Abstract
Diabetes mellitus (DM), a group of diseases characterized by defective glucose metabolism, is the most widespread metabolic disorder affecting over 400 million adults worldwide. This pathological condition has been implicated in the pathogenesis of a number of central encephalopathies and peripheral neuropathies. In further support of this notion, recent epidemiological evidence suggests a link between DM and Parkinson’s disease (PD), with hyperglycemia emerging as one of the culprits in neurodegeneration involving the nigrostriatal pathway, the neuroanatomical substrate of the motor symptoms affecting parkinsonian patients. Indeed, dopaminergic neurons located in the mesencephalic substantia nigra appear to be particularly vulnerable to oxidative stress and degeneration, likely because of their intrinsic susceptibility to mitochondrial dysfunction, which may represent a direct consequence of hyperglycemia and hyperglycemia-induced oxidative stress. Other pathological pathways induced by increased intracellular glucose levels, including the polyol and the hexosamine pathway as well as the formation of advanced glycation end-products, may all play a pivotal role in mediating the detrimental effects of hyperglycemia on nigral dopaminergic neurons. In this review article, we will examine the epidemiological as well as the molecular and cellular clues supporting the potential susceptibility of nigrostriatal dopaminergic neurons to hyperglycemia.
Highlights
Since the publication of the pioneering report of Dr James Parkinson, ‘‘An Essay on the Shaking Palsy,’’ where he described six subjects suffering from a pathological state that he termed paralysis agitans, the field of Parkinson’s disease (PD) has phenomenally progressed
The present review will lay out the epidemiological evidence linking Diabetes mellitus (DM) and PD as well as the molecular mechanisms underlying the exacerbated susceptibility of nigrostriatal dopaminergic neurons to hyperglycemia, by illustrating glucose transport and metabolism in the brain and the role of glucotoxicity in promoting neuronal damage and degeneration
We argue that nigrostriatal dopaminergic neurons display the following phenotypic idiosyncrasies that may underlie their vulnerability to oxidative stress instigated by genetic mutations, environmental toxins, aging and combinations of these factors: 1. They are embedded in a particular environment, the substantia nigra pars compacta, which stores considerable amounts of iron ions (Hirsch and Faucheux, 1998; Chinta and Andersen, 2008) accumulating with age (Daugherty and Raz, 2013) and known to participate in deleterious Fenton reactions with hydrogen peroxide to produce the very reactive hydroxyl radical (Youdim et al, 1989)
Summary
Since the publication of the pioneering report of Dr James Parkinson, ‘‘An Essay on the Shaking Palsy,’’ where he described six subjects suffering from a pathological state that he termed paralysis agitans, the field of Parkinson’s disease (PD) has phenomenally progressed. P.G2385R in the LRRK2 gene is common among Chinese and Japanese populations and approximately doubles the risk for PD (Bonifati, 2007), while the REP1 microsatellite marker of the SNCA promoter region was consistently associated with a 1.4-fold increased risk of PD (for a review, see Warner and Schapira, 2003; Polito et al, 2016) Aside from these genetic and environmental factors specific to certain individuals, the substantia nigra pars compacta appears to be relatively susceptible to aging outside of a pathological context (Rudow et al, 2008; Buchman et al, 2012; Reeve et al, 2014), as spontaneous cell loss occurs at an estimated rate of 4.7–9.8% per decade in humans (Fearnley and Lees, 1991; Ma et al, 1999). This provides further evidence for the physiological relevance of the relationship between impaired glucose metabolism, insulin resistance, DM and enhanced brain glucose uptake
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