The Medial Septum Is Insulin Resistant in the AD Presymptomatic Phase: Rescue by Nerve Growth Factor-Driven IRS1 Activation

Sposato, Valentina; Canu, Nadia; Fico, Elena; Fusco, Salvatore; Bolasco, Giulia; Ciotti, Maria Teresa; Spinelli, Matteo; Mercanti, Delio; Grassi, Claudio; Triaca, Viviana; Calissano, Pietro

doi:10.1007/s12035-018-1038-4

Cited by 22 publications

(24 citation statements)

References 70 publications

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“…20 A study of African-Americans found that IRS1 mutations and endocrine disorders caused by obesity synergistically reduce insulin sensitivity, suggesting that IRS1 variability and obesity together become an important predictor of insulin resistance. 21 In this study, we found that IRS1 produced a non-frameshift insertion mutation in the exonic region of O-T2DM patients and that IRS1 mRNA expression levels were up-regulated in O-T2DM patients compared with healthy controls (Log2fold-change = 0.11).…”

Section: Gene Name Patient Num Patientmentioning

confidence: 67%

Combined analysis of whole‐exon sequencing and lncRNA sequencing in type 2 diabetes mellitus patients with obesity

Zhang

Liu

et al. 2020

J Cellular Molecular Medi

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This study sought to find more exon mutation sites and lncRNA candidates associated with type 2 diabetes mellitus (T2DM) patients with obesity (O‐T2DM). We used O‐T2DM patients and healthy individuals to detect mutations in their peripheral blood by whole‐exon sequencing. And changes in lncRNA expression caused by mutation sites were studied at the RNA level. Then, we performed GO analysis and KEGG pathway analysis. We found a total of 277 377 mutation sites between O‐T2DM and healthy individuals. Then, we performed a DNA‐RNA joint analysis. Based on the screening of harmful sites, 30 mutant genes shared in O‐T2DM patients were screened. At the RNA level, mutations of 106 differentially expressed genes were displayed. Finally, a consensus mutation site and differential expression consensus gene screening were performed. In the current study, the results revealed significant differences in exon sites in peripheral blood between O‐T2DM and healthy individuals, which may play an important role in the pathogenesis of O‐T2DM by affecting the expression of the corresponding lncRNA. This study provides clues to the molecular mechanisms of metabolic disorders in O‐T2DM patients at the DNA and RNA levels, as well as biomarkers of the risk of these disorders.

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Section: Gene Name Patient Num Patientmentioning

confidence: 67%

Combined analysis of whole‐exon sequencing and lncRNA sequencing in type 2 diabetes mellitus patients with obesity

Zhang

Liu

et al. 2020

J Cellular Molecular Medi

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“…These results were consistent with our nding that NGF was positively related to glucose levels and insulin secretion in the second trimester. Moreover, NGF could reduce insulin resistance both in vitro and in vivo by activating insulin receptor substrate 1 (IRS1) [22,23]. These data suggest that NGF acts as a protective factor in glucose metabolism and insulin sensitivity and plays a signi cant role in glucose-induced insulin secretion.…”

Section: Discussionmentioning

confidence: 96%

Nerve Growth Factor is Closely Related to Glucose Metabolism, Insulin Sensitivity and Insulin Secretion in the Second Trimester: A Case-Control Study in Chinese

Tang¹,

Luo

Lü

et al. 2020

Preprint

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Objective: Inflammation-related factors have been shown to play a significant role throughout pregnancy. In this study, we aimed to explore the relationships between selected inflammatory cytokines and gestational diabetes (GDM) in Chinese pregnant women.Design and Methods: This was a 1:1 matched case-control study that included 200 pairs of subjects in the second trimester and 130 pairs of subjects in the third trimester. Serum levels of nerve growth factor (NGF), Interleukin-6 (IL-6), leptin, Interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α) and Interleukin-1beta (IL-1β) were measured by enzyme immunoassay. The associations of these inflammatory factors with metabolic parameters were analysed.Results: In the second trimester, GDM patients had higher NGF levels and lower IL-8 levels than did normal controls (P<0.001 and P=0.015, respectively). However, in the third trimester, only lower leptin levels were observed in the GDM group (P=0.031). Additionally, in the second trimester, NGF levels were not only positively associated with fasting, 1-h and 2-h glucose levels and the area under curve of glucose (AUCG), but also positively related to insulin sensitivity and secretion, as suggested by fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment index of β-cell secretion (HOMA-β) (all P<0.05). Moreover, IL-6 and leptin levels were positively correlated with HOMA-IR and HOMA-β, and TNF-α levels were positively related to HOMA-IR (all P<0.05). Except for the relationships between NGF and HOMA-β and TNF-α and HOMA-IR, the other correlations still existed even after adjusting for confounding factors (all P< 0.05). Conclusion: In addition to the positive associations of IL-6 and leptin with insulin resistance and secretion, NGF was higher in the GDM patients and strongly linked to glucose metabolism, insulin resistance and pancreatic β cell function in Chinese pregnant women in the second trimester.

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“…Peptides were purified by means of reverse-phase high-performance liquid chromatography by using a PrepStar 200 model SD-1 chromatography system (Varian, Palo Alto, CA, USA). NGF protein was purified from rodent submaxillary glands, as already reported [38][39][40].…”

Section: Hngf Peptides and Ngf Purificationmentioning

confidence: 99%

“…Cholinergic neurons were harvested from the septal region of E17 Wistar rat embryos, as previously described [39,40] and dissociated cells were seeded as follows: 1.5 × 10 6 cells on poly-l-lysine (Sigma) coated 35 mm plates (BD Falcon, Durham, NC, USA; 353001) for western blotting analyses and 5 × 10 4 cells on glass coverslips in 24-wells plates (BD Falcon; 351147) for immunofluorescence analysis. Cells were grown in Neurobasal (NB) medium supplemented with 2% B27 (Invitrogen) in a 5% CO 2 incubator at 37 • C (ThermoFisher Scientific, Waltham, MA, USA) for 10 days and then used for treatments (DIV10).…”

Section: Cholinergic Neurons Culturementioning

confidence: 99%

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hNGF Peptides Elicit the NGF-TrkA Signalling Pathway in Cholinergic Neurons and Retain Full Neurotrophic Activity in the DRG Assay

et al. 2020

Self Cite

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In the last decade, Nerve Growth Factor (NGF)-based clinical approaches have lacked specific and efficient Tyrosine Kinase A (TrkA) agonists for brain delivery. Nowadays, the characterization of novel small peptidomimetic is taking centre stage in preclinical studies, in order to overcome the main size-related limitation in brain delivery of NGF holoprotein for Central Nervous System (CNS) pathologies. Here we investigated the NGF mimetic properties of the human NGF 1–14 sequence (hNGF1–14) and its derivatives, by resorting to primary cholinergic and dorsal root ganglia (DRG) neurons. Briefly, we observed that: 1) hNGF1–14 peptides engage the NGF pathway through TrkA phosphorylation at tyrosine 490 (Y490), and activation of ShcC/PI3K and Plc-γ/MAPK signalling, promoting AKT-dependent survival and CREB-driven neuronal activity, as seen by levels of the immediate early gene c-Fos, of the cholinergic marker Choline Acetyltransferase (ChAT), and of Brain Derived Neurotrophic Factor (BDNF); 2) their NGF mimetic activity is lost upon selective TrkA inhibition by means of GW441756; 3) hNGF1–14 peptides are able to sustain DRG survival and differentiation in absence of NGF. Furthermore, the acetylated derivative Ac-hNGF1–14 demonstrated an optimal NGF mimetic activity in both neuronal paradigms and an electrophysiological profile similar to NGF in cholinergic neurons. Cumulatively, the findings here reported pinpoint the hNGF1–14 peptide, and in particular its acetylated derivative, as novel, specific and low molecular weight TrkA specific agonists in both CNS and PNS primary neurons.

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The Medial Septum Is Insulin Resistant in the AD Presymptomatic Phase: Rescue by Nerve Growth Factor-Driven IRS1 Activation

Cited by 22 publications

References 70 publications

Combined analysis of whole‐exon sequencing and lncRNA sequencing in type 2 diabetes mellitus patients with obesity

Combined analysis of whole‐exon sequencing and lncRNA sequencing in type 2 diabetes mellitus patients with obesity

Nerve Growth Factor is Closely Related to Glucose Metabolism, Insulin Sensitivity and Insulin Secretion in the Second Trimester: A Case-Control Study in Chinese

hNGF Peptides Elicit the NGF-TrkA Signalling Pathway in Cholinergic Neurons and Retain Full Neurotrophic Activity in the DRG Assay

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