tissues.

"These are preclinical findings developed in animals and supported by consistent evidences from human samples, and we hope they have the potential to treat insulin resistance and other metabolic disorders that are leading killers of people in the developed world," the author said.

https://news.yale.edu/2020/09/02/researchers-find-molecular-link-between-liver-disease-insulin-resistance

https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30414-9