Abstract

Objective: FGF-21 is highly expressed in the liver and regulates hepatic glucose production and lipid metabolism in rodents. However, its role in the pathogenesis of T2DM in humans remains to be defined. The aim of this study was to quantitate circulating plasma FGF-21 levels and examine their relationship with insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance.

Research Design and Methods: Forty one (41) subjects; 8 lean normal-glucose-tolerant (NGT), 9 obese NGT, 12 impaired fasting glucose/impaired glucose tolerance (IFG/IGT), and 12 T2DM subjects received an oral glucose tolerance test (OGTT) and euglycemic hyperinsulinemic clamp (80 mU/m²•min) combined with 3-[³H] glucose infusion.

Results: T2DM, IGT and obese NGT subjects were insulin resistant compared to lean NGT subjects. Plasma FGF-21 levels progressively increased from 3.9±0.3 ng/ml in lean NGT subjects to 4.9±0.2 in obese NGT subjects to 5.2±0.2 in IGT and to 5.3 ± 0.2 in T2DM subjects. FGF-21 levels correlated inversely with whole body (primarily reflects muscle) insulin sensitivity (r=-0.341, p=0.029) and directly with the hepatic insulin resistance index (r=0.432, p=0.028). FGF-21 levels also correlated with measures of glycemia: FPG (r=0.312, p=0.05), 2-h plasma glucose (r=0.414, p=0.01), and HbA_1c (r=0.325, p=0.04).

Conclusion: Plasma FGF-21 levels are increased in insulin resistant states and correlate with hepatic and whole body (muscle) insulin resistance. FGF-21 may play a role in pathogenesis of hepatic and whole body insulin resistance in T2DM.