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Permalink Reply by Judy on April 7, 2009 at 1:55pm

Well, I feel a little more comfortable w/PubMed abstracts (and preferably the full text articles when I can get them) than a google search. Here's what I found at PubMed:

1: Obesity (Silver Spring). 2007 Jun;15(6):1409-18.
Sleep apnea is induced by a high-fat diet and reversed and prevented by metformin in non-obese rats.
Ramadan W, Dewasmes G, Petitjean M, Wiernsperger N, Delanaud S, Geloen A, Libert JP.

EA 3901, Dysrégulations Métaboliques Acquises et Génétiques, Université de Picardie Jules Verne, Faculté de Médecine, 3 Rue des Louvels, F-80036 Amiens cedex 1, France. wiam.ramadan@etud.u-picardie.fr

OBJECTIVE: We assessed the relationship between a high-fat (HF) diet and central apnea during rapid eye movement and non-rapid eye movement sleep stages by recording ventilatory parameters in 28 non-obese rats in which insulin resistance had been induced by an HF diet. We also studied whether metformin (an anti-hyperglycemic drug frequently used to treat insulin resistance) could reverse sleep apnea or prevent its occurrence in this experimental paradigm. RESEARCH METHODS AND PROCEDURES: Rats were fed with a standard diet (10 rats), an HF diet (8 rats), or an HF diet concomitantly with metformin treatment (10 rats). Each animal was instrumented for electroencephalographic and electromyographic recording. After 3 weeks, ventilatory parameters during sleep were recorded with a body plethysmograph. All rats were treated with metformin for 1 week, after which time the ventilatory measurements were measured again. RESULTS: Our results showed that the three groups of animals did not differ in terms of body growth over the entire experimental period. The HF diet did not modify sleep structure or minute ventilation in the different sleep stages. A great increase (+266 +/- 48%) in central apnea frequency was observed in insulin-resistant rats. This was explained by an increase in both post-sigh (+195 +/- 35%) and spontaneous apnea (+437 +/- 65%) in the different sleep stages. These increases were suppressed by metformin treatment. DISCUSSION: Insulin resistance induced by the HF diet could be the promoter of sleep apnea in non-obese rats. Metformin is an efficient curative and preventive treatment for sleep apnea, suggesting that insulin resistance modifies the ventilatory drive independently of obesity.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 17557978 [PubMed - indexed for MEDLINE]
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2: Respir Physiol Neurobiol. 2006 Jan 25;150(1):52-65.Related Articles, Links
Effect of high-fat diet and metformin treatment on ventilation and sleep apnea in non-obese rats.
Ramadan W, Petitjean M, Loos N, Geloen A, Vardon G, Delanaud S, Gros F, Dewasmes G.

EA 3901, Dysrégulations métaboliques acquises et génétiques (DMAG-INERIS), Unité Environnement-Santé, Université de Picardie-Jules Verne, Amiens Faculté de Médecine, 3 Rue des Louvels, 80 036 Amiens Cedex 1, France. wiamramadan@hotmail.com

We investigated the effect of insulin resistance on ventilation and the incidence of sleep apnea in non-obese rats and determined whether metformin could change ventilation and occurrence of sleep apneas. Five groups of rats were studied: (1) standard chow; (2) high-fat groups, with 1 with metformin; (2) had type 2 diabetes induced by streptozotocin, with 1 with metformin. Compared to standard rats, ventilatory parameters remained unchanged in the high-fat fed diet as well as in diabetic rats. However, their oxygen consumption was reduced (p

Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't

PMID: 16448934 [PubMed - indexed for MEDLINE]
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The consistent theme thru related articles is a high-fat diet.

And on a different note: an older abstract of interest regarding central apneas. I didn't check to see if this had been followed up on and verified in more studies or not.

2: Am J Respir Crit Care Med. 1998 Mar;157(3 Pt 1):917-20.Related Articles, Links
Diazepam suppresses sleep apneas in rats.
Carley DW, Trbovic SM, Radulovacki M.

Department of Medicine, University of Illinois College of Medicine at Chicago, 60612, USA.

To test the respiratory effects of benzodiazepines in an established animal model of central apnea, we administered nonhypnotic and hypnotic doses of diazepam to nine adult male Sprague-Dawley rats chronically instrumented for sleep staging. In random order on separate days, rats were recorded following intraperitoneal injection of: (1) saline; (2) 0.05 mg/kg diazepam; or (3) 5 mg/kg diazepam. Normalized inspiratory minute ventilation increased significantly during wakefulness and non-rapid eye movement (non-REM) sleep following each dose of diazepam (p < 0.003 in each case) and following the highest dose during rapid eye movement (REM) sleep (p = 0.01). In accord with this respiratory stimulation, non-REM-related spontaneous and post-sigh apnea expression decreased following each dose of diazepam (p = 0.006 to 0.04), but REM-related apnea expression was unaffected despite significant respiratory stimulation. The durations of non-REM and REM sleep were unaffected by the low dose, but following 5 mg/kg of diazepam non-REM sleep was increased (p = 0.03) and REM sleep was decreased (p = 0.009). We conclude that both hypnotic and non-hypnotic doses of benzodiazepines may be associated with suppression of sleep-related central apnea. We further conclude that non-REM and REM-related apneas arise from at least partially distinct mechanisms.

Publication Types:
Research Support, U.S. Gov't, P.H.S.

PMID: 9517612 [PubMed - indexed for MEDLINE]

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Permalink Reply by Steven Y. Park, MD on April 7, 2009 at 2:03pm

Dina,

That's very interesting. The paper you cited hypothesized that lowering insulin resistance may improve ventilation control. Ultimately, it's hard to prove that. My feeling is that there's another unseen pathway. For example, mirtazapine was found to lower AHI scores by 50%. One possible mechanism is by suppressing REM and shifting your sleep more towards non-REM, deep sleep, where you're less likely to obstruct. Taking acid reflux meds can also lower your apnea and hypopnea scores, most likely due to less irritation and inflammation in the throat, with less swelling and obstruction. Azithromycin in theory should help also since it pro-motility effects will lessen acid reflux into the throat. The problem is that although these meds do help somewhat, it's never curative.

The only way to "prove" that you're better is to stay on it a while and then undergo a sleep study. You could do one of the home-based studies here. You may want to talk to your sleep doctor about this. Interestingly, metformin is sometimes recommended for women with PCOS.

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Permalink Reply by amott1973 on April 7, 2009 at 9:40pm

I have both sleep apnea and severe PCOS. I've been on 1500mg of metformin too, and while it does help alleviate some of the symptoms of insulin resistance it hasn't done anything for my sleep apnea. Sluggishness can be a symptom of the insulin resistance also, so perhaps that improvement in how you feel could be because your body is utilizing insulin better.

I'd definitely suggest looking into retesting for sleep apnea before stopping treatment.

My mom has a lot of trouble pulling her mask off at night too. But then she's really non-compliant about it anyway. Hopefully with consistent use or maybe even with the hypnosis treatment mentioned you'll find a way to keep the mask on.

I can tell you that my husband was given a sleep aid for a while and it was scary how he'd totally do something and not remember it at all! One night I gave him my 2 year old who needed new PJs put on after getting wet at night. While I changed the bed, my husband totally dressed my son. In the morning he had NO recollection of the night's events at all! Freaky! Maybe the sleep aids are actually making it harder.

Good luck!

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Permalink Reply by Ruth Rayceen on April 8, 2009 at 11:06pm

Dina, an interesting thought. Judy - thanks for all the research.

However, this is one (fairly) slender diabetic female, with an AIC of 5 8, who has taken 1000 mg of metiformin twice a day - for several years. I am saddened to report my sleep apnea has not improved, gone away, or disappeared.
Ruth

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Permalink Reply by Dina on April 9, 2009 at 11:50am

Its day 7 without the mask now and I am starting to feel pretty exhausted. I think I might put my mask on tonight. Interestingly enough though, I had another sleep study done (half with the mask, half without) a couple of days after I started taking metformin. I'll let everyone know whether or not it showed any improvements. I was told I wouldnt get any results for a couple of weeks at least.
Thank you for all of your help and comments, this forum is exactly what I've been missing. :-)

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Permalink Reply by Barbara on April 9, 2009 at 3:54pm

Hi Dina,
I know it must have made you so happy to think you had struck the golden cure.
My bubble busting thought is try not to get overly excited. Sorry. Although, I wouldn't be surprised at all if there aren't some connections I doubt there is such a strong link as to cure Apnea after such a short treatment time. But these are only thoughts - I don’t have a string of PhD’s after my name lol.
I have been on many different doses of Metformin (from 500mg up to 3,000mg daily for the past 20 years). I started in my teens as an off label treatment. It was not considered appropriate treatment for PCO at the time.
My current dose is 2,000mg daily. If there was some way Met. could have prevented apnea I probably wouldn't have just been diagnosed with apnea after taking the medicine for 20 years.
I have some thoughts on why you had a few days of feeling better and I'll end this post with a BIG WARNING!!!!
First idea. Even if you do not already have diabetes with PCO be aware you are extremely high risk - no matter what your weight is. So keep an eye on that. Know that the earlier you catch it after it develops the more you can control it and prevent any damage that typical diabetes can cause. One way some PCO patients are looking at this is even if not diabetic they are trying to keep their A1C in the low 5's with the goal being to never let glucose get higher than 110 even after a big meal. As low as possible - not all M.D.'s agree with this. Everyone has to research and decide for themselves. Low carb nutrition can have a profound, powerful, wowza affect on PCO so that may be something you want to consider trying at some point.
OK, if you had a few days of feeling better after the start of Met perhaps the Met was hitting your night time insulin levels like a big muscular body builder. The Met. might have stabilize your insulin levels during sleep which simply allowed you to sleep more sound as apposed to constantly fluctuating insulin levels - which can make you feel like sh*t - asleep or awake. However with Insulin and glucose our bodies adjust to the "feelings" rather quickly.
People who have blood sugar levels of 300 on a regular basis can feel 100% ok. When their sugar drops to 200 they can feel like they are going to pass out because of LOW blood sugar. They feel healthy at 300 because their body has adjusted to it. It takes time to step down into lower numbers and “feel” normal. If you had Dawn Phenomena (higher AM fasting glucose levels than a healthy non-diabetic) the Met might have adjusted that to normal levels for you which could have caused you to sleep better typically from 4am until the time you woke up. That does not mean it had anything to do with Apnea. If this is what happened all it means is that you had 2 problems (Insulin crap and Apnea) and one of the problems (Insulin) got a little better.
HEY, try not to be sad if you find this is not the big cure. It sounds like you might have done a really GOOD thing by trying to treat the PCO!! It is true untreated Apnea can do some major health damage but so can PCO. The diabetes that can result from PCO is a killer if untreated. With the addition of Met you may be on your way to becoming a healthier person.

The BIG WARNING........... BIRTH CONTROL!!!!!!!!!!!!!!!!!!!!!!!!!!!!
If your body responded in such a quick positive way to starting the Met I would HIGHLY recommend (I am not a doctor) that you use some extra strength, double duty, major powerful birth control if you are not in the market for getting pregnant right now. With PCO, when Met or low carb eating kicks in and starts working what was infertile can (not always) result in Super dooper fertile. Approach sex with CAUTION until you see how your body is responding long term to the medication.
If you run across any more Apnea/PCO research I hope you post it here. I’d love to read it. It’s VERY INTERESTING. Makes me wonder not only about women pre and post menopause as well as pre-adolescence and during pregnancy but I’m also thinking about men with and without apnea and their hormone levels. Oh, another question/thought - what about men (obviously without PCO) who have Apnea but start taking Met as a treatment for type 2 diabetes. Hummm.. All very interesting.

I hate that you are having trouble with your mask at night after 5 years - that would drive me bonkers. Seems like with all the people here they’d be able to help you figure this problem out. After only a few days on CPAP mine was not working and I took it to the medical supply place. They were shocked at how misfitted the head gear was. Switched me to a new type head gear and last night there was an improvement. Have you tried going to your supply company and stomping your foot till they make it work? It’s a thought :).
Take care,
Barbara

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Permalink Reply by Dina on April 21, 2009 at 4:49pm

Hi All,

So I have another update. I emailed back and forth with my sleep doctor and he took a look at my most recent sleep study (from a few weeks ago, right after I started Metformin). He said he did not see enough apneas to explain why I would be so extremely tired during the day. I havent worn the mask in over 2 weeks now and I've never felt so good in my life. I can honestly say that. Never in my life have I felt so energetic and alert.
My doctor went on to say that we should discuss this further in person because my situation isn't "usual or typical" - I'm assuming this means more testing is coming my way. He thinks that I may have had some other insulin or blood sugar related problem that was causing me to be so tired in addition to sleep apnea. This is bothersome to hear since I've been seeing an Endocrinologist and having regular blood tests since I was 16 for PCOS. Why wouldn't have someone seen this before??
Anyway, I'll keep you all updated with what happens next. Hopefully the end result is a happy one.
Barbara, I do take regular birth control (orthotricyclen) do you think this is enough?? I'm definitely not looking for any babies anytime soon.

Thank you all so much for your advice!

Barbara said:

Hi Dina,
I know it must have made you so happy to think you had struck the golden cure.
My bubble busting thought is try not to get overly excited. Sorry. Although, I wouldn't be surprised at all if there aren't some connections I doubt there is such a strong link as to cure Apnea after such a short treatment time. But these are only thoughts - I don’t have a string of PhD’s after my name lol.
I have been on many different doses of Metformin (from 500mg up to 3,000mg daily for the past 20 years). I started in my teens as an off label treatment. It was not considered appropriate treatment for PCO at the time.
My current dose is 2,000mg daily. If there was some way Met. could have prevented apnea I probably wouldn't have just been diagnosed with apnea after taking the medicine for 20 years.
I have some thoughts on why you had a few days of feeling better and I'll end this post with a BIG WARNING!!!!
First idea. Even if you do not already have diabetes with PCO be aware you are extremely high risk - no matter what your weight is. So keep an eye on that. Know that the earlier you catch it after it develops the more you can control it and prevent any damage that typical diabetes can cause. One way some PCO patients are looking at this is even if not diabetic they are trying to keep their A1C in the low 5's with the goal being to never let glucose get higher than 110 even after a big meal. As low as possible - not all M.D.'s agree with this. Everyone has to research and decide for themselves. Low carb nutrition can have a profound, powerful, wowza affect on PCO so that may be something you want to consider trying at some point.
OK, if you had a few days of feeling better after the start of Met perhaps the Met was hitting your night time insulin levels like a big muscular body builder. The Met. might have stabilize your insulin levels during sleep which simply allowed you to sleep more sound as apposed to constantly fluctuating insulin levels - which can make you feel like sh*t - asleep or awake. However with Insulin and glucose our bodies adjust to the "feelings" rather quickly.
People who have blood sugar levels of 300 on a regular basis can feel 100% ok. When their sugar drops to 200 they can feel like they are going to pass out because of LOW blood sugar. They feel healthy at 300 because their body has adjusted to it. It takes time to step down into lower numbers and “feel” normal. If you had Dawn Phenomena (higher AM fasting glucose levels than a healthy non-diabetic) the Met might have adjusted that to normal levels for you which could have caused you to sleep better typically from 4am until the time you woke up. That does not mean it had anything to do with Apnea. If this is what happened all it means is that you had 2 problems (Insulin crap and Apnea) and one of the problems (Insulin) got a little better.
HEY, try not to be sad if you find this is not the big cure. It sounds like you might have done a really GOOD thing by trying to treat the PCO!! It is true untreated Apnea can do some major health damage but so can PCO. The diabetes that can result from PCO is a killer if untreated. With the addition of Met you may be on your way to becoming a healthier person.

The BIG WARNING........... BIRTH CONTROL!!!!!!!!!!!!!!!!!!!!!!!!!!!!
If your body responded in such a quick positive way to starting the Met I would HIGHLY recommend (I am not a doctor) that you use some extra strength, double duty, major powerful birth control if you are not in the market for getting pregnant right now. With PCO, when Met or low carb eating kicks in and starts working what was infertile can (not always) result in Super dooper fertile. Approach sex with CAUTION until you see how your body is responding long term to the medication.
If you run across any more Apnea/PCO research I hope you post it here. I’d love to read it. It’s VERY INTERESTING. Makes me wonder not only about women pre and post menopause as well as pre-adolescence and during pregnancy but I’m also thinking about men with and without apnea and their hormone levels. Oh, another question/thought - what about men (obviously without PCO) who have Apnea but start taking Met as a treatment for type 2 diabetes. Hummm.. All very interesting.

I hate that you are having trouble with your mask at night after 5 years - that would drive me bonkers. Seems like with all the people here they’d be able to help you figure this problem out. After only a few days on CPAP mine was not working and I took it to the medical supply place. They were shocked at how misfitted the head gear was. Switched me to a new type head gear and last night there was an improvement. Have you tried going to your supply company and stomping your foot till they make it work? It’s a thought :).
Take care,
Barbara

• ▶ Reply

Permalink Reply by Barbara on April 21, 2009 at 5:51pm

Can you send some of your good health my way? I'm waiting...... :o)
It's so wonderful to hear you are feeling happy and healthy.
It SOOOO interesting! Can't wait to hear what the doc has to say when you visit face to face for a chat.
You need to be enrolled in some research studies asap.
As for the birth control pills.... I'm not a doc. Many PCO pts don't use birth control (or use condoms occasionally) because of long histories of not being able to get preg. Those are the women who will generally switch from condoms to birth control pills for safety when Met or low carb starts working. But if you are already on the pill (which if I remember is 95% - 99% effective) you may be covered quite well already. Just check with your doc if you have concerns.
KEEP UP THE GOOD HEALTH!!!
Barbara

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Permalink Reply by Dina on May 12, 2009 at 12:18pm

So guess what?? I got my results back and my study was COMPLETELY normal. No apneas, no hypopneas (well, mayne one or two).

I think the next step is to find out WHY metformin is working so well, and if it is even possible that I had severe obstructive sleep apnea as previously diagnosed, and now its gone.

Just a heads up for women with PCOS that experience extreme fatigue.....this story might be worth telling. My sleep doctor is including me in his case studies.

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Permalink Reply by Barbara on May 12, 2009 at 2:46pm

This is so cool !!
How are you feeling? Do you know if you are ovulating? How are your PCO hormone levels (ratio ect...)? Having regular periods?
How are your apnea symptoms (compare today to back whenever you initiated original sleep study).
If your doc publishes his study PLEASE post link. If not published get him to let you post it here - I am chompin at the bit wanting more info on this :o)
Enjoy feeling healthy!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Barbara

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Permalink Reply by Dina on January 14, 2010 at 1:53pm

Hi Barbara,

Sorry, I was sooo excited about not having to deal with sleep problems anymore I neglected to follow up!!

As an update, its been over 6 months since my "undiagnosis" of sleep apnea and I still feel great! I'm taking 4 500 mg capsules of metformin a day and couldn't feel better. My daytime fatigue is basically nonexistent now, compared to the days before my first sleep study where I would fall asleep in public places (and once at the wheel!). My doctor that prescribed me the metformin had no insight to share as to why my sleep apnea has gone away...any doctors I've mentioned this to seem to be baffled.

Hopefully this keeps working! I'll update with any reports my doctors publish, or if I gain any insight as to why this incredible thing has happened!

Good luck Barbara, and thank you for all your advice!! I wish you the same luck I had!

-Dina

I'll let you know

Barbara said:

This is so cool !!
How are you feeling? Do you know if you are ovulating? How are your PCO hormone levels (ratio ect...)? Having regular periods?
How are your apnea symptoms (compare today to back whenever you initiated original sleep study).
If your doc publishes his study PLEASE post link. If not published get him to let you post it here - I am chompin at the bit wanting more info on this :o)
Enjoy feeling healthy!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Barbara

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