Introduction: Oxyntomodulin (OXM) is a peptide hormone released from the gut in post-prandial state that activates both the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR). Because GLP-1 agonism has been reported to have a renoprotective effect in animal models and humans, we compared the effect of simultaneous GCGR and GLP-1 activation to matched GLP-1 agonism on kidney function in mice.
Methods: Male 16 wk old db/db BLKS/J mice (n=30) with increased serum creatinine (~3-fold) were selected and treated once daily with saline, OXM or OXM-Q3E (a peptide analog to OXM without GCGR activity) for 6 weeks. Body weight and food intake were monitored weekly. An intraperitoneal glucose tolerance test (IPGTT) was performed on week 1 after food was removed for 6h. Plasma levels were collected before and at the end of the study to evaluate plasma creatinine and ketone bodies. OXM, but not OXMQ3E, activates the GCGR in vivo as shown by increased plasma ketone bodies (OXM 7.7±0.4, OXMQ3E 4.1±0.3, Vehicle 3.5±0.4 mg/dL). During the IPGTT, OXM and OXMQ3E had similar improvement in glucose tolerance while OXM reduced body weight and serum creatinine to a greater extent than OXMQ3E.
Results: OXM, but not OXMQ3E, activates the GCGR in vivo as shown by increased plasma ketone bodies (OXM 7.7±0.4, OXMQ3E 4.1±0.3, Vehicle 3.5±0.4 mg/dL). During the IPGTT, OXM and OXMQ3E had similar improvement in glucose tolerance while OXM reduced body weight and serum creatinine to a greater extent than OXMQ3E.
Conclusions: Our results provide new insights into the mechanism of action of OXM and suggest that activation of GCGR may have beneficial effect on kidney function when delivered together with GLP-1.
G. Anvari: None. A. Pocai: None.
