The Association Between Type 2 Diabetes Mellitus and Parkinson's Disease

Abstract

In recent years, an emerging body of evidence has forged links between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM). In observational studies, those with T2DM appear to be at increased risk of developing PD, as well as experiencing faster progression and a more severe phenotype of PD, with the effects being potentially mediated by several common cellular pathways. The insulin signalling pathway, for example, may be responsible for neurodegeneration via insulin dysregulation, aggregation of amyloids, neuroinflammation, mitochondrial dysfunction and altered synaptic plasticity. In light of these potential shared disease mechanisms, clinical trials are now investigating the use of established diabetes drugs targeting insulin resistance in the management of PD. This review will discuss the epidemiological links between T2DM and PD, the potential shared cellular mechanisms, and assess the relevant treatment options for disease modification of PD.

Keywords: Parkinson’s disease; epidemiology; mechanisms; therapeutics; type 2 diabetes mellitus.

Fig. 1

Graph of the mean age of participants in case-control studies against odds ratio for risk of PD between cases and controls. This suggests that age may modify the association between T2DM and PD, potentially driven by duration of exposure, probability of PD at given ages, and/or by survival bias.

Fig. 2

Diagrammatic summary of main pathways involved in insulin signalling in the brain. IR, insulin receptor; IRS, insulin receptor substrate; PI3K, phosphoinositide-3-kinase; PDK, 3-phosphoinositide-dependent protein kinase; Akt, Protein kinase B (PKB), plays a key role in activating downstream regulators of cell metabolism, proliferation and survival; PTEN, phosphatase and tensin homolog, regulates PI3K/Akt pathway by inhibiting Akt; mTOR, mammalian target of rapamycin, regulates cell metabolism and proliferation and synapse regeneration in neurons; GSK3β, glycogen synthase kinase 3, downstream mediator involved in IDE inactivation, leading to an increase in α synuclein expression, which aggregate into amyloid fibres; FOXO1, Forkhead box O1, involved in maintaining the mitochondrial electron transport chain for ATP generation and fatty acid oxidation, preventing oxidative stress; NFκB, nuclear factor κB regulates microglial activation and the expression of inflammatory mediators such as IL1β and TNFα; cPD3β, cyclic nucleotide phosphodiesterase 3β; Shc, an adaptor protein involved in the MAPK pathway; Grb2/SOS, downstream adaptor proteins in MAPK pathway; Ras, downstream protein in MAPK pathway that recruits Raf; Raf, Ras effector that stimulates a downstream signalling cascade through phosphorylation of MAPK; MAPK, mitogen-activated protein kinase, modulates downstream protein kinases involved in regulating cell proliferation, differentiation and apoptosis, maintaining neuronal growth and survival.

Fig. 3

Diagrammatic summary of main pathways involved in GLP1 signalling in the brain. PI3K, phosphoinositide-3-kinase; PDK, 3-phosphoinositide-dependent protein kinase; Akt, protein kinase B (PKB), plays a key role in activating downstream regulators of cell metabolism, proliferation and survival; GSK3β, glycogen synthase kinase 3, downstream mediator involved in IDE inactivation, leading to an increase in α synuclein expression, which aggregate into amyloid fibres; FOXO1, Forkhead box O1, involved in maintaining the mitochondrial electron transport chain for ATP generation and fatty acid oxidation, preventing oxidative stress; NFκB, nuclear factor κB regulates microglial activation and the expression of inflammatory mediators such as IL1β and TNFα; cAMP, cyclic AMP, activated by binding of GLP1 to GLP1 receptor; PKA, protein kinase A, activates downstream processes via MAPK pathway; MAPK, mitogen-activated protein kinase, modulates downstream protein kinases involved in regulating cell proliferation, differentiation and apoptosis, maintaining neuronal growth and survival.