FGF-21 was discovered during a high-throughput assay for secreted proteins that increased glucose uptake in 3T3L-1 adipocytes (9
). Subsequent studies (4
) showed that administration of recombinant FGF-21 in rodent models of diabetes and in diabetic rhesus monkeys improved blood glucose and the lipid profile. However, in none of these studies were the plasma levels of FGF-21 compared between diabetic and nondiabetic animals.
In the present study, we demonstrate that plasma FGF-21 levels are elevated in insulin-resistant states (obesity, IGT/IFG, type 2 diabetes) and are inversely correlated with both peripheral and hepatic insulin sensitivity. This is consistent with two other reports (15
) in humans that demonstrated elevated plasma FGF-21 concentration in obesity, IGT, and type 2 diabetes. The novelty of our study is that we demonstrate for the first time in humans that the increase in plasma FGF-21 levels are strongly correlated with the severity of whole-body (primarily reflects muscle) and hepatic insulin resistance.
Our study is in agreement with two previous studies in Asians, in which increased plasma FGF-21 levels were observed in newly diagnosed, drug-naïve diabetic subjects and in treated type 2 diabetic subjects (26
). In a Chinese population, plasma FGF-21 levels correlated with markers of the insulin resistance (metabolic) syndrome (16
). However, this later study did not measure either hepatic or peripheral insulin sensitivity.
In rodent models, FGF-21 stimulates glucose uptake in 3TL3 adipocytes and increases GLUT4 expression in adipocytes. Arner et al. (27
) demonstrated that FGF-21 inhibits lipolysis in human adipocytes and suggested that this may contribute to the protein's insulin-sensitizing effect in humans. A synergistic interaction has been described between FGF-21 and rosiglitazone to stimulate glucose uptake (28
). Contrary to these observations, in the present study plasma FGF-21 concentrations were positively correlated with adipocyte insulin resistance. With regard to the liver, in animal models FGF-21 has been shown to be expressed primarily in liver, and its glucose-lowering effects of FGF-21 have been suggested to be mediated by its actions on liver (9
). In contrast, in the present study, we demonstrate a positive correlation between elevated FGF-21 levels and hepatic insulin resistance.
The apparently divergent results of the current study in humans and previous studies in animals could reflect a true species difference in the metabolic effects of FGF-21 in humans versus animals or may be less contradictory than they appear. Thus, the elevated plasma FGF-21 levels in insulin-resistant states may simply reflect a compensatory response to offset the peripheral and/or hepatic insulin resistance and not be a cause of the insulin resistance. Since our observations are cross-sectional in nature, it is not possible to establish a cause-and-effect relationship (i.e., what is primary and what is secondary). It also is not possible to distinguish whether the increased plasma FGF-21 levels in obese subjects and subjects with IGT/IFG and type 2 diabetes are related to insulin resistance or obesity, since all three groups had similarly elevated FGF-21 levels. Further studies will be required to further elucidate the role of FGF-21 in glucose homeostasis and whether FGF-21 will sensitize target issues (liver, adipocytes, muscle) to insulin, as has been reported in animal models of diabetes.
Recent studies have suggested that plasma FGF-21 concentrations are affected by the glomerular filtration rate and therefore may be related to the level of renal function (25
). Patients undergoing dialysis have significantly increased plasma FGF-21 levels compared with control subjects, and this is independent of the glucose/lipid metabolic status (25
). Although none of the participants enrolled in our study had impaired renal function, glomerular filtration rate spanned a wide range. Nonetheless, we did not find a significant relationship between plasma FGF-21 concentration and estimated glomerular filtration rate. Thus, in our sample, FGF-21 concentrations are unlikely to be affected by this parameter.
In summary, elevated plasma FGF-21 concentrations in humans appear to be related to the presence of hepatic and peripheral insulin resistance. Whether the increase in plasma FGF-21 represents a compensatory effect to offset insulin resistance or is a causative factor in the development of insulin resistance is yet to be determined.