In this large population of older adults in the U.S., we found that diabetes was associated with a modest increase of PD risk. Further analysis suggested that the higher risk was primarily limited to study participants who had had diabetes for more than 10 years before the baseline survey. Multivariate and stratified analyses suggest that these results were not confounded or modified by known or suspected PD risk factors, nor could they be accounted for by poorer baseline health status or the presence of vascular diseases or cancers as shown in the sensitivity analyses.
Over the past decade, diabetes has been reported to be associated with increased risk of dementia (3
) and Alzheimer’s disease (4
), suggesting a potential role of diabetes or insulin dysregulation in neurodegeneration. Several lines of evidence also indicate a link between diabetes and PD. Insulin receptors are expressed in the substantia nigra (15
). The dopamine agonist bromocriptine improves glycemic control (16
) and was recently approved for adjunctive treatment of diabetes. Conversely, the insulin sensitizer rosiglitazone protects dopaminergic neurons in animal models of PD (17
). From an etiologic perspective, it is also important to point out that both diabetes and PD are age-related chronic diseases and some pathogenic processes may underlie both conditions. For example, systemic chronic inflammation, which increases the risk of diabetes, was also found to be associated with higher risk of PD (18
). Furthermore, oxidative stress and mitochondria abnormalities have been implicated in both diseases (20
A few epidemiological studies have investigated the association between diabetes and PD. Several case-control studies (6
), but not all (5
), reported that PD patients were less likely to report diabetes. A closer examination of these studies revealed further uncertainties. For example, the diabetes-PD association did not persist in the multivariate analysis of one study (7
) and another study showed different results across subgroups (6
). Despite these uncertainties, it has been hypothesized that the lower prevalence of diabetes among PD patients is a result of impaired autonomic functions and fewer cardiovascular risk factors among PD patients (7
). However, alternative explanations such as chance or bias could not be excluded since these studies were often based on small sample sizes, prevalent cases of patients with PD, and retrospective exposure assessment. For example, a spurious inverse association between diabetes and PD could arise in a case-control study with prevalent cases if PD adversely affects the survival of diabetic patients or vice versa. Finally, case-control studies were not ideal to address the temporal relationships between diabetes and PD because of the use of prevalent cases and sometimes unspecified time window of exposure assessment.
Unlike case-control studies, prospective studies collect exposure data before outcome identification and therefore are less prone to recall and selection biases. To the best of our knowledge, three prospective studies to date have examined diabetes in relation to future risk of PD (9
). In contrast with case-control studies, none of the prospective studies found lower PD risk among diabetic patients. The Health Professionals Follow-up and Nurses Health Studies reported similar risk of PD between individuals with and without diabetes (RR = 1.04) (11
). On the other hand, the Finnish study reported an 83% higher risk of PD among diabetic patients than participants without PD (10
). Cases in this study were identified from the Finnish nationwide drug register without further diagnostic validation and therefore some caution is needed in interpreting the result. The third study was conducted in the Physicians Health Study and was the only one that took into account the duration of diabetes in the analyses (9
). This study also reported a higher PD risk (RR = 1.34) among diabetic patients, but further analysis showed that the increment was limited to diabetic patients with <10 years of the disease. Therefore, the authors attributed this finding to potential ascertainment bias, reverse causality, or common mechanisms that underlie both diabetes and PD (9
In addition to some design differences, all previous studies had fewer than 60 exposed cases (PD participants with diabetes), which may have contributed to the heterogeneous results. In comparison, the current study was substantially larger with 172 PD participants with diabetes and 1,393 PD participants without diabetes. Furthermore, in data analysis, we controlled for or stratified by known or suspected PD risk factors to examine the robustness of our result, and similar results were found across subgroups. Like the Finnish and the Physicians Health studies, we observed a modestly higher risk of PD among individuals with baseline diabetes. In contrast with the Physicians Health Study, we found the higher risk was largely limited to diabetic patients who had been diagnosed more than 10 years before baseline. This association was evident for both PD participants diagnosed between 1995 and 1999 and participants diagnosed after 2000; PD diagnoses in the latter group were at least 4 to 5 years after the report of baseline diabetes status. Finally, neither vascular conditions or cancers nor poorer health status at baseline accounted for the association of diabetes with PD risk. Taken together, our results are consistent with the hypothesis that diabetic patients had higher risk of PD, which could not be explained by reverse causality.
The higher PD risk among diabetic patients could potentially be explained by two intertwined possibilities. It is possible that common pathogenic processes such as chronic inflammation or oxidative stress may first lead to diabetes and then years later to a higher risk of PD. Alternatively, one can speculate that diabetes and insulin dysregulation or other aspects of diabetes may themselves increase the risk of PD. In either case, the evidence to date is indirect and the relevance of these speculations to our observed diabetes-PD association needs to be evaluated in future studies.
Our study has several limitations. In such a large population, we had to rely on self-reports to identify PD participants cost effectively. This might have led to diagnostic and reporting errors, particularly underreports since some PD patients might not report their diagnoses on the follow-up questionnaire. However, we were able to confirm ~88% of diagnoses among self-reported patients whose medical information was available. Furthermore, we excluded from analyses patients in the case group with erroneous reports identified in the validation study. Diabetes was also self-identified; however, previous studies showed satisfactory agreement (κ = 0.76) between self-reports of diabetes and medical records despite a modest sensitivity (66%) (25
). The lack of annual glucose tolerance screening in the cohort also resulted in underreports and under-diagnosis of diabetes. Nevertheless, because diabetes status was assessed before PD case ascertainment, inaccurate reporting of diabetes should be nondifferential and thus might have underestimated the true association between diabetes and PD. Another limitation on diabetes assessment was the lack of information on diabetes complications and treatments. We therefore could not evaluate the possibility that diabetes medications and treatments or diabetes complications might have contributed to higher risk of PD, particularly among long-term diabetic patients. It was also possible that diabetic patients might have more frequent physician visits than individuals without diabetes. Although we conducted sensitivity analysis by excluding participants with poor/fair health or several chronic diseases, we could not exclude the possibility of identification bias from this source. Finally, the current analyses were limited to participants of the follow-up survey. A spurious association might be induced if more diabetic patients with PD survived and participated in the follow-up survey than diabetic patients without PD.
In conclusion, this study showed higher PD risk among diabetic patients in a large cohort of older adults. The nature of this association should be evaluated in future studies.