Circulating Fibroblast Growth Factor-21 Is Elevated in Impaired Glucose Tolerance and Type 2 Diabetes and Correlates With Muscle and Hepatic Insulin Resistance

OBJECTIVE

Fibroblast growth factor (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 type 2 diabetes 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 subjects (8 lean with normal glucose tolerance [NGT], 9 obese with NGT, 12 with impaired fasting glucose [IFG]/impaired glucose tolerance [IGT], and 12 type 2 diabetic subjects) received an oral glucose tolerance test (OGTT) and a hyperinsulinemic-euglycemic clamp (80 mU/m² per min) combined with 3-[³H] glucose infusion.

RESULTS

Subjects with type 2 diabetes, subjects with IGT, and obese subjects with NGT were insulin resistant compared with lean subjects with NGT. Plasma FGF-21 levels progressively increased from 3.9 ± 0.3 ng/ml in lean subjects with NGT to 4.9 ± 0.2 in obese subjects with NGT to 5.2 ± 0.2 in subjects with IGT and to 5.3 ± 0.2 in type 2 diabetic subjects. FGF-21 levels correlated inversely with whole-body (primarily reflects muscle) insulin sensitivity (r = −0.421, P = 0.007) and directly with the hepatic insulin resistance index (r = 0.344, P = 0.034). FGF-21 levels also correlated with measures of glycemia (fasting plasma glucose [r = 0.312, P = 0.05], 2-h plasma glucose [r = 0.414, P = 0.01], and A1C [r = 0.325, P = 0.04]).

CONCLUSIONS

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 type 2 diabetes.Fibroblast growth factors (FGFs) represent a group of peptides that regulate diverse biological functions, including cell differentiation, cell growth, and angiogenesis (1,2). Recently, a subfamily of FGFs that interact with nuclear receptors has been identified that plays an important role in liver, bone, and adipose tissue metabolism (3,4). This subfamily contains FGF-19, which regulates energy expenditure (5,6); FGF-23, which regulates phosphate metabolism and excretion (7); and the recently described FGF-21, which regulates glucose homeostasis (8,9).FGF-21 is a novel protein that has been implicated in the regulation of lipid and glucose metabolism under fasting and ketotic conditions (9,10). In murine models, FGF-21 was reported to be expressed predominantly in liver (11), but its expression has also been reported in adipose tissue and pancreatic β-cells (12). In a primate model of diabetes, Kharitonenkov et al. (9) reported a reduction in plasma glucose, insulin, triglycerides, LDL cholesterol, and HDL cholesterol levels following 6 weeks of recombinant FGF-21 administration. In diet-induced obese mice, FGF-21 reversed hepatic steatosis and improved insulin sensitivity (13). In adipose tissue, FGF-21 was shown to increase glucose uptake (9). Based on these observations, FGF-21 has been proposed as a potential therapeutic agent for type 2 diabetes in humans (14). However, few studies in humans have examined the relationship between FGF-21 and glucose/lipid metabolism. Chen et al. (15) reported that patients with newly diagnosed type 2 diabetes had significantly higher plasma FGF-21 concentrations than nondiabetic control subjects, and FGF-21 negatively correlated with fasting plasma glucose. More recently, Zhang et al. (16) found that FGF-21 concentrations are elevated in obese nondiabetic individuals compared with lean healthy control subjects and that the circulating levels correlated positively with adiposity and fasting insulin and negatively with HDL cholesterol. Conversely, in patients with anorexia nervosa, plasma FGF-21 concentrations are decreased and increased following weight gain (17). In the present study, we examined the relationship between plasma FGF-21 concentrations and direct measurements of peripheral and hepatic insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance.