Inositol is a sugar alcohol that is widely distributed in the human body and that is the foundation of the phosphoinositide second messenger system — the network of membrane-bound signalling molecules that transmits the signals from the cell surface receptors to the intracellular target enzymes and transcription factors. The phosphoinositides are a family of phospholipids that are embedded in the inner leaflet of the cell membrane, and they consist of a glycerol backbone that is attached to two fatty acids and to a head group that contains the inositol sugar. The inositol head group can be phosphorylated at up to five positions (D-1, D-2, D-3, D-4, D-5), and the different phosphorylation patterns create the distinct phosphoinositide species (PI, PIP, PI(4,5)P2, PI(3,4)P2, PI(3,4,5)P3) that are the specific molecular identifiers of the different signalling pathways. The most important phosphoinositide for the cellular signalling is the phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), which is the substrate for the phospholipase C (PLC) enzyme that cleaves it into the two second messengers — the inositol 1,4,5-trisphosphate (IP3) and the diacylglycerol (DAG) — that are the primary mediators of the hormone and the neurotransmitter signalling in the cells.
The Phosphoinositide Second Messenger System
The phosphatidylinositol (PI) is the most abundant phosphoinositide in the cell membrane, and it is the precursor of all the other phosphoinositide species through the action of the PI kinases and the PI phosphatases. The PI(4,5)P2 is the most important of these species for the cellular signalling — when a hormone or a neurotransmitter binds to its receptor on the cell surface (a G-protein-coupled receptor that activates the PLC enzyme), the PLC cleaves the PI(4,5)P2 to produce the IP3 and the DAG. The IP3 diffuses through the cytoplasm to the endoplasmic reticulum (ER), where it binds to the IP3 receptor and releases the calcium from the ER stores into the cytoplasm — producing the calcium signal that activates the calcium-dependent enzymes (including the protein kinase C, the calmodulin-dependent kinases, and the calcineurin) and that triggers the cellular responses (including the muscle contraction, the secretion, the gene transcription, and the cell proliferation). The DAG remains in the membrane and activates the protein kinase C (PKC) — the serine/threonine kinase that phosphorylates a wide range of substrate proteins and that mediates the long-term cellular responses (including the cell growth, the differentiation, and the apoptosis).
The clinical importance of the inositol and the phosphoinositide signalling for the cellular function is underscored by the observation that the inositol supplementation (particularly as the myo-inositol form) has been shown to improve the insulin sensitivity, to reduce the symptoms of the depression, and to restore the normal ovarian function in women with the polycystic ovary syndrome (PCOS). The mechanism of these effects involves the restoration of the normal phosphoinositide signalling in the insulin-sensitive tissues (muscle, fat, liver), in the brain (where the phosphoinositide signalling is involved in the regulation of the monoamine neurotransmission), and in the ovaries (where the phosphoinositide signalling is involved in the regulation of the follicle-stimulating hormone (FSH) and the luteinising hormone (LH) signalling).
Inositol and the PCOS
The polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, and it is characterised by the hyperandrogenism (the excess production of the male hormones, which produces the hirsutism, the acne, and the alopecia), the ovulatory dysfunction (which produces the irregular periods and the infertility), and the metabolic dysfunction (which includes the insulin resistance, the hyperinsulinaemia, and the increased risk of the type 2 diabetes and of the cardiovascular disease). The inositol (particularly the myo-inositol and the D-chiro-inositol) has been shown in multiple clinical trials to improve the ovarian function, to reduce the hyperandrogenism, and to improve the insulin sensitivity in women with the PCOS — and it is now considered one of the first-line nutritional interventions for this condition, alongside the lifestyle modification (weight loss, exercise) and the pharmacological interventions (clomiphene, metformin).
Practical Application
For general inositol supplementation, the evidence-based approach is to supplement with 2-4g of myo-inositol daily (as the powder form, which is well absorbed and well tolerated), divided into two doses. The myo-inositol is the most abundant and the most studied form of inositol, and it is the form that is used in the clinical trials for the PCOS, for the depression, and for the insulin resistance. The D-chiro-inositol is an alternative form that is also effective for the PCOS and for the insulin sensitivity, but it is less well studied than the myo-inositol. For comprehensive cellular signalling support, inositol pairs well with the choline (which is the precursor of the phosphatidylcholine, the most abundant phospholipid in the cell membrane), with the omega-3 fatty acids (which provide the EPA and the DHA that are incorporated into the phospholipids of the cell membrane and that affect the membrane fluidity and the signalling), and with the magnesium (which is a cofactor for many of the enzymes that are involved in the phosphoinositide signalling pathway).
Leave a Reply