UCSD Team Discovers Diabetes Trigger in Fatty Diet

A new study, published in the December 29 issue of the journal Cell, reports the discovery of a molecular link between a high-fat, or Western-style, diet, and the disruption of insulin production, explaining how a high-fat diet causes type 2 diabetes.

Researchers at the University of California, San Diego (UCSD) School of Medicine have found that a single gene encoding the enzyme GnT-4a glycosyltransferase (GnT-4a) is key to enabling the pancreatic beta cells to sense blood glucose levels and appropriately produce insulin. They have further demonstrated in mice that this enzyme is suppressed by a high-fat diet. Without enough GnT-4a enzyme, pancreatic beta cell failure occurs, resulting in type 2 diabetes.

While it is widely recognized that type 2 diabetes is directly linked to a high-fat diet and obesity, until now, researchers had not been able to pinpoint how and why.

"We have discovered a mechanistic explanation for beta cell failure in response to a high-fat diet and obesity, a molecular trigger which begins the chain of events leading from hyperglycemia to insulin resistance and type 2 diabetes," said Jamey Marth, Ph.D., UCSD Professor of Cellular and Molecular Medicine and Investigator with the Howard Hughes Medical Institute. "This finding suggests new approaches to the prevention and treatment of diabetes."

Marth, first author Kazuaki Ohtsubo, Ph.D., of the Howard Hughes Medical Institute and UCSD's Department of Cellular and Molecular Medicine, and their colleagues made the discovery by studying glycosylation. This is the process that controls the formation on proteins of sugar linkages called glycans, which are linked to proteins by a large family of related enzymes such as GnT-4a. The key role of the GnT-4a enzyme is to maintain glucose transporters in place on the surface of the beta cell. Pancreatic glucose transporters are necessary at the beta cell surface to sense glucose levels in the blood. When glucose is elevated after a meal, the transport of glucose by these transporters triggers the beta cell to secrete insulin. Proper insulin secretion is essential to enable the rest of the body to metabolize glucose and convert it to cellular energy.

Analyzing mice lacking the GnT4a gene, the researchers found that these mice had elevated blood glucose concentrations. In mice, as in humans, a high level of sugar in the blood is the first measure and diagnosis of diabetes. The symptoms progressed as a result of beta cell failure to normally secrete insulin, and full blown type 2 diabetes developed.

The UCSD team then fed normal mice a high-fat diet, and found that GnT-4a gene expression was reduced. Insufficient GnT-4a expression caused the glucose transporter to leave the cell surface and become internalized. The resulting failure of the cell to sense and respond to blood glucose levels led to the development of type 2 diabetes in the mice.

"Our findings suggest that the current human epidemic in type 2 diabetes may be a result of GnT-4a enzyme deficiency," said Marth. "The GnT4a enzyme is required to synthesize a glycan structure that holds the glucose transporter in place at the beta cell surface. The loss of this key transporter is directly linked to reduced GnT-4a protein glycosylation, a high fat diet, and type 2 diabetes."