Inositol And Insulin Resistance

(This is a sample entry from the SAFM Q&A Treasure Chest, a tool with hundreds of entries to support students with their client needs. Students get unlimited access as part of SAFM’s functional medicine training program.)

Student Question:

Hi – I understand that inositol is another supplement that might be helpful for countering insulin resistance. And maybe also PCOS? I would really appreciate your insight and review of whether there is research validating either of these common patient issues. Thanks!

SAFM’s Answer:
Indeed, good research demonstrates Inositol’s effectiveness in alleviating PCOS (polycystic ovarian syndrome) in women, specifically via improving insulin resistance. This is a rich overview article of inositol and its various forms, roles, mechanisms, and considerations in supporting menstrual and reproductive function.

First of all, some basics. Inositol is often referred to as “one of the B vitamins,” though it is not consistently regarded as essential in this way. Inositol is actually a sugar alcohol and can be made in the body from glucose. We also can absorb it from our diet in a few forms, including citrus fruits and lecithin (which is a combination of inositol and choline). It is the synergistic teamwork of both inositol and choline that gives lecithin its fat-emulsifying capability, e.g., in preventing or alleviating fatty liver and reducing triglycerides. Inositol supplementation has been shown to reduce small, dense LDL levels in those with metabolic syndrome.

As with many nutrients, inositol has many different isomers, including myo-, d-chiro, and l-chiro forms. Inositol has many identified key functions in the human body, including insulin cell signaling, subcellular membranes, and intracellular calcium management. It is a component of some phospholipids found in membranes and lipoproteins. It also affects receptor sensitivity for some neurotransmitters, such as serotonin and acetylcholine. Hence, inositol is often used to counter anxiety or panic attacks, sometimes combined with other calming agents (e.g., magnesium, l-theanine, GABA, passionflower, taurine) that influence GABA-Glutamate balance (e.g., Xymogen’s RelaxMax). For example, this supplement might be helpful for patients trying to stop using alcohol or marijuana or pasta/cookies every evening to self-medicate their anxiety.

Nearly all of the research into inositol’s effectiveness to counter insulin resistance has been done specifically in the context of PCOS (and thus all in menstruating women). However, there is no apparent reason to believe that the effects would not also be significant in women without PCOS. We know one study shows significant improvement in metabolic syndrome in postmenopausal women. However, by definition, it’s unclear as to whether there would be similar benefits available to men. One might assume so, but we could find no clear evidence of this being tested or validated in clinical studies.

Inositol has been shown repeatedly to restore ovulation (and here) and increase pregnancy in women with PCOS in both normal weight and obese categories. In many of the high-dose studies (and here and here and here, from 1200-4000mg daily), there was a marked improvement in glucose, insulin, and testosterone levels as well, showing the nutrient is addressing the common metabolic and interactive hormone drivers of PCOS. There were ovulatory benefits in lower-dose studies (e.g., 200-400mg/day) but less or no marked improvement in other metabolic markers (e.g., insulin). One study also identified dramatic improvements in two common symptoms of androgen dominance (acne and hirsutism) in young women with PCOS. Duration of treatment in the studies ranged from 3-12 months, with significant benefits being demonstrated (where measured) by the three-month mark. Consider 2-3 g/day for this purpose.

Both myo- and d-chiro inositol forms have been shown in most studies to be effective at reducing insulin resistance. In fact, more rapid and sustainable benefits are likely achieved using a synergistic combination of myo- and d-chiro-inositol, as opposed to myo-inositol alone. However, studies have also revealed that the ratio of these forms is essential, with a ratio of myo- to d-chiro- ideally being about 40:1. Notably and in support of this ratio, the d-chiro form is also an aromatase inhibitor, of which high, ongoing intake would risk further exacerbating an androgen-dominant dynamic common in PCOS; thus low doses of this form would be prudent for these patients.

High-dose inositol is contraindicated (as is true for the vast majority of supplements) in those with advanced kidney disease.

Research into the use of inositol to counter depression or anxiety has used much higher doses (6-18 g/day). For example, a dose of 18 g/day was as effective as fluvoxamine (an SSRI) after a month of use in treating panic disorder. This article has an excellent overview of research into inositol for neurological and mood issues.

As an interesting aside (given we’re all nutrition buffs on some level), phytic acid (an aggressive mineral binder in the gut and a common ingredient in foods, especially those that are seeds in nature, e.g., nuts, legumes, grains) is a derivative of inositol (attached to several phosphate groups). You’ve probably seen it as a supplement with a fancy name: inositol hexaphosphate (or IP6). That’s just phytic acid. We typically break down 50% or more of the phytic acid we consume in the gut. Because phytic acid can bind with minerals, however (then we call it phytate), it’s important that our mineral intake be nice and high – and our digestion be nice and strong! Despite many myths otherwise, phytic acid is not “evil” in the body. It’s actually been shown to increase the activity of natural killer cells and perhaps confer anti-cancer capability. As with most things in the body (like estrogen and cholesterol), these substances are important, but too much of a good thing can become become dysregulated and have negative effects.