Decreased hepatic glucose production in obese rats by dipeptidyl peptidase-IV inhibitor sitagliptin.
BACKGROUND
Dipeptidyl peptidase-IV (DPP-4) inhibitors are now used to improve postprandial glycemic control in type 2 diabetes. However, their effects on hepatic glucose production (HGP) in obesity are not clear. This study was designed to test the hypothesis that gluconeogenesis and HGP can be modulated by DPP-4 inhibitors in obesity.


METHODS
Sprague Dawley male rats were divided into four groups, each on a different diet: general rat chow, n = 10 (G); G + sitagliptin, n = 10; high fat chow (obesity), n = 10 (55% fat calories, HFO); HFO + sitagliptin, n = 10. After 10 weeks, the rats were fasted overnight and glucose metabolism was determined using 3-(3)H-glucose and (14)C-glycerol as tracers.


RESULTS
Glycerol rate of appearance (P < 0.00001), plasma glycerol (P < 0.05) and free fatty acid (FFA) (P < 0.05) concentrations, and HGP (P < 0.05) were decreased in HFO + sitagliptin group compared with HFO group, but there was no significant difference between G and G + sitagliptin groups (P > 0.05). Gluconeogenesis in HFO group was five times of that in G rats (P < 0.01), but was significantly declined in HFO + sitagliptin group (P < 0.0001).


CONCLUSIONS
Gluconeogenesis and HGP were inhibited by sitagliptin in high fat-induced obese rats due to decreased glycerol availability, which was a result of reduced glycerol release from adipose tissues. The finding suggests that sitagliptin is potentially useful for controlling fasting glucose in obesity, thereby delaying or preventing the development of diabetes.
Endocrinology and Metabolism Research Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Ying-Li
YL
Lu
De-Quan
DQ
Zhou
Hua-Ling
HL
Zhai
Hui
H
Wu
Zeng-Kui
ZK
Guo
D000818:Animals; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D005947:Glucose / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism*; D011719:Pyrazines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000627:therapeutic use*
D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D005947:Glucose; D000068900:Sitagliptin Phosphate