Fibroblast growth factor-21 is induced in human skeletal muscles by hyperinsulinemia

Abstract

Objective: Fibroblast growth factor-21 (FGF-21) is a potent metabolic regulator, which in animal models has been shown to improve glucose metabolism and insulin sensitivity. Recently, FGF-21 was shown to be expressed and secreted from murine muscle cells in response to insulin stimulation.

Research design and methods: We studied muscular FGF-21 expression and plasma FGF-21 after acute insulin stimulation in young healthy men during a hyperinsulinemic-euglycemic clamp. Furthermore, we investigated systemic levels and muscle FGF-21 expression in humans with or without insulin resistance and chronic elevated insulin.

Results: FGF-21 was barely detectable in young healthy men before insulin infusion. After 3 or 4 h of insulin infusion during a hyperinsulinemic-euglycemic clamp, muscular FGF-21 expression increased significantly. Plasma FGF-21 followed the same pattern. In individuals with chronic elevated insulin, muscular FGF-21 expression was associated with hyperinsulinemia in men but not in women. In plasma, hyperinsulinemia and fasting glucose were positively associated with plasma FGF-21 while plasma FGF-21 correlated negatively with HDL cholesterol. No associations between muscle and plasma FGF-21 were found in the individuals with chronic hyperinsulinemia.

Conclusions: FGF-21 is expressed in human skeletal muscle in response to insulin stimulation, suggesting that FGF-21 is an insulin-regulated myokine. In support, we found an association between chronic hyperinsulinemia and levels of FGF-21.

FIG. 1.

Muscle and plasma FGF-21 during acute hyperinsulinemia. Healthy young men underwent a hyperinsulinemic-euglycemic insulin clamp. Fifteen subjects had muscle biopsies and blood samples before and after 3 h, while additionally eight subjects had muscle biopsies before and 2 and 4 h into the clamp. Data are presented as FGF-21 expression normalized to 18s expression. A: Muscle FGF-21 expression was significantly increased by 3–4 h (P = 0.001, paired t test). B: Plasma FGF-21 increased significantly after 3 h (P = 0.006, paired t test).

FIG. 2.

Muscle FGF-21 expression during chronic hyperinsulinemia. Men (A) and women (B) were divided into quartiles based on fasting insulin levels (low = 25% lowest, med = middle 50%, high = 25% highest). Data are presented as geometric mean and 95% CI. In men, the “high” quartile had significantly higher FGF-21 expression than the “low” quartile (P = 0.04). No significance was found in women. *P < 0.05.