Researchers have found that diets high in fat are responsible for deactivating an important metabolic enzyme, causing a process that starts an organism down the path of Type 2 diabetes.

The findings are the result of a study conducted on humans and mice. The diabetic pathway is activated in the beta cells of the pancreas, leading to operational defects in other organs and tissues. The process affects the liver, muscle tissue, and adipose tissue (fat). When combined, these defects lead to the onset of Type 2 diabetes.

“We were initially surprised to learn how much the pancreatic beta cell contributes to the onset and severity of diabetes,” said Jamey Marth. Marth is a professor of biochemistry, molecular biology and nanomedicine at the University of California in Santa Barbara.

“The observation that beta cell malfunction significantly contributes to multiple disease signs, including insulin resistance, was unexpected,” continued Marth. “We noted, however, that studies from other laboratories published over the past few decades had alluded to this possibility.” Doctors were aware that defects in the functioning of pancreatic beta cells might be contributing to the onset of diabetes, but no one knew for sure until now.

The beta cells of the pancreas, when functioning normally, utilize glucose transporters embedded in their cell membranes to monitor the level of glucose in the blood stream. When they detect elevated levels of blood glucose, especially after meals, the beta cells absorb the extra glucose and release insulin in response. The insulin influences other cells to also take in the glucose, which they use as a source of energy.

The new study found that elevated levels of fat were responsible for interfering with two transcription factors, or proteins that determine whether a gene is active or inactive.

The two transcription factors are known as FOXA2 and HNF1A and they usually stimulate the production of an enzyme called GnT-4a glycosyltransferase. This enzyme modifies proteins that have a certain glycan, or polysaccharide, structure. But if FOXA2 and HNF1A are not activating correctly, GnT-4a’s effect is lessened.

The study tested this process by feeding a high-fat diet to mice, whose pancreatic beta cells became unable to monitor blood glucose and respond to it. When the researchers ensured that GnT-4a continued to function properly, however, the development of diabetes was halted. The defect in the beta cells’ monitoring of blood glucose was shown to have a significant effect on whether or not diabetes developed, and the severity of the disease if it did develop.

“Now that we know more fully how states of over-nutrition can lead to Type 2 diabetes, we can see more clearly how to intervene,” said Marth. Marth’s team is now looking at different methods of preserving the function of the GnT-4a enzyme in humans, which may work to prevent or possibly even reverse Type 2 diabetes.

“The identification of the molecular players in this pathway to diabetes suggests new therapeutic targets and approaches towards developing an effective preventative or perhaps curative treatment,” continued Marth. “This may be accomplished by beta cell gene therapy or by drugs that interfere with this pathway in order to maintain normal beta cell function.” Now that scientists understand the mechanisms by which the pancreatic beta cells become unable to monitor blood glucose levels, they are looking toward developing treatments.

There are more than 24 million people living with diabetes in the United States, or almost eight percent of the nation’s population. Type 2 diabetes, informally called adult onset diabetes, is far more common in adults, accounting for 90 to 95 percent of newly diagnosed cases of diabetes in adults.