Diabetes and Risk of Parkinson’s Disease

CONCLUSIONS

According to this meta-analysis diabetes appears to be a risk factor for PD. Higher weight was given to the evidence derived from prospective investigations. In etiologic epidemiology the use of cohort studies is preferable, because it enables researchers to formulate a cause-effect hypothesis. However, the incidence of PD is low and shifted toward advanced age; large populations and a long follow-up are required for adequately powered risk analyses and, up to now, only one study has investigated a large number of cases (13). Thus the evidence collected is still limited. In this perspective, case-control studies could gain value and, since they have the advantage of being less expensive and time-consuming, enable the collection of a larger mass of data. However, they suffer mainly from recall (risk factors and duration of exposure) and inclusion (for both case subjects and control subjects) bias and only associations, not real causal relationships, can be inferred.

Heterogeneity among the studies retrieved and limitations of the literature search deserve comment and should be taken into account for a correct interpretation of the results. Although we used strict inclusion criteria and performed sensitivity analyses, several residuals of confounding and estimation bias could be present.

Diabetes is a metabolic disorder contributing to both large and small vessel diseases (20), and we were not sure that the study populations were confined to idiopathic PD. Although vascular parkinsonism possibly relating to major vascular disorders was generally taken into account during the recruitment phase or through adjusted analyses, the exclusion of parkinsonism related to microvascular complications should probably be based also on imaging techniques (21), even when the diagnosis of PD is made by a neurologist or a specialist in movement disorders. Nevertheless, sensitivity analyses confirmed the role of diabetes as a risk factor for future PD.

The lack of an established mechanism linking diabetes to PD is a major limitation for the interpretation of our findings. Recent studies have shown that, independently of hyperglycemia, which is mainly responsible for endothelial dysfunction (20), distinct pathologic pathways may contribute to neurodegeneration. Regarding PD, this hypothesis appears to be supported by the various associations found between PD and diabetes duration. Both insulin deficiency and insulin resistance with compensatory hyperinsulinemia might play a role (22–24). Insulin can act as a growth factor in the brain and can reduce oxidative stress. Insulin resistance has been shown to result in decreased insulin transport into the brain (9,10). Insulin receptors are densely represented in the substantia nigra and insulin increases dopamine transporter mRNA in the substantia nigra. It also regulates dopamine concentrations in the brain (9,10). During the natural history of diabetes, both changes in insulin secretion and in insulin activity may occur and have never been investigated in terms of the risk of PD. However, both insulin resistance and PD may be consequences of the aging process (1,2,25), and the clustering of PD and diabetes with age observed by Driver et al. (12) could also suggest the existence of common pathogenic processes leading first to diabetes and then to PD. In the Physicians' Health Study, the prevalence of diabetes, despite being similar to that reported by Simon et al. (5) at study entry (∼2%), was more than twice as high at the end of the follow-up (11 vs. 4.5%). Similarly, also the age at PD diagnosis appeared to be higher as well as the prevalence of PD (2.5%; about eightfold higher than in the other cohorts included in the meta-analysis). However, the increased risk for those with diabetes of shorter duration may also be explained by detection bias as a result of increased medical surveillance (12). Recently this clustering with age was not confirmed by the other prospective investigation reporting an increased risk of PD in diabetic subjects (13). In the cohort followed by Xu et al. (13) only a history of diabetes longer than 10 years was significantly associated with PD risk. However, only diabetes at baseline was included in the analyses, and differences in monitoring of diabetic and nondiabetic patients during follow-up could have contributed to estimation bias (13). It is noteworthy that the prevalence of PD at the end of follow-up was similar to that reported by Simon et al. (0.3 vs. 0.5%) (5), whereas the prevalence of diabetes at baseline was about 3.5-fold higher than in the other cohorts (7.4 vs. ∼2%) (5,6,12).

Other pathogenic mechanisms shared by diabetes and PD involve the inflammatory and mitochondrial dysfunction pathways. The contribution of chronic low-grade inflammation to the development of insulin resistance is generally accepted (26). Similarly, recent research has indicated that neuroinflammation plays a role in the pathogenesis of PD (27,28). Furthermore, recent studies support the hypothesis that the link between the two diseases may be the bioenergetic similarity of the midbrain substantia nigra and the pancreatic islet β-cells. In particular, the higher vulnerability to oxidative stress and toxins may result in lower respiratory capacity (ATP production) and cellular vitality (9,10).

Looking at prospective studies other limitations should be taken into account. First, no information on glucose control and related management was considered during the follow-up. Data from the literature suggest that insulin and insulin-sensitizers, such as thiazolidinediones, could be a viable therapeutic approach to the treatment of neurodegenerative disorders, since they would also improve systemic low-grade inflammation (10). Second, most of the information collected was self-reported, and recall bias cannot not be excluded with advancing age, particularly in the presence of concomitant deterioration in cognitive status. This applies at least to diabetes since blood glucose was not measured in prospective studies. Third, changes in the initial diagnosis of parkinsonism may also occur (29). Fourth, the potential confounding effect of other cardiovascular risk factors frequently clustered with diabetes within the spectrum of the metabolic syndrome has been considered only to some extent. Although their role still needs to be elucidated as a result of inconsistent evidence, some investigators have suggested that hypertension and high blood cholesterol are associated with an increased risk of PD (30,31). Conversely, high serum urate has been reported to be a protective factor (32,33) as well as the use of statins (34). Finally, among the several specific food items investigated (antioxidants, macronutrients, dairy products, etc.) (35), only the effect of caffeine and alcohol intake was taken into account. In regard to this, it should also be mentioned that the consumption of some foods could alternatively increase the risk of PD and reduce that of diabetes, as is the case for dairy products (36,37).

From a diagnostic point of view case-control studies probably offer some advantages, at least in terms of an accurate diagnosis of idiopathic PD. However, PD itself may influence the risk of diabetes, thus confounding the association. At least two factors should be considered. First, PD is associated with generalized sympathetic denervation (38,39), a condition that appears to contribute to reduced metabolic activity within adipose tissue and to an improved cardiometabolic profile (15,40). However, the timing of these effects is unclear, and only one study among those reviewed provided enough information on the length of diabetes history (8). Second, although some studies have reported that body weight does not change before the onset of PD, a recent literature overview reported that weight loss, above all in terms of adipose tissue, commonly occurs (3). This would be a continuous process, starting several years before the diagnosis, to which both reduced calorie intake and increased energy expenditure, secondary to motor symptoms, can contribute (3). Although BMI has been considered among the potential confounders, this parameter, together with weight loss, should probably be taken into account during control selection and inclusion. Finally, survival bias as a result of high mortality among diabetic patients could contribute to the inverse relationship between diabetes and PD in case-control studies.