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

Nupur Pathak, Nigel Irwin, Varun Pathak, Victor Alan Gault, Peter Raymond Flatt.

Abstract
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. Materials and Methods: Effects of twice daily administration of the stable Oxm analogue, (D-Ser2)Oxm[Lys38-γ-glu-PAL], was assessed in insulin-deficient streptozotocin (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-Ser2)Oxm[Lys38-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-Ser2)Oxm[Lys38-γ-glu-PAL] intervention. Moreover, expression of SYP, mTOR and IRS-1 were significantly elevated (P < 0.05 to P < 0.001) in (D-Ser2)Oxm[Lys38-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-Ser2)Oxm[Lys38-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.

Key words: Oxyntomodulin (Oxm); type 1 diabetes mellitus (T1DM); cognition, hippocampus



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