title: Sustained Treatment with Insulin Detemir in Mice Alters Brain Activity and Locomotion.
abstract: OBJECTIVE
  Recent studies have identified unique brain effects of insulin detemir (Levemir®). 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 5.63 mU 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 to maintain 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.
authors: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tuebingen, Tuebingen, Germany.|German Center for Diabetes Research (DZD), Tuebingen, Germany.|Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen (IDM), Tuebingen, Germany.
authors: Tina
authors: T
authors: Sartorius
authors: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tuebingen, Tuebingen, Germany.|German Center for Diabetes Research (DZD), Tuebingen, Germany.|Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen (IDM), Tuebingen, Germany.
authors: Anita M
authors: AM
authors: Hennige
authors: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tuebingen, Tuebingen, Germany.|German Center for Diabetes Research (DZD), Tuebingen, Germany.|Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen (IDM), Tuebingen, Germany.
authors: Andreas
authors: A
authors: Fritsche
authors: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tuebingen, Tuebingen, Germany.|German Center for Diabetes Research (DZD), Tuebingen, Germany.|Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tuebingen (IDM), Tuebingen, Germany.
authors: Hans-Ulrich
authors: HU
authors: Häring
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D000069280:Electrocorticography; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000069057:Insulin Detemir / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D013686:Telemetry
chemical_list: D007004:Hypoglycemic Agents; D000069057:Insulin Detemir