Comparison of the antidiabetic effects of brain-derived neurotrophic factor and thiazolidinediones in obese diabetic mice.
OBJECTIVE
Brain-derived neurotrophic factor (BDNF) ameliorates glucose metabolism in obese diabetic db/db mice. The antidiabetic effect of BDNF is dependent on plasma insulin levels, and BDNF enhances insulin action by modulating insulin signalling in peripheral tissues. The aim of the study was to compare the antidiabetic effects of BDNF with those of thiazolidinediones (TZDs), which are insulin-sensitizing agents, through evaluation of the effects of BDNF and TZDs on glucose metabolism, energy expenditure, pancreatic function and hepatic steatosis in db/db mice.


METHODS
The effects of BDNF, pioglitazone and rosiglitazone on blood glucose concentration, body weight and pancreatic insulin and glucagon contents and the effects of BDNF and troglitazone treatment for 3 weeks on blood glucose concentration, body and liver weights and histological liver images were examined in db/db mice. Furthermore, since BDNF reduces food intake in obese hyperphagic diabetic mice, the effects of BDNF treatment for 3 weeks on blood glucose concentration, body weight, fat pad and liver weights and rectal temparature in db/db mice were compared with those of troglitazone under pair-fed conditions.


RESULTS
BDNF, pioglitazone and rosiglitazone all ameliorated hyperglycaemia in db/db mice, but BDNF increased the pancreatic insulin content more effectively than pioglitazone and rosiglitazone. The pancreatic glucagon content decreased with BDNF, but increased with pioglitazone and rosiglitazone compared with vehicle, and body weight and liver weight increased with troglitazone, but decreased with BDNF compared with vehicle. Histological analysis of the liver showed that BDNF treatment reduced the massive vacuolization observed with vehicle, whereas troglitazone worsened the vacuolization. Body weight, fat pad and liver weights in BDNF-treated mice were significantly lower than those in pair-fed troglitazone-treated db/db mice, and rectal temperature in BDNF-treated mice was significantly higher than that in pair-fed troglitazone-treated mice, suggesting that BDNF enhances energy expenditure.


CONCLUSIONS
These data suggest that compared with TZDs, BDNF potently ameliorates pancreatic dysfunction, fatty liver and energy expenditure, thereby exerting favourable antidiabetic effects in type 2 diabetic mice.
Yamanaka
M
M
Pharmacology Research Laboratories, Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, Osaka, Japan. matsuo-taiji@ds-pharma.co.jp
Itakura
Y
Y
Tsuchida
A
A
Nakagawa
T
T
Noguchi
H
H
Taiji
M
M
D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004734:Energy Metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008820:Mice, Obese; D000077205:Pioglitazone; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*
D001786:Blood Glucose; D019208:Brain-Derived Neurotrophic Factor; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077205:Pioglitazone