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Diabetes, a Contemporary Risk for Parkinson's Disease: Epidemiological and Cellular Evidences

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Diabetes, a Contemporary Risk for Parkinson's Disease: Epidemiological and Cellular Evidences

Domenico Sergi et al. Front Aging Neurosci.

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.

Keywords: dopamine; glucotoxicity; hyperglycemia; mitochondrial dysfunction; nigrostriatal pathway; oxidative stress.

Figures

Figure 1
Figure 1
Mechanisms of neuronal glucotoxicity. In the early stages of hyperglycemia, there is an upregulation of glucose flux through glycolysis and the tricarboxylic acid cycle (TCA). This results in enhanced electron donor supply to the mitochondrial electron transport chain, leading to an increase in the proton gradient across the mitochondrial inner membrane which promotes the formation of reactive oxygen species (ROS). ROS-induced DNA damage triggers the activation of the NAD+-dependent DNA repair enzyme, poly (adenosine diphosphate-ribose) polymerase 1 (PARP1), responsible for depleting neuronal NAD+. The increase in intracellular glucose activates the polyol pathway which, in concert with PARP1, reduces intracellular NAD+ inhibiting glyceraldehyde triphosphate dehydrogenase (GAPDH) and therefore glycolysis. The inhibition of GAPDH provokes the accumulation of upstream triose phosphates then converted to glycating agents, thereby promoting the formation of advanced glycation end products (AGEs). The accumulation of fructose, another metabolite upstream GAPDH, triggers the activation of the hexosamine pathway and the subsequent build-up of UDP-N-acetylglucosamine (UDP-GlcNAc). Furthermore, the activation of the polyol pathway depletes NADPH and, alongside mitochondrial ROS, contributes to oxidative stress in light of its role as a cofactor for glutathione reductase, which, in turn, is crucial in maintaining the intracellular pool of reduced glutathione.

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