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

Cheong, Julia Ling‐Yu; Pablo-Fernández, Eduardo De; Foltynie, Thomas; Noyce, Alastair J.

doi:10.3233/jpd-191900

Cited by 134 publications

(142 citation statements)

References 124 publications

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“…One final note on the relation of the present study findings to the observations that type 2 diabetes worsens Parkinson’s Disease (PD) disease progression (progressive loss of dopaminergic neurons within the basal ganglia–substantia nigra) [ 87 , 88 ] is worthy of mention for clarification purposes. Molecular neurobiology studies indicate that each of hyperglycemia, oxidative stress and insulin resistance of type 2 diabetes contributes to dopaminergic neuron dysfunction that can exacerbate PD by blocking neuronal growth and synapse generation and potentiating inflammation, mitochondrial dysfunction, apoptosis, and amyloid aggregation [ 87 ].…”

Section: Discussionmentioning

confidence: 73%

Experimental dopaminergic neuron lesion at the area of the biological clock pacemaker, suprachiasmatic nuclei (SCN) induces metabolic syndrome in rats

Luo

Ezrokhi

Cominos

et al. 2021

Diabetol Metab Syndr

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Background The daily peak in dopaminergic neuronal activity at the area of the biological clock (hypothalamic suprachiasmatic nuclei [SCN]) is diminished in obese/insulin resistant vs lean/insulin sensitive animals. The impact of targeted lesioning of dopamine (DA) neurons specifically at the area surrounding (and that communicate with) the SCN (but not within the SCN itself) upon glucose metabolism, adipose and liver lipid gene expression, and cardiovascular biology in normal laboratory animals has not been investigated and was the focus of this study. Methods Female Sprague–Dawley rats received either DA neuron neurotoxic lesion by bilateral intra-cannula injection of 6-hydroxydopamine (2–4 μg/side) or vehicle treatment at the area surrounding the SCN at 20 min post protriptyline ip injection (20 mg/kg) to protect against damage to noradrenergic and serotonergic neurons. Results At 16 weeks post-lesion relative to vehicle treatment, peri-SCN area DA neuron lesioning increased weight gain (34.8%, P < 0.005), parametrial and retroperitoneal fat weight (45% and 90% respectively, P < 0.05), fasting plasma insulin, leptin and norepinephrine levels (180%, 71%, and 40% respectively, P < 0.05), glucose tolerance test area under the curve (AUC) insulin (112.5%, P < 0.05), and insulin resistance (44%—Matsuda Index, P < 0.05) without altering food consumption during the test period. Such lesion also induced the expression of several lipid synthesis genes in adipose and liver and the adipose lipolytic gene, hormone sensitive lipase in adipose (P < 0.05 for all). Liver monocyte chemoattractant protein 1 (a proinflammatory protein associated with metabolic syndrome) gene expression was also significantly elevated in peri-SCN area dopaminergic lesioned rats. Peri-SCN area dopaminergic neuron lesioned rats were also hypertensive (systolic BP rose from 157 ± 5 to 175 ± 5 mmHg, P < 0.01; diastolic BP rose from 109 ± 4 to 120 ± 3 mmHg, P < 0.05 and heart rate increase from 368 ± 12 to 406 ± 12 BPM, P < 0.05) and had elevated plasma norepinephrine levels (40% increased, P < 0.05) relative to controls. Conclusions These findings indicate that reduced dopaminergic neuronal activity in neurons at the area of and communicating with the SCN contributes significantly to increased sympathetic tone and the development of metabolic syndrome, without effect on feeding.

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Section: Discussionmentioning

confidence: 73%

Experimental dopaminergic neuron lesion at the area of the biological clock pacemaker, suprachiasmatic nuclei (SCN) induces metabolic syndrome in rats

Luo

Ezrokhi

Cominos

et al. 2021

Diabetol Metab Syndr

View full text Add to dashboard Cite

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“…We also observed in both risk analyses a now-recognised phenomenon of divergence in pooled effect estimates by study design, such that case-control studies tend to be associated with lower risk (even inverse risk) of PD and cohort studies with increased risk of PD. 2,4,5 This divergence appeared to be greater with lower quality studies and the phenomenon is discussed further below. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint…”

Section: Discussionmentioning

confidence: 97%

“…Both are characterised by aberrant protein accumulation, lysosomal and mitochondrial dysfunction, and chronic systemic inflammation. 1,2 Insulin resistance is a hallmark of T2DM and may be an important contributing factor to PD too. 3 Previous systematic reviews and meta-analyses have explored the link between diabetes and the risk of PD, but the results are conflicting.…”

Section: Introductionmentioning

confidence: 99%

Type 2 diabetes as a determinant of Parkinson’s disease risk and progression

Chohan

Senkevich

Patel

et al. 2020

Preprint

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ObjectiveTo investigate type 2 diabetes mellitus (T2DM) as a determinant of Parkinson’s disease (PD) through a meta-analysis of observational and genetic summary data.MethodsA systematic review and meta-analysis of observational studies was undertaken by searching six databases. We selected the highest quality studies investigating the association of T2DM with PD risk and progression. We then used Mendelian randomization (MR) to investigate causal effects of genetic liability towards T2DM on PD risk and progression, using summary data derived from genome-wide association studies.ResultsIn the observational part of the study, nine studies were included in the risk meta-analysis and four studies were included in the progression meta-analysis. Pooled effect estimates revealed that T2DM was associated with an increased risk of PD (OR 1.21, 95% CI 1.07-1.36), and there was some evidence that T2DM was associated with faster progression of motor symptoms (SMD 0.55, 95% CI 0.39-0.72) and cognitive decline (SMD −0.92, 95% CI −1.50 – −0.34). Using MR we found supportive evidence for a causal effect of diabetes on PD risk (IVW OR 1.08, 95% CI 1.02-1.14; p=0.010) and some evidence of an effect on motor progression (IVW OR 1.10, 95% CI 1.01-1.20; p=0.032), but not for cognitive progression.ConclusionUsing meta-analysis of traditional observational studies and genetic data, we observed convincing evidence for an effect of T2DM on PD risk, and new evidence to support a role in PD progression. Treatment of diabetes may be an effective strategy to prevent or slow progression of PD.

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“…44 Potentially shared cellular signalling pathways for this group of drugs and PD pathophysiology have also been highlighted. 45 It is conceivable that our results may therefore reflect confounding by drug treatment-that is, if the treatment of diabetes differs systematically between individuals at high and low risk of PD. As genetic risk for PD (quantified by genome-wide PRS) may itself be a surrogate for subtle ethnic variation, socioeconomic status and other confounders, so it is plausible that there could be real differences in access to particular antidiabetes medications between strata of the PRS.…”

Section: Movement Disordersmentioning

confidence: 92%

Parkinson’s disease determinants, prediction and gene–environment interactions in the UK Biobank

Jacobs

Belete

Bestwick

et al. 2020

J Neurol Neurosurg Psychiatry

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ObjectiveTo systematically investigate the association of environmental risk factors and prodromal features with incident Parkinson’s disease (PD) diagnosis and the interaction of genetic risk with these factors. To evaluate whether existing risk prediction algorithms are improved by the inclusion of genetic risk scores.MethodsWe identified individuals with an incident diagnosis of PD (n=1276) and controls (n=500 406) in UK Biobank. We determined the association of risk factors with incident PD using adjusted logistic regression models. We constructed polygenic risk scores (PRSs) using external weights and selected the best PRS from a subset of the cohort (30%). The PRS was used in a separate testing set (70%) to examine gene–environment interactions and compare predictive models for PD.ResultsStrong evidence of association (false discovery rate <0.05) was found between PD and a positive family history of PD, a positive family history of dementia, non-smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche. Individuals with the highest 10% of PRSs had increased risk of PD (OR 3.37, 95% CI 2.41 to 4.70) compared with the lowest risk decile. A higher PRS was associated with earlier age at PD diagnosis and inclusion of the PRS in the PREDICT-PD algorithm led to a modest improvement in model performance. We found evidence of an interaction between the PRS and diabetes.InterpretationHere, we used UK Biobank data to reproduce several well-known associations with PD, to demonstrate the validity of a PRS and to demonstrate a novel gene–environment interaction, whereby the effect of diabetes on PD risk appears to depend on background genetic risk for PD.

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

Cited by 134 publications

References 124 publications

Experimental dopaminergic neuron lesion at the area of the biological clock pacemaker, suprachiasmatic nuclei (SCN) induces metabolic syndrome in rats

Experimental dopaminergic neuron lesion at the area of the biological clock pacemaker, suprachiasmatic nuclei (SCN) induces metabolic syndrome in rats

Type 2 diabetes as a determinant of Parkinson’s disease risk and progression

Parkinson’s disease determinants, prediction and gene–environment interactions in the UK Biobank

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