Diabetes Tied to Parkinson's Risk, More Rapid Disease Progression

Erik Greb

December 10, 2021

UPDATED December 20, 2021 // Editor's note: This article has been updated with additional comments.

Diabetes mellitus (DM) is linked to an increased risk for Parkinson's disease (PD) development, as well as more severe PD symptoms and accelerated disease progression, new research suggests.

Results of a systematic review showed patients with type 2 diabetes were 34% more likely to develop PD than those without comorbid DM. In addition, patients with both conditions had significantly worse scores on the Unified Parkinson's Disease Rating Scale (UPDRS) and worse cognitive performance.

It's important for patients with DM to know whether they are at risk for PD, corresponding investigator Gennaro Pagano, MD, PhD, visiting researcher at King's College London, United Kingdom, told Medscape Medical News.

"Even if you have PD already, you could have a worse phenotype, and this is important in the context of analyzing the diagnosis and evaluating the patient," said Pagano, who is also expert medical director and group leader in early development at Roche Pharma Research and Early Development in Basel, Switzerland.

Together, the results also suggest "DM may be a facilitating factor of neurodegeneration," the investigators note.

The findings were published in a recent issue of the Journal of Parkinson's Disease.

Unanswered Questions

Researchers have long proposed a potential relationship between diabetes and PD. However, case-control studies have yielded conflicting results about this relationship ― and previous systematic reviews have failed to clarify the question.

In the current systematic review and meta-analysis, investigators identified relevant studies in databases such as MEDLINE/PubMed, Cochrane CENTRAL, and Scopus.

Eligible studies reported prevalence of DM in patients with PD, reported incidence of PD in those with and those without DM, and analyzed Parkinson's phenotype and progression in those with and those without DM.

The researchers identified 3829 articles in their initial search, evaluated 90 articles in detail, and included 43 studies in their analysis. Study quality was judged to be moderate or good, and the investigators did not find significant publication bias.

Twenty-one studies that encompassed 11,396 patients were examined to determine prevalence of DM in PD. This prevalence was calculated to be 10.02%, which is similar to the global prevalence of 9.3% reported in 2019.

The researchers also analyzed 12 cohort studies that included 17,797,221 patients to calculate risk for PD in patients with comorbid diabetes. The pooled summary odds ratio (OR) for incident PD among patients with type 2 diabetes was 1.34.

The evaluation of the effect of diabetes on PD severity was based on 10 studies that included 603 patients with both diseases. Because data on motor symptoms were not available for all studies, the researchers considered Hoehn and Yahr stage, UPDRS score, and cognitive impairment.

Patients with both conditions had a worse Hoehn and Yahr stage (standardized mean difference [SMD], 0.36; P < .001), and higher UPDRS score (SMD, 0.60; P < .001). In seven of the 10 studies, diabetes was associated with worse cognitive performance in patients with PD.

The mechanisms of the effect of diabetes on risk for and severity of PD are uncertain, but the researchers have developed hypotheses.

"Insulin resistance could be the mechanism that underlies both the onset of DM and the onset of PD," said Pagano. "One of the common pathways of the two disorders could be an overactivation of the sympathetic nervous system."

The findings have implications for the care of patients with DM, he noted.

"Nobody is evaluating if they have some minor PD symptoms yet, but this could happen in the next years if more evidence comes in this direction," Pagano said. The increased risk for PD in patients with DM underscores the need for early identification of those who should undergo screening for prodromal PD, he added.

In future research, the investigators plan to examine whether patients with PD have a high risk for developing DM, and will investigate common mechanisms of the two diseases using imaging and fluid biomarkers.

Identifying Prodromal Disease

Commenting on the findings for Medscape Medical News, Aparna Wagle Shukla, MD, professor of neurology, director of clinical trials, and co-chief of the movement disorders division at the University of Florida in Gainesville, noted that the meta-analysis was conducted rigorously -- but many studies included in the pooled review had limitations.

One limitation was that ascertainment of the clinical diagnosis in the included studies was based on a retrospective review of medical records or self-reported health questionnaires, said Wagle Shukla, who was not involved in the research. Also, information about the duration of DM and medication history for DM or PD was unavailable for most studies.

Several pathophysiologic pathways have been proposed to explain the relationship between PD and DM, she noted. Chronic hyperglycemia promotes oxidative stress, which accelerates mitochondrial dysfunction, and the latter contributes to dopaminergic neuron loss and degeneration of the nigrostriatal pathway.

"Insulin resistance further aggravates dopaminergic neuronal dysfunction by mediating alpha-synuclein expression and aggregation," said Wagle Shukla. More basic science research is needed to understand these mechanisms, she added.

She noted that as research and development for effective disease-modifying therapies continue to accelerate, identification of prodromal disease is important for early intervention and better outcomes. The current data also set a new standard for PD management.

"Neurologists should increasingly monitor blood glucose and glycosylated hemoglobin in their practice, as successful management of DM will be closely linked with a successful outcome for PD management," said Wagle Shukla.

Pagano is an employee of F. Hoffmann-La Roche. Wagle Shukla has reported no relevant financial relationships.

J Parkinsons Dis. 2021;11:1585-1596. Abstract

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