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Impairment of insulin signaling pathway PI3K/Akt/mTOR and insulin resistance induced AGEs on diabetes mellitus and neurodegenerative diseases: a perspective review

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Abstract

Insulin resistance is common in type 2 diabetes mellitus (T2DM), neurodegenerative diseases, cardiovascular diseases, kidney diseases, and polycystic ovary syndrome. Impairment in insulin signaling pathways, such as the PI3K/Akt/mTOR pathway, would lead to insulin resistance. It might induce the synthesis and deposition of advanced glycation end products (AGEs), reactive oxygen species, and reactive nitrogen species, resulting in stress, protein misfolding, protein accumulation, mitochondrial dysfunction, reticulum function, and metabolic syndrome dysregulation, inflammation, and apoptosis. It plays a huge role in various neurodegenerative diseases like Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and Amyloid lateral sclerosis. In this review, we intend to focus on the possible effect of insulin resistance in the progression of neurodegeneration via the impaired P13K/Akt/mTOR signaling pathway, AGEs, and receptors for AGEs.

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Data Availability

Data sharing is not applicable for this study as no datasets are genarated or analyzed in the current study.

Abbreviations

4E BP1:

Eukaryotic translation initiation factor 4E (elF4E)-binding protein 1

AD:

Alzheimer’s disease

AGEs:

Advances glycation end products

ALS:

Amyloid lateral sclerosis

AKT:

AK strain transforming

AMPK:

AMP-activated protein kinase

APP:

Amyloid precursor protein

APS:

Adaptor protein with Pleckstrin homology and Src homology 2 domains

ATP:

Adenosine triphosphate

ATG:

Autophagy-related gene

Bax:

Bcl-2 associated X protein

BBB:

Blood–Brain Barrier

BNIP 3:

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3

CML:

Nε-carboxy-methyl-lysine

c-Myc:

Master Regulator of Cell Cycle Entry and Proliferative Metabolism

Cpd38:

6-(2,4-difluorophenoxy)-5-((ethylmethyl)pyridine-3-yl)-8-methylpyrrolo[1,2-a] pyrazin-1(2H)-one

CREB:

cAMP-responsive element-binding protein

CVD:

 Cardiovascular diseases

DEPTOR:

 DEP domain-containing interacting protein

DPP4:

Dipeptidyl-peptidase 4

DM:

Diabetes mellitus

ERK:

Extracellular signal-regulated kinase

FOX O:

 Forehead box O transcription factor

FRK:

Fyn-related kinase

FUS/TLS:

Fused in sarcoma/translocated in liposarcoma

GLP 1:

 Glucagon-like polypeptide 1

GABA:

Gama-aminobutyric acid

GLUT:

 Glucose transporter

GPCR:

 G protein-coupled receptor

GRB:

Growth factor receptor-bound protein

GSK:

 Glycogen synthase kinase

HD:

 Huntington’s disease

HIF1a:

Hypoxia-inducible Factor-1a

HTT:

 Huntington protein

IGF:

Insulin growth factor

IL:

Interleukin

IR:

Insulin receptor

IRS:

Insulin receptor substrate

JNK:

Jun kinase

MAPK:

Mitogen-activated protein kinase

MELAS:

Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes

MLST8:

Mammalian lethal with SEC18 protein 8

mSIN- mLST 1- mTOR:

Mechanistic/mammalian target of rapamycin

NADPH:

Mitogen-activated protein kinase

NF κb:

Nuclear factor kappa-light chain-enhancer of activated B cells

Nrf:

Nuclear factor κ-light-chain-enhancer of activated B cell

NMDA:

N-methyl-D-aspartate

PD:

 Parkinson’s disease

PDK:

Phosphoinositide-dependent Protein Kinase

Pkc:

Protein Kinase C

PI3K:

 Phosphatidyl inositol 3 phosphate kinase

PIP3:

 Phosphatidyl inositol 3,4,5 triphosphate

PINK:

 PTEN putative kinase 1

PKB:

 Protein kinase B

PTEN:

 Phosphatase and tensin homolog

PTP1B:

Protein-tyrosine Phosphatase 1B

PP-242:

mTOR inhibitor

PPAR:

 Peroxisome proliferator-activated receptor

PRAS 8:

Protease-activated receptors 8

RTK:

Receptor tyrosine kinase

RAGE:

Receptor for AGEs

RAPTOR:

 Regulatory associated protein of mTOR

RHEB:

 Ras homologous enriched in the brain

RICTOR:

 Rapamycin-insensitive companion of mTOR

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

RXR:

 Retinoid transcription factor

SREBP1:

Sterol regulatory element-binding transcription factor 1

SGK:

Serine/threonine-protein kinase

SR:

Scavenger receptor

S6K:

Ribosomal s6 kinase

SOXS3:

Suppressor of cytokine signaling 3

SOD1:

Superoxide dismutase 1

STAT:

Signal transducer and activator of transcription

SHcA:

SHC transforming protein 1

TDP-43:

TAR DNA-binding protein 43

TSC:

Tuberous sclerosis proteins

TNF:

 Tumor necrosis factor

VEGF:

 Vascular endothelial growth factor

Wnt:

Wingless-related integration site

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  1. Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632014, India

    Kanagavalli Ramasubbu & V. Devi Rajeswari

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All authors contributed in manuscript design and study conception. Kanagavalli Ramasubbu collected the data and wrote the manuscript. Devi Rajeswari V contributed to the drafting of the manuscript. All the authors approved the final version of the manuscript.

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Ramasubbu, K., Devi Rajeswari, V. Impairment of insulin signaling pathway PI3K/Akt/mTOR and insulin resistance induced AGEs on diabetes mellitus and neurodegenerative diseases: a perspective review. Mol Cell Biochem 478, 1307–1324 (2023). https://doi.org/10.1007/s11010-022-04587-x

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