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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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4. Supplementation with Inositols Alleviates Characteristic Abnormalities of MetS
The metabolic syndrome has been defined by "resistance to insulin-stimulated glucose uptake occurring in approximately 25% of the population at large"and association with a number of conditions known to be risk factors for coronary heart disease and diabetes.39-41
Supplementation with MI, or a combination of MI + DCI, has been proved to alleviate many aspects of MetS in postmenopausal and pregnant women. See Table 2 with results from four studies that have tested the effects of MI or MI + DCI supplementation on improving various metabolic markers of MetS.42-45 Three of the studies described in Table 2 have reported dramatic drops in HOMA-IR, fasting insulin, and fasting glucose, which were more pronounced than in the "placebo + diet" group.42-44 The fourth study reported only improvement in fasting glucose.45 Cardiovascular risk markers improved dramatically as well in all four studies. Also to be noted in the MI intervention groups is the enhanced weight loss versus the diet-only groups.42-44
The addition of lipoic acid in the study by Capasso may be justified by the following facts44:

  • Lipoic acid supplementation has been found to increase the insulin sensitivity by about 20% to 30%.46,47
  • Lipoic acid is a cofactor for the PDH enzyme.46 Since DCI-IPG is also a cofactor of the PDH enzyme, this further supports the possibility that these two endogenous metabolites may act in synergy and in a complementary way to boost the activity of PDH, which in turn supports the conversion of glucose to energy.

Supplementation with 4 g MI was also shown to reduce the risk of developing gestational diabetes in PCOS women in three studies.48-50 For example, D'Anna et al. supplemented pregnant PCOS women with 4 g MI and found that the incidence of gestational diabetes in the MI group was 17.4% versus 54% in the control group.18 In another study, where MI + diet was used to treat gestational diabetes, there was a significant improvement in HOMA-IR of −50% versus −29% achieved in the placebo + diet group.50
D-chiro-inositol was administered to STZ diabetic rats and rhesus monkeys and shown to decrease hyperglycemia and enhance glucose disposal regardless of sex.18 No human studies have been published so far to investigate MI or DCI for benefiting T2D, but all the evidence presented in this review supports the idea that MI and DCI supplementation may be beneficial for these patients by improving insulin sensitivity.
Pinitol, the methylated form of DCI, was tested in a few human studies using participants with T2D. The results are inconsistent and especially disappointing for obese diabetic participants.2-5 It seems that approximately 33% of pinitol is converted to DCI in the human body, and it is not clear whether it needs to be in order to be beneficial or utilized in human metabolism. It is difficult to compare the effectiveness of pinitol with MI and/or DCI because these have been tested in different types of populations and not side by side in comparative studies.

5. Considerations for Optimal Dosing of MI and or DCI for Alleviating InsR in PCOS and MetS
Based on the studies reviewed above the 4 g MI dose, and doses ranging from 500 mg to 1200 mg of DCI, seem to be effective in alleviating InsR and the related metabolic derangements in PCOS, MetS, and gestational diabetes.
Individuals with PCOS or diabetes have a significant DCI deficiency in various tissues (liver, muscle, kidney, blood) compared with normal individuals, so it makes sense to supplement them with a dose of DCI comparable to the ones used in studies so far. However, one study showed that a safety threshold for DCI supplementation in PCOS patients may be set at 300 mg DCI/day, the highest dose that will not reduce oocyte maturation.64
Based on the pharmacokinetics of supplemental inositol, it makes sense to split the daily dose and provide half of it, every 12 hours, in order to maintain continuous therapeutic levels of inositols. It is best to take inositols on an empty stomach, especially away from meals high in carbohydrates, since inositol competes with glucose for absorption in the gut and uptake from the bloodstream into cells.21,22
Patients should make sure that they have adequate intake of zinc, manganese, and magnesium, as these minerals have an important role in inositol transport and metabolism. Other supplements, such as lipoic acid and NAC, may have additive synergistic effects in improving glucose metabolism.44,46,47,51,52
In conclusion, MI and DCI may be deemed conditionally essential nutrients for conditions such as MetS, T2D, and PCOS wherein dysglycemia and InsR play critical roles. The results of the clinical studies discussed in this review show that average dietary inositol intake and endogenous inositol production need to be supplemented with additional MI and DCI in order to bring their glucose metabolism closer to homeostasis.27,36-38,53-58 This concept is also supported by the excess urinary loss of MI observed in these conditions. Thus, MI and DCI qualify as ingredients for medical foods in support of PCOS, MetS, gestational diabetes, and possibly also T2D.
For example, a dietary supplement is offered commercially by Designs for Health Inc., under the name Sensitol, which provides an inositol supplement composed of MI, DCI, and lipoic acid.
In conclusion, human clinical trials using MI and/or DCI supplementation have only employed menopausal women with InsR, women of reproductive age with PCOS, and pregnant women at risk of gestational diabetes or those who have already developed it.
However, based on all the evidence available and mechanisms of action, it is reasonable to believe that MI and DCI may also improve glucose metabolism in most women with InsR or T2D of reproductive age regardless of PCOS status. The same rationale leads us to believe that most men with InsR as part of MetS or T2D may similarly benefit from MI and/or DCI supplementation. Men related to women with PCOS, who are likely to have PCOS type genetics, may benefit from these interventions even more so.
Individuals with dysglycemia, InsR, and diabetes tend to have elevated urinary excretion of MI, while that of DCI is typically reduced.6,21,22 Excessive urinary loss of inositols may be due to elevated blood glucose which competes with inositols for reabsorption in the kidneys.22 All studies report consistently that these individuals have an elevated urinary MI/DCI ratio, which may be due in part to a poor MI to DCI conversion. Each patient may have a different genetic and metabolic situation, while their diet and degree of obesity also influence their degree of InsR and thus MI/DCI ratios in various tissues. If the measurement of plasma and urinary MI and DCI become commercially available, it may be then feasible to optimize MI + DCI supplementation based on the ongoing needs of individual patients and on objective testing in the clinical setting. In fact, the urinary MI/DCI ratio has been proposed as an index of InsR by many research groups.59-63

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