(D-Ser2)Oxm[Lys38- and #947;-glu-PAL] improves hippocampal gene expression and cognition in a mouse model of type 1 diabetes

Nupur Pathak, Nigel Irwin, Varun Pathak, Victor Gault, Peter Flatt
2016 Journal of Experimental and Integrative Medicine  
Objective: Oxyntomodulin (Oxm) is a gastrointestinal hormone with recently noted therapeutic potential for type 1 diabetes mellitus (T1DM). The present study examined the effects of a stable Oxm analogue on anxiety, exploratory behavior, cognitive function, hippocampal gene expression and metabolic control in a mouse model of T1DM. Methods: Effects of twice daily administration of the stable Oxm analogue, (d-Ser 2 )Oxm[Lys 38 -γ-glu-PAL], was assessed in insulin-deficient streptozotocin
more » ... eptozotocin (STZ)-induced T1DM mice. Results: Induction of diabetes by STZ injection significantly (P < 0.05) impaired learning and memory compared to normal control mice. However, (d-Ser 2 )Oxm[Lys 38 -γ-glu-PAL] treatment completely reversed this detrimental effect. Anxiety levels and exploratory behavior were not significantly different between all groups of mice. Hippocampal gene expression of MASH1, SYP and mTOR were reduced (P < 0.01 to P < 0.001) in T1DM mice, but significantly (P < 0.05 to P < 0.001) enhanced by twice daily (d-Ser 2 )Oxm[Lys 38γ-glu-PAL] intervention. Moreover, expression of SYP, mTOR and IRS-1 were significantly elevated (P < 0.05 to P < 0.001) in (d-Ser 2 )Oxm[Lys 38 -γ-glu-PAL] mice compared to both STZ and lean controls. These effects were accompanied by improved (P < 0.001) glucose tolerance and insulin sensitivity compared to STZ controls. Conclusion: The data highlight the potential of (d-Ser 2 )Oxm[Lys 38 -γ-glu-PAL] for the treatment of T1DM, and reveal the ability of this Oxm analogue to restore the deficits of learning and memory observed in STZ-induced T1DM.
doi:10.5455/jeim.050216.br.027 fatcat:7spg6mpbnfam3dwthw6rd5frha