Fat Disrupts Sugar Sensors Causing Type 2 Diabetes

The authors argue that a deeper understanding of the processes involved could help them develop a cure. One of the main risk factors for type 2 diabetes is being overweight -- rising obesity levels have contributed to a doubling of diabetes cases in the last 30 years.

Sugar in the blood is monitored by pancreatic beta cells. If sugar levels are too high then the cells release the hormone insulin, which tells the body to bring the levels back down. Key to this is the enzyme GnT-4a. It allows the cells to absorb glucose and therefore know how much is in the blood.

Researchers at the University of California and the Sanford-Burnham Medical Research Institute say they have shown how fat disrupts the enzyme's production. Experiments on mice showed that those on a high-fat diet had elevated levels of free fatty acids in the blood. These fatty acids interfered with two proteins - FOXA2 and HNF1A - involved in the production of GnT-4a. The result: fat effectively blinded cells to sugar levels in the blood and the mice showed several symptoms of type 2 diabetes. The same process also took place in samples of human pancreatic cells.

Lead researcher Dr. Jamey Marth said, "The observation that beta cell malfunction significantly contributes to multiple disease signs, including insulin resistance, was unexpected."

He suggested that boosting GnT-4a levels could prevent the onset of 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." "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."

Dr. Iain Frame, Director of Research at Diabetes UK, said, "The researchers have linked their results in mice to the same pathways in humans and although they did not show they could prevent or cure type 2 diabetes, they have shown it is a theory worth investigating further."

"We will watch this with great interest and hope this early work will eventually lead to some benefit to people with type 2 diabetes."

Pediatrics, Aug. 2011