Impairment of insulin receptor substrate 1 signaling by insulin resistance inhibits neurite outgrowth and aggravates neuronal cell death

Song, J.; Kang, Seung-Youn; Kim, E.; Kim, C. H.; Song, Ho Taek; Lee, Jong Eun

doi:10.1016/j.neuroscience.2015.05.072

Cited by 14 publications

(9 citation statements)

References 92 publications

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“…Some studies examined the association of genetic polymorphism between GDM and T2D and supported the hypothesis that both had common genetic background 18 29 39 . In our study, only MTNR1B 40 and TCF7L2 41 involved in impaired insulin secretion, and IRS1 42 involved in insulin resistance in T2D were significantly associated with GDM. It further supports impaired insulin secretion and insulin resistance may involve in the pathogenesis of GDM as in T2D.…”

Section: Discussionmentioning

confidence: 47%

Genetic variants associated with gestational diabetes mellitus: a meta-analysis and subgroup analysis

Cui

Tam

et al. 2016

Sci Rep

109

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Previous studies have demonstrated that gestational diabetes mellitus (GDM) and Type 2 diabetes mellitus (T2D) share common genetic polymorphisms. We conducted meta-analysis and subgroup analysis of all available variants and determined the effects of confounding and experimental components on the genetic association of GDM. Any case-controlled or cohort studies with genotype distribution compared GDM cases with controls were included. In total, 28 articles including 8,204 cases and 15,221 controls for 6 polymorphisms were studied. rs10830963(MTNR1B), rs7903146(TCF7L2), and rs1801278(IRS1) were significantly associated with the increased GDM risk. The association of rs4402960(IGF2BP2) and rs1800629(TNF-α) was significant only when the studies with control allele frequency deviation and publication bias were excluded. Further subgroup analysis showed the risk alleles of rs7903146(TCF7L2) and rs1801282(PPARG) were significantly associated with the GDM risk only in Asian, but not in Caucasian population. The OGTT test using 100 g, but not 75 g; and genotype detection by other assays, but not Taqman method, were also significantly associated with increased GDM risk in rs1801278(IRS1) and rs7903146(TCF7L2). Overall GDM was associated with rs10830963(MTNR1B), rs7903146(TCF7L2), and rs1801278(IRS1), but only rs7903146(TCF7L2) and rs1801282(PPARG) were significant in Asian populations. While rs1801278(IRS1) and rs7903146(TCF7L2) were significantly affected by OGTT protocol and genotyping methods.

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Section: Discussionmentioning

confidence: 47%

Genetic variants associated with gestational diabetes mellitus: a meta-analysis and subgroup analysis

Cui

Tam

et al. 2016

Sci Rep

109

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“…This is in line with previous studies reporting that inhibition of FOXO1 and FOXO3 transcription factors plays a role in neurite growth and regeneration, as well as prevention of apoptosis upon oxidative stress in different models. 18 , 19 , 34 , 35 , 36 Altogether, these results indicate that the observed effects of miR-182-5p and miR-183-5p increase in DA PMNs are at least partially mediated by activation of the PI3K-Akt signaling pathway and downregulation of FOXO transcription factors.…”

Section: Discussionmentioning

confidence: 54%

miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons

Roser

Gomes

Halder

et al. 2018

Molecular Therapy - Nucleic Acids

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Parkinson’s disease (PD) is the second-most-frequent neurodegenerative disorder worldwide. One major hallmark of PD is the degeneration of dopaminergic (DA) neurons in the substantia nigra. Glial cell line-derived neurotrophic factor (GDNF) potently increases DA neuron survival in models of PD; however, the underlying mechanisms are incompletely understood. MicroRNAs (miRNAs) are small, non-coding RNAs that are important for post-transcriptional regulation of gene expression. Using small RNA sequencing, we show that GDNF specifically increases the expression of miR-182-5p and miR-183-5p in primary midbrain neurons (PMNs). Transfection of synthetic miR-182-5p and miR-183-5p mimics leads to increased neurite outgrowth and mediates neuroprotection of DA neurons in vitro and in vivo, mimicking GDNF effects. This is accompanied by decreased expression of FOXO3 and FOXO1 transcription factors and increased PI3K-Akt signaling. Inhibition of endogenous miR-182-5p or miR-183-5p in GDNF-treated PMNs attenuated the pro-DA effects of GDNF. These findings unveil an unknown miR-mediated mechanism of GDNF action and suggest that targeting miRNAs is a new therapeutic avenue to PD phenotypes.

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“…The complex pathomechanism of neuronal damage is only partially elucidated and the lack of appropriate preclinical model of neurodegeneration hinders the better understanding of the diseases. Recently insulin resistance in the central nervous system was suggested to contribute to neurodegenerative processes, thus it may play a role in the development of cognitive impairment and Alzheimer's disease (Song et al 2015; de la Monte 2012; Schubert et al 2004). It was previously reported that insulin signaling is compromised in the post mortem brain samples of Alzheimer's disease patients (Steen et al 2005;Freude et al 2009;Morgen and Frolich 2015) and intranasal insulin administration (Freiherr et al 2013;Chapman et al 2018), as well as some other drugs like the insulin sensitizer metformin (Koenig et al 2017;Markowicz-Piasecka et al 2017) were shown to improve the cognitive performance.…”

Section: Discussionmentioning

confidence: 99%

Lack of insulin resistance in response to streptozotocin treatment in neuronal SH-SY5Y cell line

Bagaméry

Kecsmár

et al. 2019

J Neural Transm

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Recently, it is suggested that brain insulin resistance may contribute to the development of Alzheimer's disease; therefore, there is a high interest in its investigation. Streptozotocin (STZ) is often used to induce dysregulation of glucose and insulin metabolism in animal and cell culture models. Alteration in insulin sensitivity however, has not yet been assessed in neuronal cells after STZ treatment. We aimed at studying the concentration dependence of the protective effect of insulin on STZ-induced damage using SH-SY5Y cell line. Cells were treated with STZ and cell viability was assessed by resazurin reduction and lactate dehydrogenase release assays. Low serum (LS) medium was used as control damage. The effect of various concentrations (30, 100, 300, 1000 nM) of insulin was studied on cell viability and glycogen synthase kinase-3 (GSK-3) phosphorylation, an indicator of insulin signaling. STZ induced dose-and time-dependent cytotoxicity, its 1 mM concentration exerted a low, gradually developing damage. The cytoprotective effect of insulin was demonstrated in both STZ and LS groups. Its maximal effect was lower in the STZ-treated cells; however, its effective concentration remained largely unaltered. Insulin-induced GSK-3 phosphorylation was similar in the STZ-and LS-treated cells suggesting unchanged insulin signaling. Our present results indicate that STZ does not induce significant impairment in insulin sensitivity in SH-SY5Y cells, thus in this cell line it is not a good tool for studying the role of insulin resistance in neurodegeneration and to examine protective agents acting by improving insulin signaling.

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Impairment of insulin receptor substrate 1 signaling by insulin resistance inhibits neurite outgrowth and aggravates neuronal cell death

Cited by 14 publications

References 92 publications

Genetic variants associated with gestational diabetes mellitus: a meta-analysis and subgroup analysis

Genetic variants associated with gestational diabetes mellitus: a meta-analysis and subgroup analysis

miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons

Lack of insulin resistance in response to streptozotocin treatment in neuronal SH-SY5Y cell line

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