Combined Therapy of Myo-Inositol and DCI in a 40:1 Ratio

Introduction

This article follows up on another piece I wrote concerning myo-inositol and D-chiro-inositol therapies for PCOS. That piece does a good job of comparing those two forms of inositol. PCOS women looking for answers about which form of inositol is right for them have recently discovered a new wrinkle products that offer myo-inositol and D-chiro-inositol combined in a 40:1 ratio. I have had a number of questions from PCOS women wondering what these new products are all about.


The reasoning behind 40:1

The biggest question is: why 40:1? That is a precise ratio, so we would naturally expect some precise reasoning behind it. I was able to find a recent publication that pertained to this question, a fairly good review of the clinical research regarding inositols and PCOS.1 But, the reasoning amounts to this: the ratio of myo-inositol to D-chiro-inositol in the plasma (the liquid part of blood) is 40:1. That's it. As a biochemist, I don't find this line of reasoning very compelling. The authors themselves openly acknowledge that each tissue (blood, muscle, ovary, etc.) has a different ratio and that the ratios are altered by insulin. Why we would put the plasma ratio (in women without PCOS) on a pedestal is unclear.


Why combine D-chiro-inositol and myo-inositol at all?

Even if we grant that 40:1 is a magic ratio, why are we trying to combine myo-inositol and DCI in the first place? The main argument is that the body needs both. I can't disagree with that on face. However—and this is a pitfall these authors1 have consistently failed to avoid; not just in this paper, but in several others—this reasoning ignores one important fact: that women with PCOS have been consistently shown to have altered (abnormal, but I hate that word) inositol metabolism. To understand why this is so important, we need to understand normal inositol metabolism.


Normal inositol metabolism

Myo-inositol is abundant in many of the foods we eat. DCI is in only a few, and in relatively small amounts. But, in most people, all of the enzymatic machinery is available to make myo-inositol from sugar (if you're detecting some biochemical irony right now, you're not alone) and to make D-chiro-inositol from myo-inositol. If all of this is working well, you would have no need to take a supplement of either. The transformations look something like this:

glucose -> a few distinct pathways with a few steps each -> myo-inositol -> one pathway with a few steps -> D-chiro-inositol

To be clear, your body does not convert all of the myo to DCI (nor does it convert all the glucose to myo).


D-chiro-inositol insufficiency in PCOS


A number of studies have shown in various ways that women with PCOS have a functional deficit of DCI that correlates strongly with insulin resistance.2,3,4 And animal models have shown that an inability to convert myo-inositol to D-chiro-inositol produces diabetes.5,6 At this point, the question naturally arises: if DCI is insufficient in women with PCOS, why try myo-inositol at all?


Why try myo-inositol at all?

The simple answer is that PCOS is not one homogeneous thing. Each instance of PCOS is different. One woman might be almost completely unable to make DCI, in which case DCI is the only solution. Another woman might be able to make DCI to a limited extent; in this case, flooding the body with myo-inositol (e.g. 4 grams or more daily) might help her make enough DCI. And, without a doubt, numerous other factors contribute to the substantial variation in PCOS.


Which again begs the question, why combine?

I'd like to quote part of an email I received recently from a customer who has tried myo-inositol, D-chiro-inositol, and one of the commonly available combination products:

After seeing how my body responds to myo inositol, DCI, and then the [40:1] combination of the two, I have noticed that my symptoms are resolved with all 3 supplements. BUT I feel like when I was taking Chiral Balance I had more overall energy and a kind of zest for life, lightness, and happiness about me that seems to go away when I take myo inositol either alone or [a 40:1 combo product].

I think that her experience sums up what most women could expect from trying one of the 40:1 combination products. They simply have too little DCI to work as well as a standard dose of DCI. But, they have enough myo-inositol to work about as well as myo-inositol alone.


The evidence

Neither of the products currently available in the US have been tested in clinical trials. Examination of the products literature reveals two papers concerned with PCOS: one uncontrolled observational study7 (meaning that the effects of the combination therapy were not compared to placebo or another treatment) and one controlled trial.8 Both of these studies were conducted with a product that is not available in the US. The product is similar in that it combines myo and DCI in the 40:1 ratio, but the dosages and delivery mechanism are vastly different.

The controlled trial is odd. The authors compared the combination therapy to a 2000 mg dose of myo inositol, which is half the normal dose. At the end of the trial, there was no statistical difference in the two treatment groups. That is to say, the combination treatment worked as well as half the normal dose of myo-inositol. And yet, they titled the paper: "The combined therapy with myo-inositol and D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone".

I rarely editorialize, but...

On that note, I'm not a fan of the 40:1 products. They offer no significant benefits over myo-inositol alone,8 and because the amount of DCI is so low, they aren't meaningfully different than myo-inositol alone. They succeed in confusing an already confusing topic and in providing the illusion of a 3rd alternative. They also greatly increase the likelihood that a woman will decide that neither form of inositol works for her, when in fact, there isn't enough DCI in the product to make that determination (the two major combination products in the US market provide 100-200 mg of DCI daily; the standard dose is 1200 mg). I'm optimistic that the extremely sharp PCOS community at large will recognize that these combination products are more an attempt to cash in on the promise of DCI therapy than meaningful additions to the PCOS arsenal.



Citations

1. Dinicola S, Chiu TT, Unfer V, Carlomagno G, Bizzarri M. The rationale of the myo-inositol and D-chiro-inositol combined treatment for polycystic ovary syndrome. J Clin Pharmacol. 2014;54(10):1079-92.
PubMed abstract: http://www.ncbi.nlm.nih.gov/pubmed/25042908

2. Baillargeon JP, Iuorno MJ, Apridonidze T, Nestler JE. Uncoupling between insulin and release of a D-chiro-inositol-containing inositolphosphoglycan mediator of insulin action in obese women With polycystic ovary syndrome. Metab Syndr Relat Disord. 2010;8(2):127-36.
PubMed abstract: http://www.ncbi.nlm.nih.gov/pubmed/20156067
Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC31401...

3. Baillargeon JP, Diamanti-kandarakis E, Ostlund RE, Apridonidze T, Iuorno MJ, Nestler JE. Altered D-chiro-inositol urinary clearance in women with polycystic ovary syndrome. Diabetes Care. 2006;29(2):300-5.
PubMed abstract: http://www.ncbi.nlm.nih.gov/pubmed/16443877
Free full text: http://care.diabetesjournals.org/content/29/2/300...

4. Cheang KI, Baillargeon JP, Essah PA, et al. Insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome. Metab Clin Exp. 2008;57(10):1390-7.
PubMed abstract: http://www.ncbi.nlm.nih.gov/pubmed/18803944
Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC25744...

5. Pak Y, Hong Y, Kim S, Piccariello T, Farese R V, Larner J. In vivo chiro-inositol metabolism in the rat: a defect in chiro-inositol synthesis from myo-inositol and an increased incorporation of chiro-[3H]inositol into phospholipid in the Goto-Kakizaki (G.K) rat. Mol Cells. 1998;8(3):301-309.
PubMed abstract: http://www.ncbi.nlm.nih.gov/pubmed/9666467

6. Xia T, Wang Q. D-chiro-inositol found in Cucurbita ficifolia (Cucurbitaceae) fruit extracts plays the hypoglycaemic role in streptozocin-diabetic rats. J Pharm Pharmacol. 2006;58(11):1527-32.
PubMed abstract: http://www.ncbi.nlm.nih.gov/pubmed/17132216

7.Minozzi M, Nordio M, Pajalich R. The Combined therapy myo-inositol plus D-Chiro-inositol, in a physiological ratio, reduces the cardiovascular risk by improving the lipid profile in PCOS patients. Eur Rev Med Pharmacol Sci. 2013;17(4):537-40.
PubMed Abstract: http://www.ncbi.nlm.nih.gov/pubmed/23467955
Free fulle text: http://www.europeanreview.org/article/3314

8. Nordio M, Proietti E. The combined therapy with myo-inositol and D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone. Eur Rev Med Pharmacol Sci. 2012;16(5):575-81.
PubMed abstract: http://www.ncbi.nlm.nih.gov/pubmed/22774396