Understanding the link between type 2 diabetes mellitus and Parkinson's disease: role of brain insulin resistance

Abstract

Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden. Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms. Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes. The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease, with emphasis on brain insulin resistance, is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.

Figure 1

Insulin and GLP-1 signaling. Activation of the IR leads initially to the phosphorylation of the IRS proteins and the SHC-transforming proteins. Tyrosine residues on IRS are phosphorylated through the tyrosine kinase activity of IRs, which in turn results to the exposure of the binding sites for signaling molecules and signaling stimulation via the PI3K/AKT pathway. Activation of the PI3K/AKT pathway leads to subsequent upregulation of IκBα, a specific endogenous inhibitor of NF-κB, leading to decreased levels of neuroinflammation, providing a putative mechanism linking insulin signaling and neuroinflammation. Furthermore, activation of the PI3K/AKT/mTOR signaling pathway limits excessive autophagy and enhances cell growth and survival. Activation of the PI3K/AKT pathway leads also to inhibition of the transcription factor FoxO1, which has an important role in cell apoptosis and cell cycle regulation. GLP-1 signaling via the GPL-1 receptors potentiates insulin secretion and signaling as well as gene transcription and cell replication. Created with Microsoft PowerPoint. AKT: Protein kinase B; CREB: cAMP-response element binding protein; FoxO1: forkhead box protein O1; GLP-1: glucagon-like peptide 1; GLP-1R: glucagon-like peptide 1 receptor; IR: insulin receptor; IRS: insulin receptor substrate; mito: mitochondria; mTOR: mammalian target of rapamycin; NF-κΒ: nuclear factor kappa B; PI3K: phosphoinositide 3-kinase; PKA: protein kinase A; α-sync: alpha-synuclein.