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Insulin resistance: mechanism and implications for carcinogenesis and hepatocellular carcinoma in NASH

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Abstract

Introduction

The effects of insulin resistance in human diseases are of paramount importance. Since the original proposal by the WHO indicating insulin resistance as the common substrate of the metabolic syndrome, large data are now available on its significance in cardiovascular diseases, nonalcoholic fatty liver disease and cancer risk.

Materials and methods

We reviewed the evidence linking hyperinsulinemia to insulin resistance and ultimately to increased cancer risk. Insulin resistance, by reducing substrate flux along the PI3-K pathway, is followed by compensatory hyperinsulinemia, considered a potential stimulus for cancerogenesis along the MAP-K pathway. Adaptive mechanisms of fat storage, promoted by insulin resistance, chronically maintained in an obesiogenic environment, may lead to oxidative stress and inflammation and modify the immune responses, further increasing the carcinogenic potential. The increased cancer risk associated with obesity, type 2 diabetes and nonalcoholic fatty liver may thus be fueled by hyperinsulinemia. Insulin secretagogs and insulin treatment, by raising circulating insulin levels, further increase cancer risk, whereas insulin sensitizers are associated with decreased cancer risk (all sites) and specifically decrease hepatocellular carcinoma. Likewise, drugs related to the incretin system, which are weight neutral or even reduce whole-body and hepatic fat, improve insulin sensitivity and potentially reduce the cancer risk.

Conclusion

New diabetes treatments might thus help decrease the future burden of diabetes-associated cancer and particularly of hepatocellular carcinoma.

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Abbreviations

ChREBP:

Carbohydrate response element-binding protein

DPP-4i:

Dipeptidyl-peptidase-4 inhibitors

EGP:

Endogenous glucose production

FFA:

Free fatty acid

FPI:

Fasting plasma insulin

G6PC:

Glucose 6-phosphatase

GCKR:

Glucokinase regulatory protein

GLP-1:

Glucagon-like peptide-1

GLUT:

Glucose transporter

HCC:

Hepatocellular carcinoma

IR:

Insulin resistance

LDL:

Low-density lipoprotein

LPL:

Stimulating lipoprotein-lipase

MAP-K:

Mitogen-activated protein kinase

NAFLD:

Nonalcoholic fatty liver disease

PI3-K:

Phosphatidyl-inositol-3-kinase

PPAR:

Peroxisome proliferator-activated receptor

ROS:

Reactive oxygen species

T2DM:

Type 2 diabetes

TZDs:

Thiazolidinediones

VLDL:

Very-low-density lipoprotein

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Acknowledgements

The authors have received funding from the European Community’s Seventh Framework Program (FP7/2007–2013) under grant agreement no. HEALTH-F2-2009-241762 for the project FLIP. S.M. is supported by a specific research contract within the same program.

Compliance with Ethical Requirements

The report will present data derived from the literature; no specific experiments were carried out on human or animal subjects requiring Ethical standard statements.

Conflict of interest

Luca Montesi, Arianna Mazzotti, Simona Moscatiello Gabriele Forlani, Giulio Marchesini declare that no conflict of interest exists in relation to the material included in this report.

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Authors and Affiliations

  1. Unit of Metabolic Diseases and Clinical Dietetics, “Alma Mater Studiorum” University, Bologna, Italy

    Luca Montesi, Arianna Mazzotti, Simona Moscatiello, Gabriele Forlani & Giulio Marchesini

  2. Unit of Clinical Dietetics, “Alma Mater Studiorum” University, Policlinico S. Orsola, Via Massarenti, 9, 40138, Bologna, Italy

    Giulio Marchesini

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  1. Luca Montesi
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  2. Arianna Mazzotti
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  3. Simona Moscatiello
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  5. Giulio Marchesini
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Correspondence to Giulio Marchesini.

Additional information

Based on a lecture given at the Fourth Kolkata Liver Meeting, West Bengal, India, on 16 December 2012.

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Montesi, L., Mazzotti, A., Moscatiello, S. et al. Insulin resistance: mechanism and implications for carcinogenesis and hepatocellular carcinoma in NASH. Hepatol Int 7 (Suppl 2), 814–822 (2013). https://doi.org/10.1007/s12072-013-9451-2

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