Focusing on insulin resistance causes. Questions.

[Subby]

Long post here, sorry. Trying to sort through where I'm at and what I should be doing.

When I talk about insulin resistance here I mean what appears to be insulin resistance. It may also be other metabolic functions such as liver releasing glucose, providing the same result... times of insulin less affective, or taking a long time to act.

The use of a pump and much testing the last few months has illuminated that the reason my diabetes has always been so hard to manage is that:
- I have very large variation of insulin resistance through the day, like iceburgs floating through.
- I do not (have never) responded to my bolus insulin in a reasonably even way, from meal to meal and day to day. Enough variance to mean most times my 2 hour post test is often a big surprise. For the last 16 years.
- This is ruling out many common issues such as excessive hi GI carbs, insulin sites, lack of activity, incorrect carb counting, excessive stress, etc, on variation in insulin absorption. Of course they are all still factors but I am saying none of them are stand out to be major underlying causes of such variations I get. Please ask about issues, but on balance my comments are "all basic care taken/things considered".

In fact, many of them appear to be contributing factors but in an exacerbated way to suggest something else is causing it. For example, a car ride on a warm day for 30 min. can double my blood sugar immediately. Yes, stress would be expected to have an effect. But this seems excessive and I feel I am super sensitive to stress effects on my blood sugar. Good stresses, just a conversation that's a bit tricky, can do it.

What I've learnt lately:

- A complex variable basal rate through the pump can temporarily make things all so much more predictable, including successful boluses for the first time. (ie, suddenly I will have mostly a "normal" bolus/meal profile for the first time in my life.) Been lucky to have a few days with this (incredible health difference when it happens), but it is elusive.

I will obviously continue to use this as a primary tool yet my resistances keep shifting, and high sugars and spikes come back. Obviously my variable basal rate is the best tool I have right now to directly deal with my IR, but I am at a place I want to look at IR causes.

- Being high already (say, 13+ mml/l) seems to create more IR expotentially. (Or, this may be a period of high IR and I am being fooled here....) But once I am up it is very hard to get down. Often at 15+ mm/l it can take 4+ hours for a correctional bolus to have any affect at all.

A few more points about me

-11+ mml/l and I feel sick, have debilitating effects. I test a lot and think a lot because I want to know what is going on hour to hour and because the option is forget it and be an invalid with raging high blood sugars all day. I'm looking for practical improvements for functioning, not perfect numbers.

-slightly overweight. reasonably active. Physically active but not demanding, job. When I've been more highly active regularly, insulin needs decrease but seems unstable IR/absorption/carb action remains. But that was a while ago before the pump. Unfortunately concurrent CFS and more instability often sends me off the rails when I try. Of course the time is coming to try again.

-insulin usage total daily is over my weight in kg. In other words, I use a high amount of insulin going by the vague formulas (which would predict 45, not 110)

Today I went to my endo and demanded we look more into underlying effects of insulin resistance, which has always been trivialised and swept under the carpet by my endos and team, I think. I just want to explore and I am happy to just gain understanding on my IR, even if there is little to be done medically directly by that knowledge. I wish to explorer strategies of how I might tame these constant uneven IR periods.

I had to really press this, but she wrote up some blood tests. Some I requested from my quick research and she just put in, who knows if a result will be meaningful. Heres a partial list
Cortisol
Other adrenal functions I think
Liver function
Cholesterol (is currently high)
zinc magnesium b12 chromium

Couple more I can't read on the form.

That's where I'm at now. Do people have experience and knowledge in this area and know of other things I should be exploring to make this exhaustive? I read DHEA can be a big cause of IR, should/can this be tested? Anything else along this line.

One more thing about myself - I'm a long term CFS sufferer. I have heard that CF may be caused by inability to store vit and min. I don't really want to debate that, but just say it's a possibility... any ideas on this having interaction with my IR. Seems it may be another possibility to properly explore?

I'd appreciate any other ideas around the "treat physiological causes for insulin resistance seriously for a while" theme

Thanks for reading if you got this far

[REDLAN]

that's a long and complex post, first some stuff I do know a little about.

Insulin resistance (in muscles - the biggest user of glucose in the body) occurs in response to a reduction of expression of the GLUT4 gene - so the cell makes less GLUT4. Without insulin GLUT4 floats about in the cell, when insulin binds to it's receptor, GLUT4 binds to the cell surface and allows the influx of glucose into the cell - less GLUT4 means less glucose can get into the cell, and so you need more insulin to produce the same lowering effect.

Insulin resistance varies throughout the day - after food insulin resistance of the muscles drop, allowing the absorbed glucose to be rapidly taken up. Over night insulin resistance rises, which forces the muscles to switch to fat as a primary fuel - add in the corticosteroid rush from your adrenal glands in the early morning and you have your classic DP.

As far as I know insulin resistance is a slow adaption - it takes minutes to hours for the effect to become noticeable. Anything less than this means it's probably something else...

like glucose release from the liver.

One thing did strike home,when you spoke about the high degree of variability in regimen. Mine isn't as bad as yours, but nothing I do lasts much more than 1 to 2 weeks maximum. I get changing patterns of highs and lows, changing basal requirements, and changing bolus needs - mornings lately have been bad - same dose, with the same breakfast has me low one day high the next. And every now and again I get a big spike.

My take is that this is fairly normal, for me - it's the way my diabetes works.

You specifically mentioned corrections - once above a certain level, usually 13 mmol, the corrections do not work as well, and I can need additional corrections. I believe that the problem is caused by out of control (i.e. not enough insulin) gluconeogenesis by the liver. This then in turn causes ketones to be released by the liver.

you now need much more insulin - To a) overcome the natural insulin resistance of the muscles so get them to take up glucose, and b) turn off gluconeogenesis.

I check for ketones if I'm high - and even if there is a trace I run double corrections. - alternatively I stack corrections every 2 hours (need to account for insulin not yet absorbed by the body or this can go badly wrong).

[Subby]

Yes apologies for the long, hard to read post, I had just been fighting this out with my endo and was/am very frustrated at communicating these issues. I think it was good to just get it down though. I will revisit these issues in a more clear way as I am able.

Thanks for replying Redlan. Very useful info there about how the resistance works. The pump with variable basal infusion that I can experiment with has been invaluable working out that my insulin needs do actually rise, as opposed to the insulin effect deferred (couldn't tell which with injections). My needs raise substantially through day and usually cut down abruptly, usually at about 4pm. I wonder if this could be some kind of adrenal (cortisoidal) or liver glucose base exhaustion? I know I may never know that answer, but I think knowledge is power here and the more I know the more I can develop tactics, perhaps.

The explanation for how insulin needs increase once the blood sugar is high is invaluable for me, becuase this is so common for me. Your description really helps understand the process there and I can take a new approach to it (at the least, not freak out about where all the bloody insulin is going).

I too have thought that my variability has been "just my diabetes", just the way it goes - and maybe it is. But I spend so much time micro managing (you know what I mean ... extra tests, changing food, behaviour, dosages, constantly to try and even out) that it really has struck me the extra effort to try and help/avoid insulin resistance is not a waste.

Thanks again for sharing your knowledge.

[xMenace]

I've always believed apsorption problems caused a lot of my variability in the past. I've found since pumping I'm much much more predictable: either it works very well or it doesn't work at all. There doesn't seem to be a middle ground anymore.

[Subby]

I think I might be similar John. Since I started pumping in december I've had periods where it all clicked and worked like never before, and then periods of variation just like the bad old days (like the past few weeks). I actually think my current bad run was set off by a batch of bad insulin from a store, things just went scewy for little reason for a week, and got immediately better with newly bought insulin.

But I haven't recovered my equilibrium at this stage, I am beginning to suspect that I need 24 - 36 hours of even sugars for my body to pipe down from a state of variation. Does this ring a bell for you? Of course this could be illusion... but it's a theory I want to keep in mind. Before with injections, I never had more than say 10 hours stablility, and that was quite rare. It never seemed to have a chance to roll out into a sustained lower state of flux. It is much more possible with the pump (Variable basal being the star of the show) but... gotta keep working on getting back to the "event horizon"!

[BlueSky]

Subby,

Something a lot of people are not aware of is that the level and duration of injected insulin action is very variable. Even with the modern insulins, intraday variability of action is 20%+. It means that 10 units of insulin can have between 8 and 12 units worth of effect. That is a huge difference. And it is a major cause of blood glucose volatility. Some people have more luck with it than others. But if this is a problem for you, the best way to deal with it is to minimise the amount of insulin you are using. A 50% reduction in the amount of insulin you use, for example, will eliminate 50% of the volatility you have been experiencing.

How much carb are you eating? The easiest way to reduce blood glucose volatility is to minimise carbohydrate consumption. The less carb you need to cover, the less insulin you need to inject. I would reduce carbs to below 50 grams a day until things settle down. And they will. You can then consider systematically re-introducing some carbs in amounts and at times that are the least disruptive.

I have ended up eating virtually no carb for breakfast (because of fierce insulin resistance), 15-35 grams of carb for lunch (I am sensitive to insulin at this time of day) and about 10 - 20 grams of carb with supper (depending on what the family eats). I have reduced my total daily insulin dose from 55 units to 35 units. And, for the most part, my blood glucose is extremely stable. Achieving this was very important for me because of my history of Eplilepsy. I don't have seizure inducing sudden hypos anymore. And my blood glucose doesn't often go over 10mmol/l. I also used to have extreme difficulty bringing high blood sugars down, and I know what it is like!

[Subby]

Bluesky, thanks for your words of wisdom. The variable action of insulin is very important news to me. I suppose I suspected a little variation in itself, but I have never heard it expressed as a statement. It is yet another reason I agree with you, reducing insulin is the only way to go.

It is funny, just an hour or so I was plotting my on-coming basal fasting over the next few weeks and considering the best way to log or keep track of it. Then I thought "how about after my basal rate is improved, I try the willpower of just a small amount of carbs per meal in a similar way". I have considered this before but previously, I felt it was impossible, as in I had all sorts of terrible carb cravings. In that, I quit smoking successfully, but I doubted I could quit carbs.

But I forget that on the pump my craving is so much less now. In fact now I have two states: very little cravings when more stable, sudden strong cravings when swinging up towards and beyond 10. WHen put onto the pump I immediately without problem went from 300 - 400 g carbs to my current 150 - 230 g carbs. I think now is the time to try exactly what you are suggesting. Thanks again

[REDLAN]

some extra bits about insulin action...

The variability of insulin was part of a paper that I read (i've lost the link now) - the paper was actually looking at the viability of inhaled insulin. It's point was that variability of action and absorption of an inhaled insulin was about the same as an injected one, and should therefore prove to be a viable alternative to injected insulin especially to needle- phobics.

I didn't look up to see who sponsored the paper, but it does not take too many guesses...

The major point to take away is that there are 2 types of variation experienced

1) variation of absorption - variability is up to 25% within an individual. This is not so important - all of the insulin will get into your body and do it's work at some point - but you may have problems with post-prandials - either your BG is too low or too high.

2) variation of action - variation within an individual is actually greater than variation between individuals, and is up to 33% i.e. if you gave yourself 10 units it could be equivalent to the action of 11.6 units or as little as 8.4 units. And the paper found that individual variation in basal insulins is worse than fast-acting insulins.

Variation of action matters much more than variation of absorption - if your basal insulin isn't working as well you will go high and stay high. If it's working too well then you will go low and stay low.

Bluesky's advice is sound - lower carbs mean less insulin, and in theory fewer problems with variation. There is a lower limit - if you remove too many carbs you have to take enough insulin to switch off gluconeogenesis (carb counting will no longer work) - this limit is very low - anyone following bernstein can attest to that.

the other answer is to target your regime so that they meet a hit rate - my personal one for post-prandials is 75% that is I allow 25% of my posts to be either too low or too high - the odd hypo or high is no reason to alter my regime - I typically achieve a 70% hit rate which I think is pretty good for me. And I try and aim for an even over/under split. You could choose your own hit rate depending on what you think is realistic for you.

[Subby]

Great info and ideas guys. Thanks, gives much to work with.