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).