Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse

Michael T. Nedelcovych, Alexandra J. Gadiano, Ying Wu, Arena A. Manning, Ajit G. Thomas, Saja S. Khuder, Seung Wan Yoo, Jiadi Xu, Justin C. McArthur, Norman J. Haughey, David J. Volsky, Rana Rais, Barbara S. Slusher

Research output: Contribution to journalArticlepeer-review

Abstract

Insulin delivery to the brain has emerged as an important therapeutic target for cognitive disorders associated with abnormal brain energy metabolism. Although insulin is transported across the blood-brain barrier, peripheral routes of administration are problematic due to systemic effects of insulin on blood glucose. Intranasal (IN) administration is being investigated as an alternative route. We conducted a head-to-head comparison of subcutaneous (SC) and IN insulin, assessing plasma and brain pharmacokinetics and blood glucose levels in the mouse. SC insulin (2.4 IU) achieved therapeutically relevant concentrations in the brain (AUC brain = 2537 h·μIU/mL) but dramatically increased plasma insulin (AUC plasma = 520â»351 h·∗μIU/mL), resulting in severe hypoglycemia and in some cases death. IN administration of the same dose resulted in similar insulin levels in the brain (AUC brain = 3442 h·μIU/mL) but substantially lower plasma concentrations (AUC plasma = 354 h·μIU/mL), amounting to a ∼ 2000-fold increase in the AUC brain:plasma ratio relative to SC. IN dosing also had no significant effect on blood glucose. When administered daily for 9 days, IN insulin increased brain glucose and energy metabolite concentrations (e.g., adenosine triphosphate and phosphocreatine) without causing overt toxicity, suggesting that IN insulin may be a safe therapeutic option for cognitively impaired patients.

Original languageEnglish (US)
Pages (from-to)809-816
Number of pages8
JournalACS Chemical Neuroscience
Volume9
Issue number4
DOIs
StatePublished - Apr 18 2018
Externally publishedYes

Keywords

  • Insulin
  • energy metabolism
  • glucose
  • intranasal
  • neurocognitive impairment
  • pharmacokinetics

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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