title: Is Insulin Action in the Brain Relevant in Regulating Blood Glucose in Humans?
abstract: OBJECTIVE
  In addition to its direct action on the liver to lower hepatic glucose production, insulin action in the central nervous system (CNS) also lowers hepatic glucose production in rodents after 4 hours. Although CNS insulin action (CNSIA) modulates hepatic glycogen synthesis in dogs, it has no net effect on hepatic glucose output over a 4-hour period. The role of CNSIA in regulating plasma glucose has recently been examined in humans and is the focus of this review.
  
  
  RESULTS
  Intransal insulin (INI) administration increases CNS insulin concentration. Hence, INI can address whether CNSIA regulates plasma glucose concentration in humans. We and three other groups have sought to answer this question, with differing conclusions. Here we will review the critical aspects of each study, including its design, which may explain these discordant conclusions.
  
  
  CONCLUSIONS
  The early glucose-lowering effect of INI is likely due to spillover of insulin into the systemic circulation. In the presence of simultaneous portal and CNS hyperinsulinemia, portal insulin action is dominant. INI administration does lower plasma glucose independent of peripheral insulin concentration (between ∼3 and 6 h after administration), suggesting that CNSIA may play a role in glucose homeostasis in the late postprandial period when its action is likely greatest and portal insulin concentration is at baseline. The potential physiological role and purpose of this pathway are discussed in this review. Because the effects of INI are attenuated in patients with type 2 diabetes and obesity, this is unlikely to be of therapeutic utility.
authors.affiliation: Departments of Medicine and Physiology and the Banting and Best Diabetes Centre, and Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Satya
authors.initials: S
authors.lastname: Dash
authors.affiliation: Departments of Medicine and Physiology and the Banting and Best Diabetes Centre, and Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Changting
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Departments of Medicine and Physiology and the Banting and Best Diabetes Centre, and Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Morgantini
authors.affiliation: Departments of Medicine and Physiology and the Banting and Best Diabetes Centre, and Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Khajag
authors.initials: K
authors.lastname: Koulajian
authors.affiliation: Departments of Medicine and Physiology and the Banting and Best Diabetes Centre, and Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Gary F
authors.initials: GF
authors.lastname: Lewis
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004285:Dogs; D004734:Energy Metabolism / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D012377:Rodentia
chemical_list: D001786:Blood Glucose; D007328:Insulin