GLP-1 and its implications for neuroprotection in diabetes-associated neurodegenerative diseases

Background: There is growing evidence linking type 2 diabetes (T2D) with dementia and neurodegenerative diseases such as Alzheimer’s disease (AD). The incretin hormone glucagon-like peptide 1 (GLP-1), utilized for its insulinotropic properties in the treatment of T2D, is also synthesized in the CNS as a neuropeptide and has been demonstrated to have neuroprotective effects. We studied the effects of GLP-1 on insulin signaling in astrocytes, the only type of brain cells that store glycogen, which is utilized in learning and memory. Hypothesis: Our hypothesis was that GLP-1 would act on astrocytes and mimic insulin action at baseline conditions. In the presence of insulin, we expected GLP-1 to enhance insulin action, exhibiting a mechanism by which astrocytic glycogen storage could ultimately be augmented. Methods: We first treated astrocytes with GLP-1 and used a cAMP assay to determine if there was a functional GLP-1 receptor (GLP-1R) on the astrocytes. We then treated astrocytes with insulin alone, insulin and GLP-1 added 18 hours prior, insulin and GLP-1 added 30 minutes prior, and GLP-1 alone and determined expression of pAKT and pGSK-3B with Western Blot analysis. Results: Astrocytes appear to express a functional GLP-1R, suggesting the possibility that previously studied neuroprotective effects of GLP-1 occur via an astrocytic mechanism. GLP-1 was shown to mimic astrocytic insulin signaling at baseline conditions and enhance the phosphorylation of both AKT and GSK-3B when astrocytes are treated acutely at 30 min. as well as at 18 hours. GLP-1’s effects on insulin signaling suggest it can ultimately increase glycogen synthesis. The enhancement of insulin signaling by GLP-1 is most apparent at 10nM insulin, inducing a near maximal response. Summary: Our results suggest GLP-1 may have a role in attenuating insulin resistance and decreased glycogen storage, providing a mechanism by which GLP-1 analogs can offer neuroprotection to patients with diabetes-associated neurodegenerative disease such as Alzheimer’s.