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Role of epigenomic mechanisms in the onset and management of insulin resistance

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Abstract

The prevalence of insulin resistance (IR) is increasing rapidly worldwide and it is a relevant health problem because it is associated with several diseases, such as type 2 diabetes, cardiovascular disorders and cancer. Understanding the mechanisms involved in IR onset and progression will open new avenues for identifying biomarkers for preventing and treating IR and its co-diseases. Epigenetic mechanisms such as DNA methylation are important factors that mediate the environmental effect in the genome by regulating gene expression and consequently its effect on the phenotype and the development of disease. Taking into account that IR results from a complex interplay between genes and the environment and that epigenetic marks are reversible, disentangling the relationship between IR and epigenetics will provide new tools to improve the management and prevention of IR. Here, we review the current scientific evidence regarding the association between IR and epigenetic markers as mechanisms involved in IR development and potential management.

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Abbreviations

5mC:

5-methylcytosine

ADAM2:

ADAM metallopeptidase domain 2

ADCY9:

adenylate cyclase 9

BS:

bisulphite sequencing

C:

cytosine

CERs:

ceramides

COL11A2:

collagen type XI alpha 2 chain

COL5A1:

collagen type V alpha 1 chain

COL9A1:

collagen, type IX, alpha 1

DAGs:

diacylglycerols

DMCpG:

differentially methylated CpG

DNA:

deoxyribonucleic acid

DNMTs:

DNA methyltransferases

ER:

endoplasmic reticulum

FAM123C:

family with sequence similarity 123C

FHL2:

four and a half LIM domains 2

FTO:

FTO alpha-ketoglutarate dependent dioxygenase

GAB1:

GRB2 associated binding protein 1

GATA4:

GATA binding protein 4

GDM:

glucose disposal metabolizable glucose

GDR:

rate of whole-body glucose disposal

GLUT-4:

glucose transporter type 4

GO:

gene ontology

HDACM:

histone deacetylase

HHEX:

hematopoietically expressed homeobox

HOMA-IR:

Homeostatic Model Assessment for Insulin Resistance

IGF2BP1:

insulin like growth factor 2 mRNA binding protein 1

IGF2BP2:

insulin like growth factor 2 mRNA binding protein 2

IL:

interleukins

IR:

insulin resistance

IRS:

insulin receptor substrate

IS:

insulin-sensitive

JAZF1:

JAZF zinc finger 1

KCNJ11:

potassium voltage-gated channel subfamily J member 11

KCNQ1:

potassium voltage-gated channel subfamily Q member

KLF14:

Kruppel like factor 14

lncRNA:

long non-coding RNA

MAM:

membranes associated with mitochondria

MBD:

methyl-CpG-binding domain

miRNA:

microRNA

MS:

metabolic syndrome

MUC4:

mucin 4, cell surface associated

NAFLD:

non-alcoholic fatty liver disease

ncRNAs:

non-coding RNA

NOTCH2:

notch receptor 2

PCOD:

polycystic ovarian disease

PCR:

polymerase chain reaction

PFKFB3:

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3

PI3K:

Phosphoinositide 3-kinase

PTMs:

post-translational histone modifications

PTPRJ:

protein tyrosine phosphatase receptor type J

SAT:

subcutaneous adipose tissue

SIRTs:

Sirtuins

T2D:

type 2 diabetes mellitus

TBX5:

T-box 5

TCF7L2:

transcription factor 7 like 2

TET1:

tet methylcytosine dioxygenase 1

THADA:

THADA armadillo repeat containing

TNF-α:

tumour necrosis factor alfa

VAT:

visceral adipose tissue

WFS1:

wolframin ER transmembrane glycoprotein

ZNF518B:

zinc finger protein 518B

ZNF714:

zinc finger protein 714

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Acknowledgements

The research of the author’s lab is supported by Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn) and grants from the Instituto de Salud Carlos III-ISCIII (PI17/01287, CP17/00088) co-financed by the European Regional Development Fund (FEDER). Ana B Crujeiras is funded by a research contract “Miguel Servet” (CP17/00088) from the ISCIII.

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  1. Epigenomics in Endocrinology and Nutrition group, Instituto de Investigacion Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), C/ Choupana, s/n, 15706, Santiago de Compostela, Spain

    Andrea G. Izquierdo & Ana B. Crujeiras

  2. CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), Madrid, Spain

    Andrea G. Izquierdo & Ana B. Crujeiras

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  1. Andrea G. Izquierdo
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Highlights

- Approximately 30% of individuals in the population will present resistance to insulin and its complications throughout their lifetime.

- Changes in lifestyle have contributed to the incidence of diseases related to IR such as T2D in recent years.

- IR occurs in response to an interaction between genetic and environmental factors, suggesting that it may be subject to epigenetic regulation

- A specific methylation pattern related to insulin sensitivity and T2D was observed in adipose tissue, muscle, and pancreatic islets, as well as blood leukocytes.

- Non-coding RNAs are emerging as relevant players in the onset and management of IR.

- To find non-invasive biomarkers and therapeutic targets for IR management is an urgent necessity and epigenetic mechanisms could provide future strategies.

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Izquierdo, A.G., Crujeiras, A.B. Role of epigenomic mechanisms in the onset and management of insulin resistance. Rev Endocr Metab Disord 20, 89–102 (2019). https://doi.org/10.1007/s11154-019-09485-0

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