Review articleDiabetes, insulin and new therapeutic strategies for Parkinson’s disease: Focus on glucagon-like peptide-1 receptor agonists
Introduction
Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder, with an increasing prevalence in elderly population (about 1% in people over 65 years old). Although its etiology is still not well understood, multiple factors are known to play a role in the nigrostriatal pathway degeneration, both genetic and environmental. The special vulnerability of dopaminergic neurons to oxidative stress has led to growing research in inflammatory mechanisms to achieve possible neuroprotective strategies. Diabetes mellitus (DM) is well known to be an inflammatory condition, and has also been linked to neurodegenerative diseases through abnormal insulin pathways (Fiory et al., 2019). The results of epidemiological studies searching for evidence of a relationship between PD and DM are controversial. However, strong evidence suggests that DM might be a risk factor for PD, and that it might be limited to those patients with long diabetic disease duration (over 10 years) (De Pablo-Fernandez et al., 2017). Also, DM has been considered as a modifying factor for motor and non-motor symptoms of PD (Pagano et al., 2018). Accordingly, it is essential to clarify if a very frequent comorbidity as DM can influence the development or prognosis of PD, as well as the role of the available treatments for DM in neurodegeneration.
Section snippets
Parkinson and diabetes: epidemiological evidence
PD and DM are two well known aging-associated disorders. More importantly, DM is considered an epidemic in modern society. Therefore, it is important to determine if DM or insulin resistance involves an increased risk to develop PD or a worse prognosis. However, a large number of controversial studies have been reported, which will be analyzed in the following paragraphs.
A meta-analysis (Cereda et al., 2011) published in 2011 reviewed the relationship between pre-existing DM and PD, concluding
Parkinson and insulin
The above-mentioned epidemiological evidence is supported by molecular evidences. DM and neurodegeneration share several pathological pathways, such as oxidative stress, mitochondrial dysfunction and neuro-inflammation. Furthermore, significant evidence supports the role of insulin resistance in the interplay between DM and PD. The existence of common molecular mechanisms encourages the use of drug repurposing treatments to modify disease progression in parkinsonian patients.
Glucose uptake in
Diabetes treatment repurposing in Parkinson’s disease
Considering the evidence about the impact of insulin resistance in neurodegeneration, it seems reasonable to wonder about the role of antidiabetic drugs in the central nervous system and neurodegenerative disorders such as PD or Alzheimer’s disease. A population-based, longitudinal, cohort study (Brauer et al., 2020) reported different PD incidence among T2DM patients depending on the antidiabetic treatment received, as well as a higher risk in untreated diabetic patients. Taking into account
Treatment repurposing: evidence from human clinical trials
After obtaining positive results from experimental data, it is vital to determine if these treatments are also effective against PD in humans. In the following paragraphs we will summarize major results in clinical trials on treatment repurposing using the above-mentioned drugs for PD.
In 2013 Aviles-Olmos et al. (2013a) developed a single-blind trial with 45 moderate non-diabetic PD patients to assess exenatide treatment in PD for a 12 month period. This trial was designed as a proof of concept
Levodopa and antidiabetics
A great concern when repurposing treatments is whether they may interact with other necessary drugs required for the patients. In PD, levodopa is the most effective antiparkinsonian drug and the current gold standard treatment, so it is essential to know if repurposed treatments may modify its function. There are several animal models and some clinical data reporting a possible benefit in motor function of different antidiabetic drugs when administered with levodopa, as we will describe in this
Conclusions. Synthesis and future directions
Traditionally, patients with PD are considered as patients with a neurologic disease that may also suffer other comorbidities. The pathophysiology of PD is very complex, and is not limited to central nervous system structures. We need to comprehend PD as a systemic disease, where non-neurologic disorders can determine the severity or even the development of neurodegeneration. This can help us not only to provide a better treatment against the disease, but also to identify individuals with
Funding
Grant sponsor: Spanish Ministry of Health (PI17/00828 and CIBERNED). Grant sponsor: Galician Government (XUGA, ED431C 2018/10, ED431G/05). Grant sponsor: FEDER (Regional European Development Fund).
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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