FGF-21 as a candidate for the treatment of diabetes

It is estimated that there are more than 38 million people in the seven major markets with diabetes and this figure is set to rise to 50 million in 2012 (for an in depth evaluation of the diabetes market size and value, plus an analysis of emerging therapeutics see our recent feature Non-insulin Antidiabetics - Three New Classes Compete for Market Control). Despite the presence of well established treatments of diabetes significant unmet needs remain.

The JCI paper highlighted here identifies FGF-21, a member of the FGF family, as a novel candidate target for diabetes therapeutics. This family includes 22 known proteins which bind FGFR-1, -2, -3, and -4 and activate receptor tyrosine kinase activity. The FGF family is primarily associated with cell cycle regulation, survival and angiogensis and have hence been investigated in relation to oncology. More recently FGF-10, FGF-16 and particularly FGF-19 have been implicated in metabolic control. FGF-19, which binds FGFR-4, has been shown to cause resistance to diet-induced obesity and insulin desensitization and to improve insulin, glucose, and lipid profiles .

In addition to FGFR-4, FGFR-1 and -2 have also been implicated in diabetes. Blocking FGFR-1 receptor activation in pancreatic beta cells leads to diabetes in mice, while FGFR-2 appears to be a key molecule during pancreatic development. Lilly researchers have recently identified FGF-21 as a candidate ligand for both of these receptors. This growth factor is preferentially expressed in the liver and in their JCI paper Kharitonenkov et al report that it stimulates glucose uptake by cultured and primary human adipocytes. This effect was selective to adipocytes and appeared to be mediated by an increase in the expression of the glucose transporter, GLUT-1. In addition FGF-21 was also shown to reduce glucagon liberation from islets. Importantly given the role of the FGF family in various processes involved in tumor biology, FGF-21 was found to be non-mitogenic. Moreover, transgenic mice overexpressing FGF-21 did not develop liver tumors or show evidence of any other tissue hyperplasia.

FGF-21 therefore appears to have potential anti-hyperglycemic activity and this was confirmed in vivo with the Lilly group reporting that the administration of FGF-21 lowered fed glucose levels in control rodents as well as those with experimentally induced diabetes. Although FGF-21 reduced hyperglycemia it did not provoke hypoglycemia, a problem which occurs with other anti-diabetic agents such as insulin. Remarkably the anti-hyperglycemic activity of FGF-21 was observed following chronic administration and after each administration at time points considerably extended past the half-life of FGF-21. This second finding is consistent with the observation that the activity of FGF-21 depends on protein expression.

Finally, in addition to being anti-hyperglycemic, FGF-21 was found to confer protection against diet-induced obesity even though treated animals demonstrated increased food intake.

This important study reveals FGF-21 as a promising lead in the treatment of both diabetes and also maybe obesity. Because FGF-21 is a peptide, unless novel delivery technologies are employed, it will have to be administered via injection. The same is true however for other new classes of anti-diabetic therapies such as the GLP-1 analogs. FGF-21 will likely therefore be compared with insulin and its use would probably be reserved for later stages of therapy once oral antidiabetic drugs start to fail. Since FGF-21 does not appear to cause hypoglycemia, weight gain and/or frequent glucose monitoring it is likely to compare favorably with insulin use especially if adequate efficacy is demonstrated in the clinic. Furthermore FGF-21 stimulated glucose uptake appeared to be insulin independent and additive to insulin activity upon coadministration suggesting that FGF-21 could be used effectively prior to the initiation of insulin therapy even against a background of low insulin production and extreme insulin resistance; moreover treatment could be expected to continue to be of use once insulin use has been initiated.

Source: LeadDiscovery's TherapeuticAdvances - original article J Clin Invest. 2005 Jun;115(6):1627-35. Epub 2005 May 2 featured in DailyUpdates-Metabolic Disorders