Can a Bile Hormone Replace Insulin as the Treatment for Diabetes?

A bile hormone with a regulatory role in glucose metabolism may be a candidate to complement or replace insulin for the treatment of Type I diabetes.

Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) have been studying the hormone FGF19 (fibroblast growth factor 19) for about eight years. The FGFs are a family of more than 20 small secreted peptides. FGF19 has been shown to cause resistance to diet-induced obesity and insulin desensitization and to improve insulin, glucose, and lipid profiles in diabetic rodents.

In the current study, the investigators worked with a mouse population that had been genetically engineered to lack the gene for FGF15, which is the mouse version of FGF19. They reported in the March 25, 2011, issue of the journal Science that FGF19 stimulated hepatic protein and glycogen synthesis but did not induce synthesis of fats. The effects of FGF19 were independent of the activity of either insulin or the protein kinase Akt and, instead, were mediated through a mitogen-activated protein kinase-signaling pathway that activated components of the protein translation machinery and stimulated glycogen synthase activity.

Mice lacking FGF15 failed to properly maintain blood concentrations of glucose and normal postprandial amounts of liver glycogen. However, FGF19 treatment restored the loss of glycogen in diabetic animals lacking insulin.

"FGF19 does not make fat, and that is one of the effects that separates it from insulin,” said senior author Dr. David Mangelsdorf, professor of pharmacology at the University of Texas Southwestern Medical Center. "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. The fundamental discovery is that there is a pathway that exists that is required for the body, after a meal, to store glucose in the liver and drive protein synthesis. That pathway is independent of insulin.”

Considerable work remains, however, before FGF19 becomes a workable alternative to insulin therapy, since in some studies with rodents activating this hormone caused liver growth and cancer development.

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University of Texas Southwestern Medical Center