Brain-derived neurotrophic factor ameliorates hepatic insulin resistance in Zucker fatty rats.
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.
Kuroda
Akio
A
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Yamasaki
Yoshimitsu
Y
Matsuhisa
Munehide
M
Kubota
Minoru
M
Nakahara
Itsuro
I
Nakatani
Yoshihisa
Y
Hoshi
Ayumu
A
Gorogawa
Shin-Ichi
S
Umayahara
Yutaka
Y
Itakura
Yasushi
Y
Nakagawa
Tsutomu
T
Taiji
Mutsuo
M
Kajimoto
Yoshitaka
Y
Hori
Masatsugu
M
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002262:Carboxy-Lyases / Q000235:genetics; D005941:Glucokinase / Q000235:genetics; D005952:Glucose-6-Phosphatase / Q000235:genetics; D006003:Glycogen / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000503:physiopathology*; D008297:Male; D009765:Obesity / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker
D001786:Blood Glucose; D019208:Brain-Derived Neurotrophic Factor; D007328:Insulin; D012333:RNA, Messenger; D006003:Glycogen; D005941:Glucokinase; D005952:Glucose-6-Phosphatase; D002262:Carboxy-Lyases