Inositols for prevention of gestational diabetes

VIDEO 12

A strong body of evidence suggests that, if used early in pregnancy in women at high risk for gestational diabetes, inositols are able to significantly reduce the incidence of glucose metabolism alterations during pregnancy. Inositol acts as a mediator of the action of insulin, and it is necessary to activate key enzymes in the metabolism of glucose. Inositol‐ and antioxidant‐based supplements could then represent a valid therapeutic approach in pregnancy complicated by diabetes and by insulin resistance in order to improve glucose metabolism and delay or avoid insulin therapy when needed.

BACKGROUND

Inositol represents a family of naturally occurring cyclic polyol. Scherer, during the mid-19^th century isolated the compound from muscle tissue and named the substance “myo-inosite” which, in chemical language, indicated a polyalcohol carbohydrate detectable in muscular fiber¹. Now we know that inositols, belonging to the group of sugar alcohols, are white odorless crystals with a slightly sweet taste, soluble in water and insoluble in absolute alcohol and ether. Of note, they are stable to heat, strong acid and alkali.

Inositols (formerly incorrectly called vitamin B₇) are involved in numerous biological processes including those of cellular signaling and acts a structural element (in the form conjugated with lipids). They can occur in the form of different stereoisomers and present a high degree of phosphorylation. When we talk about inositol, we commonly refer to myo-inositol (MI), which is the most important and widespread form, structurally very similar to glucose, and detectable ubiquitously in almost all biological systems.

Overall, there are seven inositol stereoisomers that are naturally formed by means of different isomerases. Almost all inositols display insulin-mimetic activity and have an insulin-sensitizing effect, although to different degrees. They perform a large number of other important physiological roles, such as promoting ovulation and fertility. Several inositols cross the cell membrane by two cation-coupled co-transporters (sodium or proton coupled) and become components of cellular metabolism. It is important to keep in mind that inositol can also act through a receptor pathway. This occurs only when these molecules are joined to one or more phosphoric groups, forming inositol phosphates, which have specific intracellular receptors to transmit the signal.

In addition to dietary intake, inositols are regularly synthesized in the liver and kidney from glucose 6-phosphate (the first product of glycolysis). In excess, they are catabolized and eliminated in urine. Once absorbed or synthesized, MI is introduced into the bloodstream, from which, without the need for any transporter, it reaches peripheral tissues and cells. Here it is largely transformed into phosphatidylinositol, a substance endowed with numerous biological functions, some of which have yet to be clarified. We know that it is an active component of plasma membranes; as a precursor to second messengers, it participates in signal transmission systems that control cellular activity. It also stimulates the endogenous production of lecithin (phosphatidylcholine)².

One of the most significant activities performed by MI and D-chiro-inositol (DCI) involves glycemic regulation. Both stereoisomers display insulin-mimetic activity and are also effective against insulin resistance. MI significantly inhibits duodenal glucose absorption and reduces glucose rise in blood. Moreover, it improves insulin sensitivity in adipocytes by increasing lipid storage capacity and glucose uptake, and by preventing lipolysis. It also downregulates the inflammatory response, mainly in macrophages, likely through the inhibition of proinflammatory transcription factors (for example, STAT, NF-κB, and AP-1). In addition, MI induces translocation to the plasma membrane of GLUT4-transporters, which are expressed in intracellular vesicles, leading to increase in glucose uptake and decrease in plasma glucose level, under glucose-loaded hyperglycemic conditions. This effect mimics the insulin action, since insulin induces GLUT4 translocation from the endoplasmic reticulum to the plasma membrane to stimulate glucose uptake in skeletal muscle cells³.

Since the discovery of their involvement in endocrine signal transduction, MI and DCI supplementation has contributed to the clinical management of many gynecological and endocrine disorders. These compounds are useful in preventing and treating polycystic ovary syndrome (PCOS). In their meta-analysis, Zhao et al. report that, for women with PCOS, MI with DCI and metformin combined with thiazolidinediones appear superior to metformin alone in improving insulin resistance and decreasing total testosterone. MI combined with DCI is particularly efficacious in regularizing menstrual cyclicity. Inositol showed non-inferiority in most outcomes compared to the gold standard treatment (metformin), decreasing the severity of hyperandrogenism, regulating menstrual function and improving metabolic parameters such as decrease of insulin and homeostasis model assessment (HOMA) index. Both MI and DCI are well-tolerated, effective alternative candidates to the classical insulin sensitizers and can be administered for prolonged periods⁴.

Prevention in patients at risk of gestational diabetes mellitus (GDM)

Pregnancy is characterized by a physiologic increase in insulin resistance allowing alterations of glucose metabolism. If not optimally controlled, insulin resistance has a negative impact on maternal and fetal outcomes. In view of the pathophysiological mechanism of GDM, it is reasonable to hypothesize that inositol dietary supplementation may have an effect on the development of GDM and its complications.

Different interventions have been explored to prevent women from developing GDM, as summarized in the most recent overview of Cochrane systematic reviews⁵. While 11 different interventions demonstrated no clear benefit or harm, MI was identified as having the best possible benefit in reducing the incidence of GDM⁵.

Regarding maternal outcomes, the meta-analysis showed that MI supplementation may have a positive effect on reducing the incidence of two maternal conditions: GDM and hypertensive disorders of pregnancy. However, the certainty of the evidence for these outcomes was rated as low to very low, meaning that, while there is some indication of a potential benefit, more research is needed to establish a definitive association.

Regarding neonatal outcomes, one study measured the risk of having a large-for-gestational-age (LGA) infant. In this study, MI supplementation was associated with both appreciable benefit and harm, but the certainty of the evidence was rated as low. It is important to note that no studies reported on other primary neonatal outcomes, such as perinatal mortality or a composite of mortality and morbidity. Therefore, the effects of MI supplementation on such outcomes remain unknown based on the current evidence.

To summarize, MI supplementation during pregnancy may offer potential benefit in reducing the incidence of GDM and hypertensive disorders of pregnancy. However, the evidence is not yet strong enough to draw definitive conclusions and change clinical practice⁵. Additionally, the impact of MI supplementation on neonatal outcomes, particularly regarding LGA infants, requires further research⁶.

Gestational diabetes mellitus treatment

In the context of GDM, no randomized controlled trial or prospective or retrospective study has evaluated the optimal glycemic threshold for initiation of pharmacotherapy, in addition to diet and exercise. As such, those caring for women with GDM should decide individually what proportion of elevated capillary blood glucose (CBG) values merits initiation of pharmacotherapy and how rigorously these CBG values should be controlled. Harrison et al. conducted research in this area and found that initiating pharmacotherapy at a lower threshold of abnormal CBG values, ranging from 20% to 39%, was associated with improved neonatal outcomes. This suggests that earlier intervention with medication might have benefits for neonatal health. However, it is worth noting that there was an exception in their findings, which was a higher risk of small-for-gestational-age (SGA) babies⁷.

In a Cochrane review published in 2018, Martis et al. (8) tried to provide a comprehensive synthesis of evidence on the benefits and harms associated with interventions for treating GDM. This overview included 14 Cochrane reviews, 10 of which reported relevant data on 27 comparative treatments for women with GDM and borderline GDM. These 10 Cochrane systematic reviews included 128 RCTs involving 17 984 women, 16 305 babies and 1441 children. The overall evidence of various interventions for the treatment of women with GDM and their effects on the health of women and neonates are limited by quantity and quality. Lifestyle interventions in comparison to usual care were found to be ‘probably effective’ at reducing the incidence of LGA babies. Otherwise, no intervention could be classified as ‘promising’.

Some interventions are multi-component and, in Martis et al.’s review, it was not possible to determine which specific components were most promising. Long-term health outcomes for women and infants and costs are not well reported. Most of the dietary treatments assessed were from interventions reported as single studies that had relatively small numbers of participants, and only a few trials compared the same or similar dietary intervention. In this review⁸, it was reiterated that nutraceuticals should not be confused with dietary supplements, which are products intended to supplement the diet that contain one or more ingredients such as vitamins, minerals, a herb, an amino acid or a concentrate, metabolite, constituent, extract or combinations of these.

As far as inositols are concerned, there are few studies addressing the effects of supplementation on different outcomes, in women already diagnosed with GDM. Most studies used MI, even at different doses and for different time periods. A comparison group received either standard care with or without folic acid. One study evaluated the association of MI plus α-lactalbumin.

No consistent effects were found on perinatal outcomes. Treatments sometimes reduced glucose levels. Therefore, it could be concluded that, at present, inositol does not represent a treatment option for women who have developed GDM.

CONCLUSION

In conclusion, inositol, particularly MI, is involved in many biological processes related to glucose utilization in different body compartments. Inositol supplementation in pregnant and non-pregnant (PCOS) women has not been shown to lead to any significant side effect, implying tolerability and safety of these molecules.

MI supplementation in pregnant women at risk has been consistently associated with a reduction, by almost two-thirds, in GDM development. This finding implies potential clinical benefit, although it should be confirmed in non-Caucasian populations. Establishing benefits on other perinatal outcomes requires further research.

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