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Review
. 2019 Aug 16:13:868.
doi: 10.3389/fnins.2019.00868. eCollection 2019.

The Relevance of Insulin Action in the Dopaminergic System

Francesca Fiory  1   2 , Giuseppe Perruolo  1   2 , Ilaria Cimmino  1   2 , Serena Cabaro  1   2 , Francesca Chiara Pignalosa  1   2 , Claudia Miele  1   2 , Francesco Beguinot  1   2 , Pietro Formisano  1   2 , Francesco Oriente  1   2
Affiliations
Review

The Relevance of Insulin Action in the Dopaminergic System

Francesca Fiory et al. Front Neurosci. .

Abstract

The advances in medicine, together with lifestyle modifications, led to a rising life expectancy. Unfortunately, however, aging is accompanied by an alarming boost of age-associated chronic pathologies, including neurodegenerative and metabolic diseases. Interestingly, a non-negligible interplay between alterations of glucose homeostasis and brain dysfunction has clearly emerged. In particular, epidemiological studies have pointed out a possible association between Type 2 Diabetes (T2D) and Parkinson's Disease (PD). Insulin resistance, one of the major hallmark for etiology of T2D, has a detrimental influence on PD, negatively affecting PD phenotype, accelerating its progression and worsening cognitive impairment. This review aims to provide an exhaustive analysis of the most recent evidences supporting the key role of insulin resistance in PD pathogenesis. It will focus on the relevance of insulin in the brain, working as pro-survival neurotrophic factor and as a master regulator of neuronal mitochondrial function and oxidative stress. Insulin action as a modulator of dopamine signaling and of alpha-synuclein degradation will be described in details, too. The intriguing idea that shared deregulated pathogenic pathways represent a link between PD and insulin resistance has clinical and therapeutic implications. Thus, ongoing studies about the promising healing potential of common antidiabetic drugs such as metformin, exenatide, DPP IV inhibitors, thiazolidinediones and bromocriptine, will be summarized and the rationale for their use to decelerate neurodegeneration will be critically assessed.

Keywords: Parkinson’s disease; dopamine; insulin resistance; neurodegeneration; type 2 diabetes mellitus.

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Figures

FIGURE 1
FIGURE 1
Insulin signaling regulates neuronal function. Insulin binding to its receptor, through the intracellular substrates IRSs, leads to activation of PI3-K pathway which, in turn, inhibits GSK3, mTORC1 and IDE, reducing alpha-synuclein aggregation, and enhances cell survival. In addition, insulin-induced PI3K activation stimulates dopamine synthesis and turnover and mitochondrial biogenesis. This figure includes experimental results obtained in cell cultures and partially confirmed in rodent and human brain.
FIGURE 2
FIGURE 2
Role of the antidiabetic drugs on brain function. Several antihyperglycemic agents play a neuroprotective and anti-inflammatory role by directly acting on brain or by reducing insulin resistance.
See this image and copyright information in PMC

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References

    1. Aarsland D., Creese B., Politis M., Chaudhuri K. R., Ffytche D. H., Weintraub D., et al. (2017). Cognitive decline in Parkinson disease. Nat. Rev. Neurol. 13 217–231. 10.1038/nrneurol.2017.27 - DOI - PMC - PubMed
    1. Abdelsalam R. M., Safar M. M. (2015). Neuroprotective effects of vildagliptin in rat rotenone Parkinson’s disease model: role of RAGE-NFkappaB and Nrf2-antioxidant signaling pathways. J. Neurochem. 133 700–707. 10.1111/jnc.13087 - DOI - PubMed
    1. Aghanoori M. R., Smith D. R., Roy Chowdhury S., Sabbir M. G., Calcutt N. A., Fernyhough P. (2017). Insulin prevents aberrant mitochondrial phenotype in sensory neurons of type 1 diabetic rats. Exp. Neurol. 297 148–157. 10.1016/j.expneurol.2017.08.005 - DOI - PMC - PubMed
    1. Aime P., Hegoburu C., Jaillard T., Degletagne C., Garcia S., Messaoudi B., et al. (2012). A physiological increase of insulin in the olfactory bulb decreases detection of a learned aversive odor and abolishes food odor-induced sniffing behavior in rats. PLoS One 7:e51227. 10.1371/journal.pone.0051227 - DOI - PMC - PubMed
    1. Alcalay R. N., Gu Y., Mejia-Santana H., Cote L., Marder K. S., Scarmeas N. (2012). The association between mediterranean diet adherence and Parkinson’s disease. Mov. Disord. 27 771–774. 10.1002/mds.24918 - DOI - PMC - PubMed

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