Combination of Insulin with a GLP1 Agonist Is Associated with Better Memory and Normal Expression of Insulin Receptor Pathway Genes in a Mouse Model of Alzheimer's Disease

J Mol Neurosci. 2019 Apr;67(4):504-510. doi: 10.1007/s12031-019-1257-9. Epub 2019 Jan 11.


Disruption of brain insulin signaling may explain the higher Alzheimer's disease (AD) risk among type 2 diabetic (T2D) patients. There is evidence from in vitro and human postmortem studies that combination of insulin with hypoglycemic medications is neuroprotective and associated with less amyloid aggregation. We examined the effect of 8-month intranasal administration of insulin, exenatide (a GLP-1 agonist), combination therapy (insulin + exenatide) or saline, in wild-type (WT) and an AD-like mouse model (Tg2576). Mice were assessed for learning, gene expression of key mediators and effectors of the insulin receptor signaling pathway (IRSP-IRS1, AKT1, CTNNB1, INSR, IRS2, GSK3B, IGF1R, AKT3), and brain Amyloid Beta (Aβ) levels. In Tg2576 mice, combination therapy reduced expression of IRSP genes which was accompanied by better learning. Cortical Aβ levels were decreased by 15-30% in all groups compared to saline but this difference did not reach statistical significance. WT mice groups, with or without treatment, did not differ in any comparison. Disentangling the mechanisms underlying the potential beneficial effects of combination therapy on the IR pathway and AD-like behavior is warranted.

Keywords: Alzheimer’s disease; Exenatide; Insulin; T2D.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Drug Combinations
  • Exenatide / administration & dosage
  • Exenatide / pharmacology
  • Exenatide / therapeutic use*
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / administration & dosage
  • Insulin / pharmacology
  • Insulin / therapeutic use*
  • Male
  • Maze Learning
  • Mice
  • Mice, Inbred C57BL
  • Receptor, Insulin / metabolism
  • Signal Transduction


  • Amyloid beta-Peptides
  • Drug Combinations
  • Hypoglycemic Agents
  • Insulin
  • Exenatide
  • Receptor, Insulin