3.1. Linagliptin reduced plasma triglyceride levels without altering blood glucose and serum insulin levels in OSI-906-treated mice
In this study, wild-type C57BL/6J mice were orally injected with OSI-906 at a dosage of 45 mg/day, thereby blunting IR and IGF1R-mediated signaling in the liver and white adipose tissue (Shirakawa et al., 2020; Tajima et al., 2017). Linagliptin was administered by oral gavage at a dosage of 3 mg/kg/day, thereby significantly inhibiting DPP-4 activity and significantly increasing the GLP-1 level (Kern et al., 2012). The mice were treated with the vehicle, linagliptin (Lina), OSI-906, or OSI-906 in combination with linagliptin (OSI-906 + Lina) for 7 days (Figure 1a). The oral administration of OSI-906 transiently decreased the body weight gain observed on day 3 (Figure 1b). Linagliptin prevented the OSI-906-induced reductions in body weight gain observed on day 3 (Figure 1a). Blood glucose levels became significantly elevated at 4 hours after OSI-906 administration, and linagliptin partially reduced the blood glucose levels observed on days 1 and 2 (Figure 1c). However, hyperglycemia elicited by OSI-906 administration did not improve with linagliptin treatment after day 3 (Figure 1c).
On day 7, the serum insulin levels became significantly higher after OSI-906 administration, consistent with the inhibition of IR/IGF1R. Treatment with linagliptin did not influence the hyperinsulinemia observed in mice treated with OSI-906 (Figure 1d). On the other hand, linagliptin canceled the OSI-906-induced elevation in plasma triglyceride levels, although no significant differences in plasma free fatty acid (FFA) levels were observed between the OSI-906 and OSI-906 + Lina groups (Figure 1e and F). The serum glutamic pyruvic transaminase (GPT) levels were not altered by the administration of OSI-906 or by treatment with linagliptin (Figure 1g).