Parkinson's disease and diabetes mellitus: common mechanisms and treatment repurposing

Abstract

In the last decade, attention has become greater to the relationship between neurodegeneration and abnormal insulin signaling in the central nervous system, as insulin in the brain is implicated in neuronal survival, plasticity, oxidative stress and neuroinflammation. Diabetes mellitus and Parkinson's disease are both aging-associated diseases that are turning into epidemics worldwide. Diabetes mellitus and insulin resistance not only increase the possibility of developing Parkinson's disease but can also determine the prognosis and progression of Parkinsonian symptoms. Today, there are no available curative or disease modifying treatments for Parkinson's disease, but the role of insulin and antidiabetic medications in neurodegeneration opens a door to treatment repurposing to fight against Parkinson's disease, both in diabetic and nondiabetic Parkinsonian patients. Furthermore, it is essential to comprehend how a frequent and treatable disease such as diabetes can influence the progression of neurodegeneration in a challenging disease such as Parkinson's disease. Here, we review the present evidence on the connection between Parkinson's disease and diabetes and the consequential implications of the existing antidiabetic molecules in the severity and development of Parkinsonism, with a particular focus on glucagon-like peptide-1 receptor agonists.

Keywords: Parkinson’s disease; antidiabetic; diabetes mellitus; dopamine; exenatide; glucagon-like peptide-1; insulin; neurodegeneration; neuroinflammation; repurposing.

Figure 1

Mechanisms induced by antidiabetic drugs leading to anti-inflammatory and prosurvival effects in dopaminergic neurons. Blue arrows indicate blood-brain barrier penetration. Green arrows indicate activatory/beneficial effects. Red lines indicate inhibitory effects. Akt/PKB: Protein kinase B; DDP4: dipeptidyl-peptidase 4; GLP1R: glucagon-like peptide-1 receptor; GLP1RA: glucagon-like peptide-1 receptor agonists; IDE: insulin degrading enzyme; IGF-1: insulin-like growth factor-1; IR: insulin receptors; IRS: insulin receptor substrates; MAPK: mitogen-activated protein kinase; mTOR: mammalian target of rapamycin; PGC1α: peroxisome proliferator activated receptor gamma coactivator 1-alpha; PI3K: phosphatidylinositol 3-kinase; PPARγ: peroxisome proliferator-activated receptor gamma. Created with BioRender.