Brain-derived neurotrophic factor (
BDNF), a member of the
neurotrophins, has been reported to ameliorate
hyperglycemia in obese diabetic animal models. To elucidate the mechanism of
BDNF on
glucose metabolism, we determined the
glucose turnover under basal and euglycemic hyperinsulinemic (
insulin infusion rate, 54 pmol. kg(-1). min(-1)) clamp conditions in obese
insulin-resistant rats, male Zucker fatty rats, which had been acutely administered a
subcutaneous injection of
BDNF (20 mg/kg) (n = 9,
BDNF) or vehicle (n = 8, vehicle). Under the basal condition, acute administration of
BDNF did not affect the
blood glucose level, plasma
insulin level, rate of
glucose disappearance (Rd), and endogenous
glucose production (EGP). Under the clamp condition, the
glucose infusion rate (GIR) was significantly higher in
BDNF than in vehicle (mean +/- SD, 61.4 +/- 19.1 v 41.4 +/- 4.9 micromol. kg(-1). min(-1), P <.05). There was no significant difference in Rd and EGP between the 2 groups under the clamp condition, but the
insulin-mediated suppression ratio of endogenous
glucose production in
BDNF was significantly greater than in vehicle (48.9 +/- 22.2 v 22.4% +/- 20.6%, P <.05). In
BDNF,
mRNA expressions of hepatic
phosphoenolpyruvate carboxykinase (PEPCK) and
glucose-6-phosphatase (G6Pase) were comparable to those of vehicle, while hepatic
glucokinase (GK)
mRNA expression was significantly higher (1.57 +/- 0.33 v 1.03 +/- 0.17, P <.05). We conclude that
BDNF mainly improves hepatic
insulin resistance in obese
insulin-resistant rats, probably by affecting the hepatic GK flux.