Diabetes Mellitus as a Risk Factor for Parkinson’s Disease: a Molecular Point of View

Biosa, Alice; Outeiro, Tiago F.; Bubacco, Luigi; Bisaglia, Marco

doi:10.1007/s12035-018-1025-9

Cited by 61 publications

(50 citation statements)

References 96 publications

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“…There are previous review articles that discuss the association between T2DM and PD [4,[11][12][13][14][15] or the common therapeutic approaches to T2DM and PD [4,13,16,17]. Our review provides an updated discussion on the epidemiological association between T2DM and PD, the shared pathways involved in T2DM and PD pathophysiology, and the common therapeutic approaches to T2DM and PD.…”

Section: Introductionmentioning

confidence: 99%

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

Cheong

Pablo-Fernández

Foltynie

et al. 2020

JPD

132

120

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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.

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Section: Introductionmentioning

confidence: 99%

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

Cheong

Pablo-Fernández

Foltynie

et al. 2020

JPD

132

120

View full text Add to dashboard Cite

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“…Metabolic changes presented as insulin resistant brain state (IRBS) have recently gained more and more attraction as the pathophysiological core of AD (Hoyer 2004;Defelice and Ferreira 2002;de la Monte et al 2014), particularly after the results of epidemiological studies demonstrating that type 2 diabetes mellitus (DM) is a risk factor for AD (Santiago and Potashkin 2013). However, some studies provided evidence that IRBS is also occurring in PD patients (Athauda and Foltynie 2016;Yang et al 2018) and that DM is a risk factor for PD as well (Biosa et al 2018). Consequently, clinical trials have been designed to test the therapeutic potential of antidiabetic drugs, in particular intranasal insulin (Claxton et al 2015) and incretins (glucagon-like peptide-1 [GLP-1] analogues) in AD and PD patients (Athauda and Foltynie 2016;Femminella and Edison 2014).…”

Section: Introductionmentioning

confidence: 99%

Shared cerebral metabolic pathology in non-transgenic animal models of Alzheimer's and Parkinson's disease

et al. 2020

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Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common chronic neurodegenerative disorders, characterized by motoric dysfunction or cognitive decline in the early stage, respectively, but often by both symptoms in the advanced stage. Among underlying molecular pathologies that PD and AD patients have in common, more attention is recently paid to the central metabolic dysfunction presented as insulin resistant brain state (IRBS) and altered cerebral glucose metabolism, both also explored in animal models of these diseases. This review aims to compare IRBS and alterations in cerebral glucose metabolism in representative non-transgenic animal PD and AD models. The comparison is based on the selectivity of the neurotoxins which cause experimental PD and AD, towards the cellular membrane and intracellular molecular targets as well as towards the selective neurons/non-neuronal cells, and the particular brain regions. Mitochondrial damage and coexpression of insulin receptors, glucose transporter-2 and dopamine transporter on the membrane of particular neurons as well as astrocytes seem to be the key points which are further discussed in a context of alterations in insulin signalling in the brain and its interaction with dopaminergic transmission, particularly regarding the time frame of the experimental AD/ PD pathology appearance and the correlation with cognitive and motor symptoms. Such a perspective provides evidence on IRBS being a common underlying metabolic pathology and a contributor to neurodegenerative processes in representative non-transgenic animal PD and AD models, instead of being a direct cause of a particular neurodegenerative disorder.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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“…The comorbidity of iPD and T2DM has been described in numerous epidemiological studies [9][10][11]. Despite an initial controversy [12,13], the established risk for presenting iPD in T2DM patients is 38% [14].…”

Section: Introductionmentioning

confidence: 99%

“…It is also known that T2DM may predispose to a PD-like pathology and induce a more aggressive phenotype when coexisting with PD [15]. In fact, T2DM is a well known established risk factor for iPD development [16].…”

Section: Introductionmentioning

confidence: 99%

“…Recent evidences points towards shared deregulated molecular pathways between PD and DM such as protein misfolding and depot, endoplasmic reticulum stress or in ammation [17,18]. Among these, growing evidences support metabolic and mitochondrial dysfunction to play a critical role in the development of both diseases [9,11,13,17,[19][20][21]. Speci cally, mitochondrial respiratory chain (MRC) dysfunction, oxidative stress, altered mitochondrial dynamics and morphology have been reported in iPD [22].…”

Section: Introductionmentioning

confidence: 99%

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Disrupted Mitochondrial and Metabolic Plasticity Underlie Comorbidity Between Age-related and Degenerative Disorders as Parkinson Disease and Type 2 Diabetes Mellitus

Juárez‐Flores

Ezquerra

Gonzàlez-Casacuberta

et al. 2020

Preprint

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Background. Idiopathic Parkinson’s disease (iPD) and Type 2 Diabetes Mellitus (T2DM) are chronic, degenerative, multisystemic and age-related diseases, with eventual epidemiological co-morbidity and potential overlap in molecular basis. This study aims to explore if metabolic and mitochondrial alterations underlie the suggested epidemiologic and clinical co-morbidity at molecular level. Methods. To evaluate the adaptation of iPD to a simulated pre-diabetogenic state, we exposed primary cultured fibroblasts from iPD patients and controls to standard (5mM) and high (25mM) glucose concentrations to further characterize metabolic and mitochondrial resilience.Results. iPD fibroblasts showed increased levels of organic and amino acid levels related to mitochondrial metabolism with respect to controls, and these differences were enhanced in high glucose conditions (citric, suberic and sebacic acids levels increased, as well as alanine, glutamate, aspartate, arginine and ornithine amino acids; p-values between 0.001 and p=0.05). The accumulation of metabolites in iPD fibroblasts was associated (and probably due) to the concomitant mitochondrial dysfunction observed at enzymatic, oxidative, respiratory and morphologic level. Metabolic and mitochondrial plasticity of controls was not observed in iPD fibroblasts, that were unable to adapt to different glucose conditions. Impaired metabolism and mitochondrial activity in iPD may limit energy supply for cell survival. Moreover, deficient plasticity to adapt to disrupted glucose balance characteristic of T2DM may underlay the comorbidity between both diseases. Conclusions:Fibroblasts form iPD patients showed mitochondrial impairment resulting in the accumulation of organic and amino acids related to mitochondrial metabolism, especially when exposed to high glucose condition. Mitochondrial and metabolic defects down warding cell plasticity to adapt to changing glucose bioavailability may explain the comorbidity between iPD and T2DM.

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Diabetes Mellitus as a Risk Factor for Parkinson’s Disease: a Molecular Point of View

Cited by 61 publications

References 96 publications

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

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

Shared cerebral metabolic pathology in non-transgenic animal models of Alzheimer's and Parkinson's disease

Disrupted Mitochondrial and Metabolic Plasticity Underlie Comorbidity Between Age-related and Degenerative Disorders as Parkinson Disease and Type 2 Diabetes Mellitus

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