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From the Townsend Letter
August/September 2015

Inositol Modulation of Essential Metabolic Pathways of Insulin Resistance in Metabolic Syndrome, Polycystic Ovarian Syndrome, and Type 2 Diabetes
by Cristiana Paul, MS, and David M. Brady, ND, DC, CCN, DACBN
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This article will review the evidence for the abilities of myo-inositol (MI) and D-chiro-inositol (DCI) to improve dysglycemia and related characteristics of metabolic syndrome (MetS), type 2 diabetes (T2D), gestational diabetes, and polycystic ovarian syndrome (PCOS) by acting in critical metabolic pathways of insulin resistance (InsR).

1. Basic Facts About Inositols
Inositol occurs naturally as nine isomers in a variety of vegetarian and animal foods as well as in the human body. The two isomers MI and DCI have been recognized to be the most predominant and with important functions in human physiology. D-pinitol (a methylated form of DCI) also occurs in human tissues and in certain foods. See Figure 1 for details.
MI and DCI are components of intracellular signaling mediators of insulin action1,2 (see details in Figure 2). Most compelling research to date has been performed with the MI and DCI forms of inositol.
Only a few human studies have used the D-pinitol form and had mixed results. Orally administered D-pinitol was shown to be partially (approximately 33%) converted to DCI in the human body, but no clinical studies are available to date to show how its effects compare with those of MI and/or DCI supplementation.2-5
Inositol is not considered an essential nutrient in human nutrition, since MI and DCI can be synthesized in the human physiology from glucose. MI converts into DCI at rates that are specific for various types of tissues.6 However, MI to DCI conversion has been found to be much lower than normal in patients with T2D or PCOS, as evidenced by their measurement in blood, tissues and urine. For example, one study assessed the urinary ratio of MI/DCI in various populations and the results were as follows6:

  • 2.5 for control subjects;
  • 20.4 for type 2 diabetic patients which may include PCOS patients;
  • 13.2 for nondiabetic relatives of type 2 diabetes patients;
  • 13.6 for type 2 diabetic patients.

The conversion of MI to DCI is achieved by an epimerase enzyme and its activity was observed to correlate inversely with the degree of insulin resistance.6,7 Some researchers have categorized this epimerase downregulation as an "enzyme defect" associated with syndromes that display InsR. However, there are reasons to believe that this so-called defect may not simply represent a random genetic mutation but may be the result of evolutionary pressures for adaptation to variable food intake and survival, which selected genetic types more susceptible to developing InsR.8-14 Thus, the downregulation of epimerase may be viewed instead as a genetically programmed metabolic switch meant to downregulate glucose utilization, thus favoring metabolism of fat for fuel. Specifically, epimerase inhibition results in the reduction of DCI produced from MI in various tissues, while intracellular glucose disposal is influenced by DCI derived cellular mediator DCI-IPG. Figure 2 depicts the intracellular roles of DCI-IPG. Thus, when DCI levels are lowered, glucose metabolism is impaired and this explains in part the state of InsR.6
Some researchers hypothesize that this adaptation may have occurred during an "evolutionary type of InsR" triggered by famine, in which case body fat stores release more free fatty acids (FFA). In contrast, the "modern type of InsR" often occurs in the setting of excess caloric intake, especially from fat and high body fat. However, these two distinct metabolic states are similar in the sense that they both display elevated plasma free fatty acids. Excess fatty acids have been shown to impair glucose disposal through well known metabolic switches, which can cause or aggravate InsR.13,14

2. MI and DCI Derivatives Alleviate Insulin Resistance
MI and DCI were revealed to be components of a large family of intracellular insulin-signaling mediators. These include phosphoinositol phosphates (PIPs) and inositol phosphoglycans (IPGs; MI-IPG and DCI-IPG). The structure of DCI-IPG contains a methylated form of DCI and galactosamine, while that of MI-IPG contains MI and glucosamine and both types of IPGs contain Zn and Mn.6,15
Figure 2 illustrates the intracellular roles of MI and DCI derived mediators of insulin signaling for glucose disposal.6,15-18
Inositols and their derivatives support an improvement of glucose metabolism, as follows:
1.  MI derived phosphoinositol-3-phosphate (PIP3) upregulates glucose transport inside the cells by stimulating GLUT4 translocation to the cell membrane.15
2.  DCI derived DCI-IPG supports enhancement of glucose conversion to ATP by increasing its transport in the Krebs cycle. This is achieved by the stimulation of the pyruvate dehydrogenase (PDH) enzyme.15,16
3.  MI and DCI derivatives PIP3 and DCI-IPG, respectively, increase glucose storage as glycogen inside cells. This is achieved by the stimulation of the glycogen synthase enzyme (GS).7,15,16
4.  MI derivative MI-IPG supports downregulation of free fatty acids (FFA) release from adipose tissues by inhibiting the enzyme adenylate cyclase.16 This effect is beneficial because FFA have been shown to impair glucose disposal, thus causing InsR and increased triglycerides synthesis.19
The four inositol mechanisms of action listed above tend to counteract some of the important metabolic deregulations occurring in InsR syndromes such as impaired glucose transport and insufficient cellular disposal along with elevated plasma fatty acids.19,20
In conclusion, researchers hypothesize that supplementation with MI and/or DCI is likely upregulating the production of MI-IPG, DCI-IPG, and PIPs in the body, and by doing so it is at least partially counteracting some of the metabolic deregulation specific to the state of InsR.6,18
Also, since MI to DCI conversion is impaired in indivi­duals with InsR, it is important to always include DCI along with supplemental MI. Conversely, supplementing with DCI (or D-pinitol) alone cannot not fulfill the MI roles that are distinct from DCI, since DCI does not convert to MI.
Metformin is an insulin-sensitizing pharmaceutical drug and it is important to remark here that one of its mechanisms of actions involves the release of DCI-IPGs from cell membranes, making them available to participate as secondary messengers in insulin signaling. However, the efficiency of metformin's action may be dependent on having adequate DCI-IPG stores in the body, which were shown to be inadequate when InsR was present.21-23 Thus, we hypothesize that supplementation with MI and DCI may be warranted in most patients that are prescribed metformin for glucose control.

3. Supplementation with Inositols Forms MI and/or DCI Alleviates InsR and Related Abnormalities of PCOS
Polycystic ovary syndrome and its characteristic physiological imbalances. PCOS is characterized by hyperandrogenism, oligoanovulation, and oligomenorrhea and has been reviewed extensively by P. W. Smith in the May 2014 issue of the Townsend Letter and by Saha, Marshall, and Murray.24-26 Many researchers consider PCOS a subset of MetS with exaggerated InsR and additional dysregulation of sex hormones affecting 5% to 10% of women.8-11 PCOS was also referred to as "Syndrome XX," since it is a more severe form of Syndrome X or a phenotypical subset of T2D.1,24,25,27,28
Women with PCOS are more susceptible to display elevated insulin levels and to develop MetS with its associated comorbidities.27,28 Hyperinsulinemia occurs in approximately 80% of obese PCOS women, as well as in 30% to 40% of lean PCOS women.1,29 PCOS women tend to have 30% to 40% lower glucose disposal than weight-matched normal controls.28 One cause of the exacerbated InsR in PCOS is believed to be due, at least in part, to a number of postinsulin receptor signaling alterations which affect glucose transport and its cellular metabolism.30-32
Since PCOS often involves genetic polymorphisms on insulin signaling pathways, it will likely manifest with InsR in all phases of a woman's life. For example, for PCOS women in menopause the syndrome manifests as an exacerbated state of InsR and displays an above average risk of obesity, metabolic syndrome, diabetes, and cardiovascular disease.33
A syndrome similar to PCOS is believed to affect men who are relatives of women with PCOS with the same 5% to 10% incidence as in women. PCOS-specific genes are inherited as an autosomal inherited trait (not related to the sex chromosomes). Men with PCOS genetics have similar hormonal patterns as PCOS women (elevated androgens and low SHBG) and – more importantly – a similar exaggerated state of insulin resistance and risk of cardiovascular diseases. This type of male syndrome is often associated with early onset baldness in the 20s.34,35

Summary of Studies that Used MI and/or DCI for PCOS.
Since 1998 numerous studies have been published which investigated the potential for MI and DCI to alleviate the main physiological imbalances of PCOS: infrequent ovulation, oligomenorrhea, elevated androgens, and hyperinsulinemia, a manifestation of InsR.
Table 1 includes a listing of the results from the most relevant studies that used either MI or DCI alone, or a combination of both for alleviating PCOS. All MI and/or DCI interventions achieved significant improvements in the PCOS characteristic deregulations. Ovulation and menstrual regularity were restored in a significantly higher percentage of women in the treatment groups. Total and free testosterone levels were significantly lowered in all studies that measured it (see Table 1). One study also showed improvement in LH and LH/FSH ratio.36
All 10 inositol interventions summarized in Table 1 achieved dramatic reductions in homeostatic model assessment of insulin resistance (HOMA-IR), while 5 studies reported impressive lowering of insulin (area under the curve [AUC] post glucose load) and glucose (fasting and/or AUC post a glucose tolerance test).
The dyslipidemia markers (triglycerides, HDL, total cholesterol) were reported in 6 of the studies listed in Table 1 and all show statistically significant improvements. Most dramatic changes were observed in triglyceride lowering, while notable improvements were also seen for HDL, total cholesterol and blood pressure.
Most studies have investigated either DCI or MI for PCOS interventions, but it is not clear why researchers chose one form over the other in any particular study. Two studies tested a combination of MI + DCI (the equivalent of 3300 mg MI + 84 mg DCI in powder form), while 1 of them compared the effects of this combination with that of 4g MI alone (see results in Table 1).27,37 After 6 months of treatment, both MI and MI+DCI groups showed improvement in all the measured metabolic parameters. However, the MI + DCI combination reduced HOMA-IR twice as much with the rest of the results also superior to those obtained in the MI alone group. It is interesting to note that the results obtained at the end of the study (after 6 months) were significantly better than at midpoint (after 3 months), which implies that MI and/or DCI interventions needed some time to realize their full potential.
The rationale for using the MI + DCI combination was stated by the study authors as follows: "Both myo-inositol (MI) and D-chiro inositol (DCI) glycans administration has been reported to exert beneficial effects at metabolic, hormonal and ovarian level. Beside these common features, MI and DCI are indeed different molecules: they belong to two different signal cascades and regulate different biological processes."37 This concept is also substantiated by the distinct metabolic roles of MI versus those of DCI and their respective derivatives as outlined in Section 2 and Figure 2.
One recent study showed that interventions with 4 g/d MI or 1 g/d DCI yielded very similar results in parameters measured such as improved ovulation, HOMA-IR, androgen levels, and blood pressure (see Table 1).38 This may be explained by the fact that the 4 g/d doses of MI could possibly push the conversion of MI to DCI to an extent that may correct the DCI deficiency, at least in part. So, from this study alone one could conclude that DCI is 4 times more potent than MI in alleviating certain PCOS symptoms.
Larner authored many studies investigating and reviewing DCI, and he proposes that this is the more potent form of inositol for alleviating InsR.6,16,18 On the other hand, MI is needed for oocyte quality and maturation. Concerns have been expressed by some researchers regarding supplementation with DCI without MI, since it may cause an MI deficit in the ovary.7
Overall, the MI doses used in studies ranged from 2 to 4 g/day, while a meta-analysis study of MI for PCOS concluded that the higher dose of 4 g/d seems to achieve much better results than lower doses in a higher percentage of subjects. Also, the benefits of inositol supplementation seem to correlate inversely with body fat, prompting researchers to speculate that obese patients may need and benefit from higher doses than 4 g/d.29 Inositols compete with glucose for entry in the cells, so high blood glucose levels may require increased amounts of inositol.
Many of the MI, DCI, and MI + DCI interventions presented in Table 1 showed a trend for enhancing weight loss as evidenced by small but statistically significant reductions in BMI, while some also showed a reduced waist/hip ratio, an indication of reducing abdominal fat. Intra-abdominal fat generates inflammatory cytokines and contributes more to plasma free fatty acids than subcutaneous fat stored in the rest of the body. Plasma free fatty acids and inflammation are contributing factors to insulin resistance.

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