The Role of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) in Diabetes-Related Neurodegenerative Diseases

Abstract

Recent clinical guidelines have emphasized the importance of screening for cognitive impairment in older adults with diabetes, however, there is still a lack of understanding about the drug therapy. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are widely used in the treatment of type 2 diabetes and potential applications may include the treatment of obesity as well as the adjunctive treatment of type 1 diabetes mellitus in combination with insulin. Growing evidence suggests that GLP-1 RA has the potential to treat neurodegenerative diseases, particularly in diabetes-related Alzheimer's disease (AD) and Parkinson's disease (PD). Here, we review the molecular mechanisms of the neuroprotective effects of GLP-1 RA in diabetes-related degenerative diseases, including AD and PD, and their potential effects.

Keywords: Alzheimer’s disease; Parkinson’s disease; cognition; diabetes mellitus; glucagon-like peptide-1.

Figure 1

Insulin and GLP-1-dependent intracellular signal transduction pathways are similar. Insulin binds to the insulin receptor and further activates the PI3K/Akt and MAPK pathways signaling. PI3K/Akt pathway modulates some cellular processes, such as cell survival, proliferation, apoptosis, protein synthesis, inflammation, ER stress, mitochondrial function, autophagy, synaptic strength in neurodegenerative disorders. MAPK pathway regulates various cellular activities including synaptic plasticity and neuroinflammation. When GLP-1 binds to the GLP-1 receptor, adenosine cyclase is activated and intracellular cAMP increases, thereby activating PKA and PI3K. The downstream pathways are mainly the PI3K and MAPK pathways; hence, the GLP-1 signaling and insulin signaling pathways are similar and partially overlapping.