A recent Yale study provides evidence for a link between non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes — two extremely common diseases affecting millions of patients in America and around the world.

Insulin resistance, caused by the body’s incorrect use of insulin, produces a harmful increase in blood sugar and is a major cause of type 2 diabetes. The Mayo Clinic’s website states that NAFLD occurs when extra fat builds up in liver cells for reasons other than excessive alcohol consumption. The clinic estimates that NAFLD affects 80 to 100 million people worldwide, and according to Yale School of Medicine professor Gerald Shulman, people who have type 2 diabetes often also have NAFLD.

In the study, which was published in the Journal of Clinical Investigation on Oct. 17, Shulman and his researchers hypothesized and found that the causal link between NAFLD and type 2 diabetes results from an existing molecular mechanism.

Shulman expressed his excitement regarding the research results, noting that finding the “missing link” in the causal relationship between NAFLD and type 2 diabetes can lead to new drug therapies and mechanisms for treatment.

According to the Centers for Disease Control and Prevention, 9.3 percent of the United States population suffers from diabetes. While type 1 diabetes predominantly affects young people, type 2 diabetes accounts for 95 percent of all diagnosed cases of the disease in American adults.

However, according to Max Petersen MED ’18, lead author of the study, “some children are now developing type 2 diabetes, a disease that is linked to obesity and ectopic lipid accumulation.”

Despite this strong prominence in various diseases, Petersen described NAFLD as a “silent epidemic,” adding that although a third of the US population lives with the disease, many are not aware of their condition.

The research was a collaboration between the Shulman lab and the lab of medical school professor Jesse Rinehart. According to the study, liver insulin resistance in NAFLD mouse models occurs when the amino acid threonine undergoes phosphorylation — the addition of a phosphate group to a molecule.

“When you phosphorylate that threonine, insulin receptor activity goes basically to zero,” Petersen said. When activity between insulin receptors and cells decreases, cells cannot correctly respond to insulin, and thus develop insulin resistance.

According to the study, in mouse models of NAFLD, the researchers mutated this threonine molecule into another amino acid: an alanine which cannot undergo phosphorylation. The study stated that these mice did not develop hepatic insulin resistance, demonstrating the possibility of preventing insulin resistance despite the presence of fatty liver disease. Thus, preventing threonine phosphorylation could potentially treat type 2 diabetes.

“Our work really identifies a negative consequence of NAFLD and provides impetus to identify people with NAFLD,” Petersen said.

He added that in addition, by identifying this “missing” or “final” link in the causal relationship between NAFLD and type 2 diabetes, the researchers have found a “specific molecular mechanism” that can be targeted for future development of drug therapies and treatments.

According to Shulman, future research into the link between NAFLD and type 2 diabetes can concern various treatment mechanisms and drug therapies that were previously not possible.

Shulman is co-director of the Yale Diabetes Research Center and serves as an investigator of the Howard Hughes Medical Institute.