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polycystic ovary syndrome, gestational diabetes, metabolic syndrome, poor sperm development and retinopathy of prematurity.

Fig. 1. The distribution, relative amounts and interconversions of Ins phospholipids in a generalized mammalian cell. This figure is reproduced, with permission, from reference (10), but the legend is mine. This generalised representation of a cell summarizes the distributions and relative quantities of the various organelles and of phosphatidylinositol (PtdIns) and the various polyphosphoinositides (PPIn) in these membrane subcompartments of eukaryote cells. The relative areas of membrane and volumes of the various organelle compartments, and thus their relative contents of membrane lipids (including PtdIns and PPIn) will vary substantially between cell-types. Important points to note include the following: (1) in many cells the endoplasmic reticulum (ER)/nuclear envelope continuum (the blue reticulum in this image) usually contains a larger proportion of a cell’s membranes than other organelle systems; (2) PtdIns is made in the ER (blue) and is the only phosphoinositide there (except maybe for transient traces of PtdIns4P); (3) PtdIns is a structural lipid that is distributed amongst all cell membranes (with less in the mitochondrial inner membrane), and is also the substrate for synthesis and turnover of all of the compartment-specific PPIn that are in the various non-ER and non- mitochondrial membrane systems (images of which are schematically expanded in the coloured boxes in this diagram).

Do inositol supplements enhance phosphatidylinositol supply and thus support endoplasmic reticulum function?.pdf

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British Journal of Nutrition, page 1 of 16 doi:10.1017/S0007114518000946 © The Authors 2018

Do inositol supplements enhance phosphatidylinositol supply and thus support endoplasmic reticulum function?

Robert H. Michell*

School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK (Submitted 29 November 2017 – Final revision received 26 February 2018 – Accepted 14 March 2018)

Abstract

This review attempts to explain why consuming extra myoinositol (Ins), an essential component of membrane phospholipids, is often beneficial for patients with conditions characterised by insulin resistance, non-alcoholic fatty liver disease and endoplasmic reticulum (ER) stress.

For decades we assumed that most human diets provide an adequate Ins supply, but newer evidence suggests that increasing Ins intake ameliorates several disorders, including polycystic ovary syndrome, gestational diabetes, metabolic syndrome, poor sperm development and retinopathy of prematurity.

Proposed explanations often suggest functional enhancement of minor facets of Ins Biology such as insulin signalling through putative inositol-containing ‘mediators’, but offer no explanation for this selectivity. It is more likely that eating extra Ins corrects a deficiency of an abundant Ins-containing cell constituent, probably phosphatidylinositol (PtdIns). Much of a cell’s PtdIns is in ER membranes, and an increase in ER membrane synthesis, enhancing the ER’s functional capacity, is often an important part of cell responses to ER stress.

This review:

(a) reinterprets historical information on Ins deficiency as describing a set of events involving a failure of cells adequately to adapt to ER stress;

(b) proposes that in the conditions that respond to dietary Ins there is an overstretching of Ins reserves that limits the stressed ER’s ability to make the ‘extra’ PtdIns needed for ER membrane expansion; and

(c) suggests that eating Ins supplements increases the Ins supply to Ins-deficient and ER-stressed cells, allowing them to make more PtdIns and to expand the ER membrane system and sustain ER functions.

Key words: Insulin resistance: Gestational diabetes mellitus: Polycystic ovarian syndrome: Spermatogenesis: Hypothyroidism: Non- alcoholic fatty liver disease: Endoplasmic reticulum stress

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