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 3-³H-glucose and ¹⁴C-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.