Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson's disease occurring with Type 2 diabetes in a Taiwanese population cohort
Introduction
Parkinson's disease (PD) is common among age-related neurodegenerative diseases [1]. PD, Alzheimer's disease, depression as well as diabetes mellitus are probably entwined [2]. Its incidence is expected to increase numerically most among Chinese despite possibly less of an age-relationship [3]. Differences in PD prevalence by locality [4], [5], gender [6], and ethnicity [1], [3], [6] provide some clues as to genetic [7] and environmental factors [8] in its complex pathogenesis.
There are various ways in which a shared pathogenesis of diabetes, dementia, and PD may occur. One is that there might be an underlying disorder of mitochondrial bioenergetics, manifest in pancreatic beta-cells and adipose tissue; this might be attributable to limited activation of PGC-1α (PPAR-ɤ co-activator-1α) and its link to AMP kinase in the substantia nigra and dopaminergic neurons [9]. Another overlapping cytotoxic disorder is that of abnormal protein folding [10], [11], [12] which is associated with amylin-derivative effects on pancreatic beta-cells in diabetes, the neurodegenerative tauopathies (hyperphosphorylation of tau, low levels of soluble tau) [13], the formation of amyloid precursor protein (characteristic of Alzheimer's disease) and with synucleinopathies in neurodegenerative disorders characterized by neurofibrillary aggregates of alpha-synuclein protein in neurons and glial cells in PD [14]. Susceptibility of these mechanisms to oxidative stress, notably in substantia nigral and dopaminergic neurons, is likely. That abnormal glucose tolerance is common among PD patients was noted by Sandyk [15] and, in animal studies, chronic hyperglycemia decreases striatal dopaminergic transmission [16]. Each of these phenomena may be more evident with insulin resistance [11]. Yet another way in which shared pathogeneses might operate is through macrovascular disease which may increase both the risk of PD and related mortality.
Conversely, idiopathic PD appears not to be a risk for diabetes [16]. Certain studies indicate that diabetes may antedate PD [17], [18], [19] or that PD clusters near to the diabetes diagnostic date [20]. However, there are also negative studies [21], [22] or even apparent protection [23]. The negative studies have not considered the effect of T2DM on PD without oral antihyperglycaemic agent (OAA) usage. Schernhammer et al. found that not only diabetes, but also OAAs increased the risk for PD. We are interested in whether all OAAs increase the risk of PD, since metformin might reduce the risk of dementia [24]. Apart from possibly the Mediterranean diet [25], decreasing vitamin D deficiency [26] and avoidance of Parkinsonogenic substances [27], there is little on offer for PD prevention. The present cohort study explores whether Type2DM or any of the commonly used OAAs might play a role in the development of PD among Taiwanese.
Section snippets
Data sources and study subjects
This study was approved by the Institutional Review Board of the National Health Research Institutes of Taiwan. Taiwan initiated national health insurance (NHI) in 1995. By 2007, 98.4% of Taiwan's 22.96 million population was enrolled. From it, an NHI Research Database is derived. The Longitudinal Health Insurance Database 2000 contains all claims data for 800,000 beneficiaries, randomly sampled from the year 2000 Registry [28]. We have studied the database with antecedent data from 1st January
Study 1
There was a 2.18-fold (95% confidence intervals (CI), 1.27–3.73) increase in risk for PD in those with T2DM but without OAAs, compared with those who were diabetes-free, matched for age and gender (Fig. 1). For T2DM patients who were on OAA, the hazard ratio (HR) was 1.30 (95% CI, 0.77–2.19), and lower than that for T2DM without OAA therapy. Similar findings were evident for both genders (Fig. 1).
We have calculated the age-specific prevalences of T2DM and PD for the year 2000 (Supplementary
Discussion
Our findings in the Taiwanese population support T2DM as a risk factor for PD. PD risk doubled with the advent of T2DM and only 1.3-fold with OAA therapy. However, not all OAA therapy would appear to reduce PD risk. For sulfonylureas, the HR was 1.57 and, in the population who did not use insulin, 1.74. However, combined with metformin, the corresponding HRs were 0.78 with insulin and 0.88, without insulin. But, without insulin, if metformin was first used, the HR for its combination with
Potential conflict of interest disclosure
There are no conflicts of interest for any of the authors.
Funding
The National Health Research Institutes, Taiwan.
Authors' contributions
MLW, MSL, CCHand SYC designed and managed the study; MLW, CCH, MSL, and HNT analyzed and interpreted the data; MLW and MSL wrote the paper with critical neurological input from JL; MLW, CCH, MSL, SYC, JL and HNT read, revised and approved the final manuscript.
Acknowledgments
We gratefully acknowledge the support of the Department of Health and the National Health Insurance agency in Taiwan for their encouragement and cooperation in the conduct of this investigation.
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