Insulin-Independent Pathway that Plays a Role in Glucose Metabolism Discovered

Further research is needed to assess the potential of activating FGF19 to treat diabetes and obesity.

Researchers at UT Southwestern Medical Center have discovered a hormone pathway, independent of insulin, that stores glucose in the liver after a meal and drives protein synthesis. They found that fibroblast growth factor 19 (FGF19) has insulin-like characteristics beyond its role in bile acid synthesis.

Unlike insulin, FGF19 does not cause excess glucose to turn to fat. The investigators thus suggest that its activation could lead to new treatments for diabetes or obesity. They caution, however, that much more work is needed to achieve this. In some of the studies conducted by the UT Southwestern team, activating the hormone in rodents caused the liver to grow and develop cancer.

Results were published March 25 in Science in a paper titled “FGF19 as a Postprandial, Insulin-Independent Activator of Hepatic Protein and Glycogen Synthesis.”

The researchers studied mice lacking FGF15, the rodent equivalent of FGF19. After eating, these mice could not properly maintain blood concentrations of glucose and normal amounts of liver glycogen. Glycogen is a form of glucose storage found mainly in liver and muscle tissue.

The mice were then injected with FGF19 to evaluate its effects on metabolism in the liver. FGF19 restored glycogen levels in the rodents, according to the UT Southwestern team. When administered to diabetic mice lacking insulin, FGF19 also corrected the loss of glycogen.

“FGF19 does not make fat, and that’s one of the effects that separates it from insulin,” explains David Mangelsdorf, Ph.D., chairman of pharmacology at UT Southwestern and a co-senior author on the Science paper. “Insulin also does not really have a dramatic effect on bile acid synthesis. So, the two pathways are different even though they both function in glycogen and protein synthesis.”

Considering the side effects observed with FGF19 treatment in their research, Dr. Mangelsdorf suggests that the nuclear bile acid receptor FXR could offer a more promising route of treatment. FXR induces expression of FGF19, and modulators of this receptor are reportedly showing promise in lowering triglycerides and improving cholesterol profiles in preclinical models.