Although we have a lot of information from ADA Evan David Rosen, M.D., Ph.D. Assistant Professor of Medicine, Harvard Medical School, brings us more research he uncovered about a new protein like drug from Lilly. FGF-21 is unique because as an anti-diabetic drug it appears to increase glucose uptake in an insulin-independent fashion. Learn more at A New Face In The Crowd: FGF-21
Drugs for type 2 diabetes usually belong to one of two broad categories: they either induce the secretion of insulin from the pancreas, or they make the insulin that’s already present more effective. Sulfonylurea drugs like glyburide and glipizide are examples of the former category, as are newer agents like repaglinide (Prandin™) and nateglinide (Starlix™). Examples of the second category include thiazolidinediones like pioglitazone (Actos™) and rosiglitazone (Avandia™), as well as metformin (Glucophage™). A lot of energy and expense continues to be spent on finding newer, more efficacious drugs in these two groups, and there have been some incremental advances with that approach. A new paper in the Journal of Clinical Investigation, however, alerts us to a molecule that seems to improve diabetes (at least in rodents) using a different mode of action.
The authors of this study, based at Eli Lilly, were screening human proteins for their ability to induce glucose uptake into fat cells. One of the positive hits from their assay was a protein called fibroblast growth factor 21 (FGF-21). FGF-21, as the name implies, is a member of a large family of fibroblast growth factors, most of which are relatively understudied.
One of the characteristics of FGF-21 that make it interesting as an anti-diabetic is its ability to increase glucose uptake in an insulin-independent fashion. This distinguishes it from insulin-sensitizing agents, which require the presence of insulin in order to reduce glucose levels. This effect requires several hours to take effect, is maximal a few days into FGF-21 administration, and likely involves the induction of glucose transporter 1 (GLUT1) expression in adipose tissue. GLUT1 protein is a transporter that allows glucose to move from the blood into cells even when insulin is not present, thus reducing blood sugar levels. Another beneficial effect of FGF-21 is its ability to suppress the secretion of glucagon from the pancreas, a hormone that acts like an anti-insulin to raise blood sugar levels.
The net effect of FGF-21 was the reduction of blood glucose levels in obese, diabetic rats and mice. There was also a salutary effect on blood triglycerides, which would be a nice bonus if the same result were seen in human trials.
When injected into animals, no significant effect was noted on body weight, which is also a positive thing, given the well known weight gain effects of insulin, thiazolidinediones, and many other anti-diabetic drugs. It may be that longer periods of dosing will be required to see weight gain, but I doubt it. The Lilly team created a genetically engineered mouse that expresses lots of FGF-21 over the course of its entire life, and those animals actually weighed less than control animals and had less adipose tissue. The basis for this effect is not clear, nor is it obvious that the same thing will occur with chronic dosing by injection, but at least it seems that weight gain is unlikely to be an issue. There was also no evidence of blood sugars that were too low, a fact that I find somewhat surprising given the ability of FGF-21 to drive sugar into cells and to block glucagon secretion.
One area of concern is the known tendency of fibroblast growth factors to cause cells to divide. This might predispose someone taking an FGF to develop cancer, a clear kiss of death for a promising anti-diabetic drug. Interestingly, FGF-21 appears not to have this problem, for unknown reasons. The authors show that other FGFs do cause cell division, but FGF-21 is neutral in this regard. Also, the mice engineered to express very high levels of FGF-21 do not seem to develop cancer, at least up to the longest time studied (a bit less than a year).
So where does this leave us? First, it shows that while many labs are looking for synthetic drugs to aid in the war on diabetes, our own bodies may have some hidden tricks yet to discover. FGF-21 is a naturally occurring protein that had previously escaped scientific attention. Second, the ability of FGF-21 to reduce blood sugar levels without the involvement of insulin should open new doors in the search for new drugs. It is important to note that not every drug that increases basal glucose uptake will be beneficial; the hormone TNF-a, for example, has this effect but actually tends to worsen diabetes. Nonetheless, the FGF-21 story will open the minds of some folks about just what an effective anti-diabetic drug should look like. Finally, FGF-21 is a protein, which means that it would need to be injected to maintain its biological activity using current technology. Rapid advances in drug delivery, however, such as new inhalers and skin patches, may improve this situation. It’s also possible that a small non-protein drug can be found that will mimic the activity of FGF-21, and I’m sure the Lilly team is actively pursuing this line of investigation.
FGF-21 won’t be on your pharmacy shelves any time soon, but there’s a lot to like about this unexpected new player in metabolic disease research.
Alexei Kharitonenkov, Tatiyana L. Shiyanova, Anja Koester, Amy M. Ford, Radmila Micanovic, Elizabeth J. Galbreath, George E. Sandusky, Lisa J. Hammond, Julie S. Moyers, Rebecca A. Owens, Jesper Gromada, Joseph T. Brozinick, Eric D. Hawkins, Victor J. Wroblewski, De-Shan Li, Farrokh Mehrbod, S. Richard Jaskunas, and Armen B. Shanafelt. FGF-21 as a novel metabolic regulator. Journal of Clinical Investigation. 2005 115: 1627-1635.
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