Toxicity of insulin due to phenol and metacresol

[tim2000s]

Agree, but at present we just dont know - the sciencedirect article references a whole lot of interesting studies, and by following the references in some of these I have realised how much more complex the infusion site issues in particular may be, especially over the long term, and how much they are being studied.

It's not just infusion sites. One of the greatest unknowns in T1 is injection sites and there is a lot of work going on looking at this as well.

 

[ann34+]

And given the percentage of T1s using CSII compared with the number using injections, it will remain a low priority. As it stands, this is a first world problem with limited value in large amounts of investigation. I'm sure it will continue but I don't expect fast progress.

It might be faster than we think - It is surprising that over half a million do use pumps -
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909532/
and there seems to be a fair amount of research already, and some mention the m-cresol etc issues -
http://www.ncbi.nlm.nih.gov/pubmed/26341262

Though days of use, and adiposity etc all seem more relevant, just a pity that this research does not seem to be much discussed - i imagine there is not time, but it is frustrating. Good that there is this forum.

 

[Nnora]

The question is whether it removes the proteins in a way that they can be reused in insulin in an effective manner.

That is a good question, I would just add one important detail- the costs. From experience in a process industry, engineers are always pushed to lower the operative costs and increase the yields. Different separation resins are probably more expensive.
May I ask what would you choose? It is so unfair to have to accumulate toxins in your body just because the production in a different way is less profitable.
We have an example in furniture industry, where formaldehyde resins are being replaced with non- toxic bioresins. End product is safer and consumers are happier

 

[pinewood]

Gosh, this is all rather depressing! I think I'll stay naive to the additives/cancer risk possibilities et al

 

[noblehead]

Gosh, this is all rather depressing! I think I'll stay naive to the additives/cancer risk possibilities et al

Likewise @pinewood

 

[Nnora]

Guys, never had an intention to upset anyone. The benefit of insulin is unquestionable comparing to the risks of toxins. However, after spending some time in search for better preservatives, I came back with one simple question:
Why is there a preservative anyway?
The use of phenol and m-cresol dates back to 1920's. At that time there were definetly not modern sterilization techniques available, such as gamma irradiation.
If I use a sterile reservoair, a sterile needle and a sterile infusion set, there would be minimal chances to 'catch a bug' and inject it under the skin, I presume in 24 h period (continous infusion).
Only the insulin solution is not sterilized. I shall ask a friend of mine who works as a process technologist at NovoNordisk. Whish me good luck

 

[tim2000s]

If you consider that the method for using insulin from a 10ml phial is to inject the same amount of air into the phial as you will withdraw insulin, every time you do this, you are injecting bacteria into the phial. As all injectable insulins are made with this delivery mechanism in mind, would you prefer to inject a sterile insulin or a non-sterile insulin containing who knows what bacterial cultures? That's effectively what the Phenol and Cresol prevents.

 

[Nnora]

If you consider that the method for using insulin from a 10ml phial is to inject the same amount of air into the phial as you will withdraw insulin, every time you do this, you are injecting bacteria into the phial. As all injectable insulins are made with this delivery mechanism in mind, would you prefer to inject a sterile insulin or a non-sterile insulin containing who knows what bacterial cultures? That's effectively what the Phenol and Cresol prevents.

Depends on how much bacteria 'flow' in the air. Besides, we can think about 'ready for use sterile reservoairs' already filled with insulin.

 

[tim2000s]

Great but the same insulin is used in both sterile and non-sterile environments, and I'd rather inject low levels of toxins than bacteria that can multiply. The phenol and m-cresol also maintains the stability of the hexamer form which makes non-human insulin effective.

 

[noblehead]

Depends on how much bacteria 'flow' in the air. Besides, we can think about 'ready for use sterile reservoairs' already filled with insulin.

Don't worry yourself too much about these things, it can wear you down if your not careful @Nnora

Just be thankful we have insulin otherwise the alternative is unthinkable.

 

[Robinredbreast]

I have a Nurses handbook from 1910, it belonged to my mum. No Insulin then, it was diet with Opium, Arsenic and Sulphuric acid, we didn't survive long and 'most wasted away' so Insulin is a must have and after 27 years of taking it, I am still in one piece and doing everything I did as a 30 year old, fit, healthy and active.

 

[Nnora]

Great but the same insulin is used in both sterile and non-sterile environments, and I'd rather inject low levels of toxins than bacteria that can multiply. The phenol and m-cresol also maintains the stability of the hexamer form which makes non-human insulin effective.

Hi, after some time I'm back on the same topic. Why? Because one more issue with the commercially available insulins: their onset and duration of action.
In the healthy islets, with presence of Zn atoms, insulin takes hexameric (inactive) form which is also more appropriate because allows more dense packing. Commercial insulin, I agree with you is also in hexameric form around phenolic group. But I disagree- it does not make it more but less effective, lasting 3-5 hours and perfectly designed for MDI therapy.

In my modest opinion, the pump users would have the opportunity to perfectly control their BG if only they had a monomeric insulins in their reservoairs.
Look for example this article:
https://www.ncbi.nlm.nih.gov/m/pubmed/2226110/
This means that a perfect cloosed-loop systems (fully automatic pump + CGM) are possible, but somehow, they are not on the market. Besides, it would allow a diabetic to eat with less worries, even the fast sugars. Would you not like it?
So, the presence of phenol in insulin formulations is not favorable in terms of both safety and efficacy.

 

[tim2000s]

@Nnora The faster acting insulins (Apidra, Humalog and NovoRapid) are all Monomeric.

You aren't diabetic, are you? The long acting ones are the Hexameric ones.

 

[yingtong]

I have a simple statement to say,I have taken insulin for close on 55 years and it has kept me alive and very good Heath and I intend to carry on taking it ,albeit via a pump now and I have good insulin sensitivity.So ****** all this twaddle I'll carry on what I have doing,it surely will keep me going for the rest of my life and I intend to keep going for a few year yet.

 

[Nnora]

@Nnora The faster acting insulins (Apidra, Humalog and NovoRapid) are all Monomeric.

Hi, thank you for your reply. According to:

Setter SM, et al. Ann Pharmacother. 2000.
Insulin aspart: a new rapid-acting insulin analog

"Insulin aspart exists as hexamers that rapidly dissociate into monomers and dimers on subcutaneous injection."

The above mentioned, NovoRapid and other are so-called rapid-acting insulin analogs. In the presence of phenolic group, and because the natural tendency to form hexamers, they stay active during 3-5 hours after the injection.

I share my thoughts openly and criticize what I think is wrong. Diabetes, with or without me is a nation of nearly 300 mil. people, but without any government and institutions. Nation of such a size could afford for a proper research, to find a way to improve the quality of life?

Respect to all the people here with a positive attitude; my experience with diabetes is different...

 

[Kristin251]

I'm with Tim and all others who just take their insulin ad needed and best availablele. We have enough to deal with without scrutinizing what could be. We have two options. I jest what we have or die. Our best option would be to not need insulin. However, if we want to live we need to take it. Best option we have for now. Making us paranoid doesn't help. We have little choice. We do the best we can and live the best we can. Insulin is what it is and until it changes....let it go. Life or death....

 

[Nnora]

You do not work for one of those pharmaceutical companies, do you?

 

[tim2000s]

Hi, thank you for your reply. According to:

Setter SM, et al. Ann Pharmacother. 2000.
Insulin aspart: a new rapid-acting insulin analog

"Insulin aspart exists as hexamers that rapidly dissociate into monomers and dimers on subcutaneous injection."

The above mentioned, NovoRapid and other are so-called rapid-acting insulin analogs. In the presence of phenolic group, and because the natural tendency to form hexamers, they stay active during 3-5 hours after the injection.

I share my thoughts openly and criticize what I think is wrong. Diabetes, with or without me is a nation of nearly 300 mil. people, but without any government and institutions. Nation of such a size could afford for a proper research, to find a way to improve the quality of life?

Respect to all the people here with a positive attitude; my experience with diabetes is different...

You are aware I hope that your original link was to something produced by Novo Nordisk in their development of Novorapid? And that the monomer insulin it refers to is the insulin analogues you were not impressed with where the links between the dimers and hexamers have been replaced with Amino Acids using recombinant DNA? The tricky bit with insulin in general is that its structure dictates that it forms dimers and hexamers and keeping it out of that form is not something that has yet been achieved?

This might be of interest: http://middleeast.thelancet.com/journals/lancet/article/PIIS0140-6736(96)06032-1/fulltext

 

[bvanant]

Actually it is a bit more complicated rather than simple. Phenolic preservatives are included in insulin formulation to keep bacteria from growing in the vial and to kill any bacteria that you might inject through the skin. To have "bacterial efficacy" means that you will kill all of the common skin bacteria that you might get on your needle before you inject. Sadly there are very few anti-bacterial compounds that are both safe for insulin (meaning that it won't cause the insulin to either clump together or denature to an ineffective form) and safe for human tissue. Injection site or infusion site infections can be very nasty and hard to treat.
As for monomeric insulin, it has been tried and the time to peak for a pure monomeric insulin such as described by Jens Brange show that insulin concentration is more important than state of aggregation for time to peak studies. It is true that the current fast insulins (lispro, aspart and apidra) are not really monomeric but the fact that phenolic preservatives help stabilize them in the vial is completely fortuitous. From a study by Kang and colleagues
"The absorption rate of insulin aspart is not statistically significantly different from a purely monomeric analogue such as AspB9, GluB27 [96]. To get to faster time to peak i.e. to help the possibility of a true AP we will need to figure out how to better put insulin into people. Putting insulin into the peritoneum is indeed much faster but making implantable pumps work well is a big job.

 

[DCUKMod]

Actually it is a bit more complicated rather than simple. Phenolic preservatives are included in insulin formulation to keep bacteria from growing in the vial and to kill any bacteria that you might inject through the skin. To have "bacterial efficacy" means that you will kill all of the common skin bacteria that you might get on your needle before you inject. Sadly there are very few anti-bacterial compounds that are both safe for insulin (meaning that it won't cause the insulin to either clump together or denature to an ineffective form) and safe for human tissue. Injection site or infusion site infections can be very nasty and hard to treat.
As for monomeric insulin, it has been tried and the time to peak for a pure monomeric insulin such as described by Jens Brange show that insulin concentration is more important than state of aggregation for time to peak studies. It is true that the current fast insulins (lispro, aspart and apidra) are not really monomeric but the fact that phenolic preservatives help stabilize them in the vial is completely fortuitous. From a study by Kang and colleagues
"The absorption rate of insulin aspart is not statistically significantly different from a purely monomeric analogue such as AspB9, GluB27 [96]. To get to faster time to peak i.e. to help the possibility of a true AP we will need to figure out how to better put insulin into people. Putting insulin into the peritoneum is indeed much faster but making implantable pumps work well is a big job.

Hi there @bvanant - It looks like at least part of your post is from some sort of paper or article. Could you please post a link to the source information? Many thanks.