A recently discovered growth factor seems to have a surprisingly prominent role in the regulation of glucose metabolism and may offer a valuable therapeutic target for the treatment of diabetes mellitus.

Researchers have traditionally linked the fibroblast growth factor (FGF) family of proteins, which currently contains 22 known members with activities relating to the regulation of cell growth and division. However, some recent evidence has suggested that certain of these FGFs may also participate in metabolic regulation. In a recent article from the Journal of Clinical Investigation (published online 2 May; doi:10.1172/JCI23606), Alexei Kharitonenkov and his colleagues at the Lilly Research Laboratories (Indianapolis, IN) report the surprising finding that FGF-21, one of the more recently discovered and enigmatic of the FGFs, may be involved in the regulation of glucose homeostasis.

Adipocytes treated with FGF-21 assimilate more glucose from the culture medium than treated cells, in response to a signaling pathway that seems to be fully insulin independent. Following several days of treatment with FGF-21, the researchers observed a significant drop in blood glucose in a number of genetically obese and diabetic rodent strains; accompanying this effect was a decrease in blood triglyceride levels, and an increase in insulin sensitivity and glucose clearance.

Kharitonenkov's team followed these experiments by generating a transgenic mouse line that overexpresses FGF-21 specifically in the liver; unlike other FGFs, FGF-21 does not seem to trigger cell proliferation, and transgenics were not predisposed to tumor formation. By the age of 9 months, the transgenics weighed less, had lower fasted blood glucose levels and more brown fat, and showed greater insulin sensitivity and more efficient glucose clearance than their wild-type counterparts. Surprisingly, there was no hypoglycemia observed in fasted FGF-21–treated or transgenic mice, reinforcing a model in which FGF-21 acts independently of insulin. The transgenics also proved resistant to diet-induced obesity.

Beyond these intriguing findings, the authors are uncertain of FGF-21's precise mode of action. Among other possibilities, they speculate that its effects could be mediated by increasing the expression of a glucose transporter protein or by downregulating secretion of glucagon, insulin's counterpart hormone. Nevertheless, the metabolic effects of FGF-21 could potentially make it a prime target for the design of future therapeutics and may suggest an exciting new direction for diabetes research.