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Insulin-mediated immune dysfunction in the development of preeclampsia

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Abstract

Epidemiological observations implicate insulin resistance as a predisposing factor in the development of preeclampsia (PE). It is also well established that PE manifests in the context of a dysregulated immune response at the maternal-foetal interface, though all the underlying drivers of such immune dysregulation remains to be accounted for. Although it has long been known that various immune cells express insulin receptors following immune activation, it is only recently that insulin signalling has been shown to play a key role in immune cell differentiation, survival and effector function through its canonical activation of the PI3K/Akt/mTOR pathway. Here we argue that hyperinsulinemia, manifesting either from insulin resistance or from intensive insulin therapy, likely plays a direct role in driving immune cell dysfunction which plays a central role in the development of PE. This line of reasoning also explains the superior results of insulin-sparing interventions compared to intensive insulin therapy as monotherapy.

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Abbreviations

PE:

Preeclampsia

GD:

Gestational diabetes

AGE:

Advance glycation end products

RAGE:

Receptor for AGE

mTOR:

Mechanistic target of rapamycin

IR:

Insulin receptor

MAPK:

Mitogen-activated protein kinase

PI3K:

Phosphoinositide 3-kinase

IC:

Immune checkpoint

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed death-ligand 1

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

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Funding

The authors acknowledge funding support from the Cancer Association of South Africa (CANSA), the National Research Foundation (NRF), the Medical Research Council of South Africa (SAMRC) and the Claude Leon Foundation.

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  1. Department of Physiological Sciences, University of Stellenbosch, c/o Merriman & Bosman Street, Stellenbosch, South Africa

    Gustav van Niekerk, Claudia Christowitz & Anna-Mart Engelbrecht

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  1. Gustav van Niekerk
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GVN conceptualise the theme for the article, performed the literature search and drafted the manuscript. CC and AME critically revised the work, assisted with the literature search and helped develop ideas and arguments expressed in the manuscript.

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Correspondence to Gustav van Niekerk.

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van Niekerk, G., Christowitz, C. & Engelbrecht, AM. Insulin-mediated immune dysfunction in the development of preeclampsia. J Mol Med 99, 889–897 (2021). https://doi.org/10.1007/s00109-021-02068-0

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