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Sartorius, T. ; Hennige, A.M. ; Fritsche, A. ; Häring, H.-U.

Sustained treatment with insulin detemir in mice alters brain activity and locomotion.

PLoS ONE 11:e0162124 (2016)

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Aims Recent studies have identified unique brain effects of insulin detemir (Levemir (R)). Due to its pharmacologic properties, insulin detemir may reach higher concentrations in the brain than regular insulin. This might explain the observed increased brain stimulation after acute insulin detemir application but it remained unclear whether chronic insulin detemir treatment causes alterations in brain activity as a consequence of overstimulation. Methods In mice, we examined insulin detemir's prolonged brain exposure by continuous subcutaneous (s.c.) application using either micro-osmotic pumps or daily s.c. injections and performed continuous radiotelemetric electrocorticography and locomotion recordings. Results Acute intracerebroventricular injection of insulin detemir activated cortical and locomotor activity significantly more than regular insulin in equimolar doses (0.94 and 5.63mU in total), suggesting an enhanced acute impact on brain networks. However, given continuously s.c., insulin detemir significantly reduced cortical activity (theta: 21.3 +/- 6.1% vs. 73.0 +/- 8.1%, P<0.001) and failed tomaintain locomotion, while regular insulin resulted in an increase of both parameters. Conclusions The data suggest that permanently-increased insulin detemir levels in the brain convert its hyperstimulatory effects and finally mediate impairments in brain activity and locomotion. This observation might be considered when human studies with insulin detemir are designed to target the brain in order to optimize treatment regimens.

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