title: The brain response to peripheral insulin declines with age: a contribution of the blood-brain barrier?
abstract: OBJECTIVE
  It is a matter of debate whether impaired insulin action originates from a defect at the neural level or impaired transport of the hormone into the brain. In this study, we aimed to investigate the effect of aging on insulin concentrations in the periphery and the central nervous system as well as its impact on insulin-dependent brain activity.
  
  
  METHODS
  Insulin, glucose and albumin concentrations were determined in 160 paired human serum and cerebrospinal fluid (CSF) samples. Additionally, insulin was applied in young and aged mice by subcutaneous injection or intracerebroventricularly to circumvent the blood-brain barrier. Insulin action and cortical activity were assessed by Western blotting and electrocorticography radiotelemetric measurements.
  
  
  RESULTS
  In humans, CSF glucose and insulin concentrations were tightly correlated with the respective serum/plasma concentrations. The CSF/serum ratio for insulin was reduced in older subjects while the CSF/serum ratio for albumin increased with age like for most other proteins. Western blot analysis in murine whole brain lysates revealed impaired phosphorylation of AKT (P-AKT) in aged mice following peripheral insulin stimulation whereas P-AKT was comparable to levels in young mice after intracerebroventricular insulin application. As readout for insulin action in the brain, insulin-mediated cortical brain activity instantly increased in young mice subcutaneously injected with insulin but was significantly reduced and delayed in aged mice during the treatment period. When insulin was applied intracerebroventricularly into aged animals, brain activity was readily improved.
  
  
  CONCLUSIONS
  This study discloses age-dependent changes in insulin CSF/serum ratios in humans. In the elderly, cerebral insulin resistance might be partially attributed to an impaired transport of insulin into the central nervous system.
authors.affiliation: 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.forename: Tina
authors.initials: T
authors.lastname: Sartorius
authors.affiliation: 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.forename: Andreas
authors.initials: A
authors.lastname: Peter
authors.affiliation: 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.forename: Martin
authors.initials: M
authors.lastname: Heni
authors.affiliation: Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Maetzler
authors.affiliation: 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.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.affiliation: 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.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: 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.forename: Anita M
authors.initials: AM
authors.lastname: Hennige
mesh_terms: D000368:Aged; D000375:Aging / Q000097:blood* / Q000134:cerebrospinal fluid / Q000473:pathology; D000418:Albumins / Q000134:cerebrospinal fluid / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000134:cerebrospinal fluid / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D012709:Serum Albumin
chemical_list: D000418:Albumins; D001786:Blood Glucose; D007328:Insulin; D012709:Serum Albumin; D005947:Glucose