Recent studies have highlighted the potential connection between Diabetes Mellitus (DM), a very common condition, and Parkinson’s Disease (PD). These studies raised a number of questions about the interrelation between these disorders. The main points in the current discussion are whether there are common pathophysiological mechanisms in diabetes and PD and whether this association may create new therapeutic opportunities for PD. We have asked two experts in the field, Tom Foltynie and Marios Politis, to provide their point of view. A seasoned clinical neurologist and movement disorder expert, Eduardo Tolosa, provides a final commentary.

Is there strong evidence that diabetes increases the risk for Parkinson's disease (PD)?



Tom Foltynie

Exploring the possible relationship between PD and Diabetes requires good quality epidemiology. Anecdotal observations from Diabetes or PD clinics will confirm that there are indeed some patients with both diseases, but the vast majority of Diabetes patients do not have PD, and the vast majority of PD patients do not have a diagnosis of Diabetes. There have been reviews of different types of epidemiological studies that have quantified the possible association between the two diseases. In a meta-analysis of these studies, the authors distinguished between case-control and cohort studies, given that the former type of study measures a single snapshot in time (prevalent cases of PD) whereas cohort studies gather data over a longer term (incident cases of PD). As a rule, cohort studies include more participants and are at lower risk for selection bias than case control studies. In cohort studies, diabetes is consistently a risk factor for future PD. However, there was no association between diabetes and PD in the case-control studies.

Marios Politis

In an attempt to probe this further, a recent meta-analysis of seven observational cohort studies (with prospective or retrospective study design) investigated the association of preexisting type 2 diabetes with the risk of developing PD in over 1.7 million individuals. Compared to nondiabetic patients, patients with type 2 diabetes had a 38% increased risk for developing PD. This effect persisted in analysis stratified by study quality, research country, study design, sample size, published year and sensitivity analyses, which confirmed the strength of the association. Taken together, these observations suggest that patients with type 2 diabetes may have an increased risk for developing PD, although the prevalence of diabetes is not higher in patients with PD compared to the general population. This discrepancy may be due to decreased life expectancy of patients with the combination of the two diseases, or a selection-bias of case-control studies.

How much do we know about the mechanisms involved in this association?



Tom Foltynie

Both small and large vessel atherosclerosis developed in Diabetes might lead to vascular parkinsonism rather than neurodegenerative PD, and intuitively this might be a tempting explanation of the association. However; this is not supported by the epidemiology, which suggests that the association is maintained after exclusion of patients with vascular disease. An alternative explanation is that there might be common genetic risk factors. There appear to be overlapping associations with mitochondrial dysfunction and inflammatory cascades, as well as insulin signaling pathways relevant to both diseases. This has been formally explored using network-based approaches, which show substantial overlap between the genetic risks associated with both diseases. The notion that insulin signaling/insulin resistance might be relevant to neurodegeneration is becoming of increasing interest. There is loss of insulin receptor mRNA in the substantia nigra of PD patients preceding the death of dopaminergic neurons. Furthermore, insulin resistance was detected in 50-80% of PD patients formally tested for glucose tolerance. However, it is unclear if central insulin resistance in PD is a cause for or a consequence of neurodegeneration.

Further insights may be gained from the study of abnormal protein accumulation in these diseases. Analogous with the idea of abnormal spreading of pathological alpha-synuclein, in a prion-like manner, causing disease propagation in PD, an abnormal form of the protein islet amyloid polypeptide IAPP is readily detectable in the pancreatic beta islets of patients with type 2 diabetes. Fibrils of this protein induce aggregation of normal IAPP in normal pancreatic tissue and subsequent development of diabetes, also likened to a prion-like manner. Indeed there appears to be a potential for interaction between alpha synuclein and IAPP, in that misfolded forms of one can induce or accelerate the formation of misfolded forms of the other.

Marios Politis

Common potential pathophysiological mechanisms include mitochondrial and endoplasmic reticulum malfunction, inflammatory response and loss of central and peripheral synapses, which together with genetic susceptibility and lifestyle factors, may cause protein misfolding and insulin resistance, which contribute to the development of both PD and diabetes. Protein aggregation and prion-like propagation are especially interesting in this regard. These concepts are well established as possible pathogenetic factors centering around alpha-synuclein in PD, but more recently they have been shown to potentially apply to diabetes as well. The protein Islet Amyloid Polypeptide (IAPP) takes an abnormal conformation, which may alter the normal protein in a prion-like fashion in pancreatic islet cells in diabetics. Interestingly, there is also evidence for cross-seeding between IAPP and alpha-synuclein.

Is Parkinson's disease different in diabetics?



Tom Foltynie

Several publications report that patients with diabetes who develop PD have a more aggressive form of the disease. This includes the earlier development of cognitive impairment and postural instability. Again, this association persists after exclusion of patients with vascular pathology, or in the case of postural instability, after exclusion of patients with peripheral neuropathy. A caveat here would be to examine the potential role of medications used to treat diabetes in the development of more aggressive phenotype.

Marios Politis

There are emerging data that support this notion, however it remains unclear whether this reflects mere comorbidity, or a biologically more aggressive form of PD in diabetics. Consistent with the latter, we presented preliminary findings at the last MDS congress in Vancouver of a case-control study comparing DAT scans of PD patients with diabetes to those without diabetes, suggesting that the former have more severe nigrostriatal degeneration.

Could anti-diabetic medications help to improve symptoms or have neuroprotective effects in Parkinson's disease? What could be the mechanisms involved?



Tom Foltynie

The most compelling evidence that specific anti-diabetic medications may help in the treatment of Parkinson’s disease comes from the publication of two randomized PD trials of exenatide, a Glucagon-like peptide 1 (GLP-1) receptor agonist licensed for the treatment of type 2 diabetes. These build upon a substantial body of in vitro and in vivo evidence that GLP-1 receptor agonists have neurotrophic effects. The first study was an open label trial and thus potentially vulnerable to placebo effects. This did show however that 1 year treatment with exenatide improved both motor and cognitive deficits of PD. Furthermore, patients were followed up for 1 year after stopping exenatide injections, and the effects on motor and cognitive performance were sustained. The second trial was a double blind, placebo controlled trial and demonstrated a similar improvement in motor, but not cognitive performance in patients treated with exenatide. The major concern regarding this trial relates to its small size, thus it is imperative that these results are reproduced in larger numbers of patients with longer term of exposure. Other anti-diabetic agents have also been of interest, notably Pioglitazone. This thiazolidinedione has neuroprotective effects in a range of experimental models, but failed in a double-blind clinical trial in PD patients, possibly because the treatment period was too short. In summary, the role of anti-diabetic agents in the treatment of PD is becoming of great interest. There is much to learn regarding the mechanisms involved, and undoubtedly there will be better-tolerated and more potent agents to be discovered.

Marios Politis

GLP-1 agonists might exert a neuroprotective effect by reducing vascular risk factors and preventing synaptic loss. GLP-1 agonists improve micro and macro-vascular complications by reducing cerebral ischaemia in diabetic patients. They also prevent synapse loss by reducing the soluble Aβ oligomers in experimental model of Alzheimer’s disease. However, the combined activation of GLP-1 and Glucose-dependent Insulinotropic Peptide (GIP) pathways might have a much stronger neuroprotective effect, as shown in a number of preclinical studies in animal models of PD, where they were found to have neurotrophic and anti-apoptotic effects. In experimental models of parkinsonism, pharmacological inhibition of dipeptidyl peptidase-4 (DPP4) exerted neuroprotective effects by reducing inflammation, oxidative stress and apoptotic pathways, and improving mitochondrial function. Whether the combined actions on GLP-1 and GIP underlie such effects is presently unclear. DPP4 inhibitors are anti-diabetic drugs able to activate both GLP-1 and GIP pathways. DPP4 inhibitors might be potential candidates for future trials aimed to slow PD progression, though a few challenges still need to be faced. DPP-4 inhibitors have lower penetration of the blood brain barrier compared to GLP-1 agonists. However, DPP-4 inhibitors are orally administered and generally well tolerated, with a lower incidence of hypoglycemia and no weight gain compared to GLP-1 analogues, making them popular for use in conjunction, or as an alternative to metformin in diabetics. In addition, some DPP-4 inhibitors are excreted by kidney, while others are hepatically metabolized. As a result, the potential for their use in those with either renal or liver impairment is greater, offering benefits to a greater range of patients.

To the best of my knowledge, there are no ongoing human trials using DPP-4 inhibitors to alleviate symptoms or arrest progression of PD. However, a recent case-control study from a large population in Sweden associated the use of such inhibitors with reduced incidence of PD, suggesting that their effects may be beneficial in a clinical setting.

Would you consider at the present time treating PD patients with (or without) diabetes with GLP-1 agonists?



Tom Foltynie

A patient who has both diabetes and PD may benefit most from the use of a GLP-1 agonist. Exenatide has been proven to improve glucose control, and tends to cause weight loss, which is usually beneficial in this sub-group. While the effects of Exenatide on PD progression require confirmation, it can easily be argued that there is already sufficient evidence that patients with diabetes and PD should be considered for Exenatide prescription. While there may be beneficial effects across the whole class, there is insufficient data on the ability of other GLP-1 receptor agonists to penetrate the blood brain barrier to favor the use of Liraglutide, Semaglutide or Lixisenatide.

Regarding PD patients without diabetes, data supporting exenatide treatment are still too sparse to advocate its routine use. Furthermore, weight loss and GI side effects may limit its tolerability. Given the patients’ growing interest in this drug class, it is essential that further confirmatory trials are conducted as soon as possible to clarify whether PD patients without diabetes should be offered this treatment.

Commentary



Eduardo Tolosa

A link between type 2 diabetes mellitus (T2DM) and neurodegeneration has been suggested for decades. A number of common risk factors have been suggested for PD, Alzheimer disease (AD), as well as T2DM, including oxidative stress, inflammation and insulin deficiency or resistance. Both DM and neurodegenerative disorders such as PD or AD are considered protein conformational disorders. AD has even been considered as a brain specific form of diabetes characterized by insulin resistance, a “Type 3 Diabetes”.

Studies on the relationship between DM and PD have led to tentative, sometimes controversial, observations. Tom Foltynie and Marios Politis have reviewed these relationships and speculations in the preceding text. Both of them have contributed studies that support such a relationship. Most clinicians consider increasing age, positive family history of PD and non-smoking as established risk factors for PD but have, in general, and I include myself here, not considered DM, a very common condition, a risk factor for this movement disorder. I must actually confess I did not think DM had much to do with PD until recently... But, even if the prevalence of diabetes is not higher in patients with PD compared to the general population, analysis of epidemiological cohort studies suggests that diabetes may be a risk factor for future PD and substantial overlap between the genetic risks associated with both diseases has been reported. In addition, preclinical in vitro and in vivo studies have implicated common pathophysiological mechanisms in both conditions. In patients, some observations have been intriguing and even controversial: more aggressive form of PD in patients with DM, more axial symptoms in diabetic patients than in those without DM, better metabolic control of DM when occurring in PD. These preliminary observations had not been considered by clinicians earlier, and have been the results of recently focused studies.

The recent clinical trials showing that exenatide improves motor symptomatology in PD have generated renewed interest on the PD-DM link. Exenatide trials were implemented following the repurposing strategy of licensed drugs, for which data on safety and tolerability are already available, and based on the suspected neuroprotective and regenerative effects of the drug. As is the case with any double-blind randomized trial, these results need to be replicated; a long-term simple multi-site trial design will be necessary to establish the long-term effects of exenatide treatment on daytime function in PD, and specifically whether exenatide can delay the development of levodopa-refractory symptoms. In any case, the recently published work is important, particularly since we do not have drugs with established disease modification effect for PD. It is of course possible, as discussed above, that the putative treatment effects of exenatide are not-disease-modifying after all. Certainly, these findings have stimulated research in the field of DM-PD.

From a very practical point of view they actually raise the question whether we should perhaps be treating patients with PD, with or without DM, with this GLP-1 agonist. It could be argued that the results with exenatide are encouraging and tolerance acceptable, and that they support the use of a drug already licensed and accordingly well known in terms of tolerance and safety. Nevertheless, the safety of exenatide in PD is not sufficiently known and the trials have limitations and included only small numbers of patients. A long term multicenter trial with sufficiently large number of subjects should, in my opinion, confirm and extend the results of the London group before this medication is administered to patients with PD. A positive trial would be a strong indication also that GPL-1 receptor agonists or related drugs may have a useful role in future treatment of PD.