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Connecting Pathway Errors in the Insulin Signaling Cascade: The Molecular Link to Inflammation, Obesity, Cancer, and Alzheimer’s Disease

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Emerging Research in Science and Engineering Based on Advanced Experimental and Computational Strategies

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Abstract

Insulin resistance is characterized by molecular defects in the insulin-signaling pathway. Such defects disrupt cellular homeostasis and impede normal biochemical response. The mechanistic obstruction of biomolecules in the pathway leads to a number of health consequences that are grouped into a cluster of illnesses widely known as “metabolic syndrome” which creates abnormal health states of chronic condition like heart disease, diabetes, cancer, and Alzheimer’s disease, a type of dementia also known as “diabetes type 3,” which all have a profound effect and greatly impact the overall health. The interplay of major pathways leading to glucose homeostasis and energy production is explored. Molecular docking is utilized to understand possible intermolecular forces between key molecules in the signaling pathways. Emphasis is placed on the major components of insulin signaling, especially on how individual protein molecules of the pathways are interacting with each other in the signaling cascade. The relationship between the respective diseases and the signaling cascades is explored. Molecular links in the insulin pathway will be explored in detail, in order to correlate major mechanisms that lead to insulin resistance and related pathological conditions.

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Abbreviations

4EBP1:

Eukaryotic translation initiation factor 4E-binding protein 1

AD:

Alzheimer’s disease

Akt:

Protein kinase B (PKB)

APP:

Amyloid precursor protein

APS:

Adaptor protein with pleckstrin homology

AS160:

TBC1 domain family member 4 (TBC1D4)

Aβ:

Amyloid beta

BAD:

BCL2 associated agonist of cell death

C3G:

Cyanidin 3-glucoside

CAP:

Cbl-associated protein

Cbl:

Cas-Br-M ecotropic retroviral transforming sequence homologue

CrK:

Adapter molecule CrK (proto-oncogene c-Crk)

elk1:

ETS like-1 protein Elk-1

eNOS:

Endothelial NO synthase

ERK:

Extracellular regulated kinase

ET-1:

Endothelin-1

FFAs:

Free fatty acids

FOXO:

Forkhead box O

GAP:

GTPase-activating protein

GEF:

Guanine nucleotide exchange factor

GLUT4:

Glucose transporter type 4 (SLC2A4)

GRB10:

Growth factor receptor-bound protein 10; insulin receptor-binding protein Grb-IR

Grb2:

Growth factor receptor-bound protein 2

GSK-3:

Glycogen synthase kinase 3

GSK-3β kinase:

Glycogen synthase kinase 3 beta

IDE:

Insulin degrading enzyme

IKK:

IκB kinase

IKK-β:

IκB kinase-β (inhibitor of nuclear transcription factor kappa-B kinase subunit beta)

IR:

Insulin receptor

IRS:

Insulin receptor substrate

JNK:

c-jun N-terminal kinases

L803-mts:

Selective peptide inhibitor of glycogen synthase kinase-3 (GSK-3)

MAPK:

Mitogen-activated protein kinase

MAP2K:

Mitogen-activated protein kinase kinase

MAP3K:

Mitogen-activated protein kinase kinase kinase

MCP-1:

Monocyte chemoattractant protein-1

MEK:

MAPK and ERK kinases

MIP-1:

Macrophage inflammatory protein 1

Mnk:

Mitogen-activated protein kinase interacting protein kinase

mTOR:

Mammalian target of rapamycin

NF-kB:

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

NFT:

Neurofibrillary tangles

NO:

Nitric oxide

PDK-1:

Pyruvate dehydrogenase lipoamide kinase isozyme 1

PI3K:

Phosphoinositide 3-kinase (phosphatidylinositol 3 kinase)

PIP2:

Phosphatidylinositol 4,5-bisphosphate

PIP3:

Phosphatidylinositol-trisphosphate

PKC:

Protein kinase C

POS:

Polycystic ovarian syndrome

PPAR-y:

Thiazolidinedione family of Insulin-sensitizing peroxisome proliferator-activated receptor gamma

PTEN:

Phosphatase and tensin homolog

PTP1B:

Protein-tyrosine phosphatase 1B

Raf:

Raf kinase family member (rapidly accelerated fibrosarcoma); RAF proto-oncogene serine/threonine-protein kinase

Ras:

Ras GTPase

ROS:

Reactive oxygen species

RSK:

Ribosomal S6 kinase

RTK:

Receptor tyrosine kinase

S6K:

Ribosomal protein S6 kinase beta-1

Shc:

Src-homology-2-containing protein

SHP2:

Tyrosyl phosphatase

SOS:

Guanyl nucleotide exchange factor son-of-sevenless

STZ:

Streptozotocin

T2DM:

Type 2 diabetes mellitus

TC10:

Ras homologue gene family, member Q (ARHQ)

TLR:

Toll-like receptor

TLR4:

Toll-like receptor 4

TNF:

Tumor necrosis factor

TNF-α:

Tumor necrosis factor-α

TSC:

Tuberous sclerosis 1

TZD:

Thiazolidinediones

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Authors and Affiliations

  1. STEM Biotechnology Division, Roxbury Community College, Boston, USA

    Yessica J. Sosa, Harolin M. Sosa, Victor A. Epiter-Smith & Kimberly A. Stieglitz

  2. Department of Biology, College of Arts & Sciences, Boston University, Boston, USA

    Gemma R. Topaz

  3. Department of Chemistry, College of Arts & Sciences, Boston University, Boston, USA

    Kimberly A. Stieglitz

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  1. Yessica J. Sosa
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  1. Dept de Química, Univ Tecno Federal do Parana, Londrina, Brazil

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  2. Centro Brasileiro de Pesquisas Físicas, Rio de Janeiro, Brazil

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Sosa, Y.J., Sosa, H.M., Epiter-Smith, V.A., Topaz, G.R., Stieglitz, K.A. (2020). Connecting Pathway Errors in the Insulin Signaling Cascade: The Molecular Link to Inflammation, Obesity, Cancer, and Alzheimer’s Disease. In: La Porta, F., Taft, C. (eds) Emerging Research in Science and Engineering Based on Advanced Experimental and Computational Strategies. Engineering Materials. Springer, Cham. https://doi.org/10.1007/978-3-030-31403-3_9

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  • Print ISBN: 978-3-030-31402-6

  • Online ISBN: 978-3-030-31403-3

  • eBook Packages: EngineeringEngineering (R0)

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