LANTUS & LEVEMIR - What is the Insulin Depot?

You may have heard reference to the Lantus or Levemir Insulin Depot. What does that mean?

Lantus and Levemir both fall into the category of “depot drugs.” Pharmacologically, the two insulins work in different ways, but both have the characteristic of being absorbed slowly by the body. The result is an extended action. These insulins tend to display a cumulative effect, meaning that what happens in one cycle can affect the next cycle, or even the next several days. This is part of what allows Lantus and Levemir to create those beautiful, flat curves, so it is worthwhile to spend the time to understand the depot.

Here is a great reference that explains the Lantus and Levemir depots in layman’s terms:

Lantus and Levemir: What’s the Difference

Glargine (Lantus):

Detemir (Levemir):

Have you ever wondered why, when you are giving the same amount of insulin every time, the response is different in each cycle? Sometimes the numbers go up for the whole cycle, sometimes they go down, sometimes they stay flat, and sometimes they actually “curve.” The answer often lies in the depot. Did you skip a shot or give a partial shot at some time in the past few days? That can result in higher numbers for several days as the depot replenishes some of its lost stores. Did you increase the dose? This can result in a change in the size of the depot and can lead to a temporary adjustment in the amount of insulin available for use. Did you decrease the dose recently? A dose reduction will usually result in a need for less stored insulin. The excess may be released into the bloodstream faster than usual, especially if several dose reductions are done back-to-back.

Another interesting note from the Boulder Medical Center:

So sometimes, the answer is “just because.”

How long does it take to fill or empty the depot?

Again, from Boulder Medical Center:

Practical experience on FDMB shows that as a generalization, the depot can affect up to 6 cycles. The time tends to be less when a cat is on a smaller dose, and more when a cat is on a larger dose. Other factors can apply as well, but using the generalization of 6 cycles is a good starting point until you have learned your particular cat's patterns.

Now you are probably asking "How on earth can I use this information to understand my cat?".

Try to look at your spreadsheet not in 12-hour cycles, but in “waves” of action over a period of several days. Look for overall trends more than individual numbers. If something jumps out and doesn’t seem to make sense, go back 2-3 days and think about any changes that might have occurred in insulin, timing, exercise, health, food, etc. If the big picture is making sense but you see one cycle that doesn’t fit, then keep that 20-50% variation in mind and just wait it out.

More reading about the glargine and detemir depots:

Internet Journal of Endocrinology: Insulin Detemir and its Unique Mechanism of Action
Textbook of Diabetes Mellitus by B. B. Tripathy
The Mechanism of Protraction of Insulin Detemir

Additional note:
The Insulin Depot is not to be confused with Carryover (insulin effects lasting past the insulin’s official duration) and Overlap (the period of time when one insulin shot is diminishing and the next is taking effect).

 

I'd like to know what the scientific citation is for this statement:

Why? To me that is like don't call it this, call it that. What is "carryover"? What is "official duration"?

Overlap is exactly what it is. With any insulin and any given dose there is onset, action, and fading. If there was no dose before or after that given dose you go from no exogenous insulin to no exogenous insulin in some amount of time. That these two insulins have a "lingering" action of several hours does not change that fact. And string together doses, you will always have a level of circulating insulin that varies from preshot to nadir in, as you put it, waves. I think this could be somewhat replicated with other insulins if you could find the duration for a given cat and shoot more often.

The difference with lantus and lev is the mechanisms they use to "slow" absorption rate and extend duration by having a nonusable form that needs to either breakdown or unbind to be usable.

I still do not believe there is a "Depot/shed" but that it is just overlap of doses we are experiencing. I also think that overlap is an easy concept for people to understand and work with.

 

Yeah, there comes a point where it's all semantics. Sheila, perhaps you could repost the information you gave the other day in Shakespeare's thread "5/27 - start tonight." I don't want to repost it myself as you might want to add more to it. I like the more scientific aspect to the explanation.

Although I know we are all hurting tonight over the loss today of precious Musette. So maybe another day.

 

Just trying to differentiate between the science and the more colloquial descriptions that are common on FDMB. ;-) You can follow the links to read the wikia definitions (the links in my post are live) of Overlap and Carryover. I didn't write them. If you do not consider the petdiabetes wikia to be a reliable source, feel free to bypass those links and read the scientific publications instead.

There is a pharmacological difference in how various insulins are made. Lantus and Levemir are manufactured to form a depot. Read through the links I provided, and a Google search will provide more comparisons. Most of the comparisons I found were done between Lantus/Levemir and NPH. This link is fairly comprehensive. It is one of the first links you will find if you just type "is detemir a depot insulin" into Google. I have not researched the other pet insulins to find out if they form depots or not (notice that my post does not imply that these are the ONLY depot insulins for cats). My post refers specifically to Lantus and Levemir because those are the insulins I have researched.

Incidentally, there is discussion of the insulin's duration in the same ispub link. The observation is that duration is dependent on dose:

Novo-Nordisk notes that detemir exerts more than 50% of its maximum effect from 3 to 4 hours up to approximately 14 hours after dose administration. They also note a terminal half-life of 5 to 7 hours. (see pages 4 and 5).

Important note - these citations refer to duration in humans. Obviously there is no official documentation of duration in cats because the insulins are not designed for use in cats.

Overlap, sure, every insulin can be dosed in such a way as to create overlap. You can even create even more overlap by over dosing a cat, and I'm sure that is true with any insulin. However, you cannot force an insulin to become a depot drug if it is not designed that way.

Exactly! That is called a depot.

All I can do is present the facts. Each person will have to read the research and draw their own conclusions. ;-)

Notice that I did not mention the word "shed" in my post anywhere. That is one of our slang terms that seems to cause some confusion, and which would never be recognized outside of FDMB. Depot is a term that is understood by pharmacists.

I do not think overlap is a difficult concept. If I inject some insulin, and there is still some left when I inject the next dose in 12 hours, overlap will result.

The depot does seem to be a difficult concept for people to understand. We need to understand that (for Levemir) about 98% of the insulin that I inject right now is not available for use right now. The insulin I injected this morning or yesterday might be available right now, but the insulin I just injected will be waiting to be used later. If I skip a shot, then I am using up some of the insulin in the depot, but I am not replenishing it at the same time. At some point that will likely catch up with me because there will not be enough insulin in the depot until it has an opportunity to fully replenish. If I shoot too much insulin, then that insulin might all go into the depot, but at some point it will not be needed and will be used up at a higher rate than might be expected. WHEN that will happen seems to be an ECID thing, and will also be somewhat dependent on the size of the dose. It's not an easy concept!

eta: I've been trying to keep opinion out of this, but on a personal note, after spending some time working with a high dose cat on Levemir I developed a huge respect for the depot. When Jazzy was up to around 12 units, it took 5 cycles for any changes to take effect. Sometimes skipping a shot had no effect at all. That can be quite humbling when you are trying to stay ahead of a cat whose dosing needs are changing quickly.

 

This is just amazing!

Thank you for spending time on this and giving it to us.

heather

 

Just to clarify a point. Lantus and Lev are not the only medications that are depot drugs. There are a host of other medications that are in that category (e.g., Depo Provera, Prolixin, haldol decanoate, Zoladex). Depot drugs are designed and manufactured to be long acting by nature of their releasing a consistent dose over a long period of time. All depot drugs are long-acting but not all long-acting drugs are depot type.

 

Here is the revised version of my post in the other thread - as requested by Vicky. I rewrote for clarification and after following some of the links posted above:

Levemir and Lantus are no different than any other exogenous insulin. You inject the dose, it sets in, acts for a while, and fades away. The DIFFERENCE is that they last a LONG time with action times around 10-14 hours (my guess at total effective time in a cat versus 24 hours in a human). There is a good chance that some insulin is still active when the next dose is given. In fact, that is desired. Finding the balance between fade of one dose and onset of the next is one goal. The other goal is the correct amount of insulin in the dose.

How they work is what makes them last longer. Lantus forms a clump (precipitate) under the skin that breaks down into smaller (hexamers) and smaller (dimers) clumps and finally to monomers that can penetrate the capillary membrane. Levemir binds to albumin under the skin and in the blood stream making it unavailable. The binding to albumin is “reversible” meaning it will unbind over time. Insulin is usable in the monomer/unbound forms.

These characteristics cause there to be a "usable" amount and an "unusable" amount of insulin once injected. Both insulins have a process of slowly breaking down unusable insulin into insulin monomers (usable insulin molecules). If the body needs more insulin than is available it runs out of the usable insulin and BGs run high. Conversely, needing less insulin than is circulating would cause the BG to drop low. Getting the right dose is a balancing act specific to that particular cat.

Where there is overlap of dose action is where you have to be careful and "find the balance". If you wait too long, or the cat’s insulin needs are greater than the amount dosed, the previous dose is all gone and the new dose takes time to "get up to speed" leaving a window of opportunity for BGs to climb. This was always the problem with the fast and moderate acting insulins. On the other hand, if you shoot early you are creating a longer overlap and a potential for that dose to peak before the previous one has faded enough – or is you shoot too much – you are risking lower than desired BGs. There is no shed or depot. There is only an overlap of insulin action to balance. If PZI or vetsulin lasted longer, or were shot more often, they would have overlap too.

As to “depot” as it applies to a long-acting drug, this isn’t a “thing” or single “place” you fill and refill, top-off, or what have you. It’s is a descriptor for the mechanism of action of these drugs: a drug that is injected to be slowly absorbed. The deposit of insulin stays under the skin, not immediately absorbed, and will last only for a certain amount of time - determined by factors such as body temp, hydration, exercise, metabolism, etc. – then it is gone. This process repeats each time you inject the insulin. Yes, there could (and should be) be a new dose injected before the previous one is totally absorbed – that is overlap.

I still maintain that there is no such thing as an insulin depot that is a single entity/place/vessel/tank to be filled or build up, whatever you want to call it. The insulin depot is only the most recent dose you gave sitting under the skin.

 

Good thread. I am going to add onto this thread just a little bit. What Sheila said:

Addressing the absorption part, as I understand it, the rate of absorption is also determined by the amount of insulin injected. This was referred to a couple of times on the old board. Copied from Dr. Bernstein's book:

"When you inject insulin, not all of it reaches your bloodstream. Research has shown that there's a level of uncertainty as to just how much absorption of insulin actually takes place. The more insulin you use, the greater the level of uncertainty.

When you inject insulin, you're putting beneath your skin a substance that isn't, according to your immune system's way of seeing things, supposed to be there. So a portion of it will be destroyed as a foreign substance before it can reach the bloodstream. The amount that the body can destroy depends on several factors. First is how big a dose you inject. The bigger the dose, the more inflammation and irritation you cause, and the more of a "red flag" you send up to your immune system. Other factors include the depth, speed, and location of your injection.

Your injections will naturally vary from one time to the next. Even the most fastidious person will unconsciously alter minor things in the injection process from day to day. So the amount of insulin that gets into your bloodstream is always going to have some variability. The bigger the dose, the bigger the variation."

Also here:

Why Smaller Shots of Insulin Get Absorbed Faster, Peak Sooner, and Are Out of Your System Quicker
Scott King
Nov 28, 2007

Note: refer to the link for the graphic:

http://www.diabeteshealth.com/read/...ak-sooner-and-are-out-of-your-system-quicker/


For my contribution this month, I wanted to share an important lesson I learned about twenty years ago from Peggy Wong at the UCSF Diabetes Teaching Center. It concerns how long insulin lasts after you push down that plunger and create a "depot" of insulin under your skin.

We know a shot of insulin does not make a perfect sphere when injected, but it does create a pool of insulin in the subcutaneous tissue that approximates a ball or sphere. After the insulin is injected, it starts to be absorbed by the tissue it actually contacts. As you will see from the formulas and examples below, the larger the shot, the more time it takes to be absorbed by your body.

In the chart below, we have calculated the volume and surface area for seven different-sized injections. You might remember from a past math class that the radius of a sphere is the distance from the center to the surface of the sphere. The chart shows that as the radius (r) grows, the amount of surface area in relation to the volume gets smaller and smaller.

For example, let's say you test your blood sugar and it is 220 mg/dl. You decide that you need 4 units of insulin to bring it back to 100 mg/dl.

Let's look at the chart to see the difference between taking one shot of 4 units versus taking four shots of 1 unit. Both provide equal amounts of insulin.

With the 4-unit shot, there is only approximately 0.6 mm of surface area available for the insulin to "escape" into the surrounding tissues. With four shots of 1 unit each, there is actually 0.96 mm of surface area - about fifty percent more!

So which one do you think is going to hit the blood faster? Yes, the one with the most surface area. In fact, I have had healthcare pros recommend splitting up a dose like this to get a high blood sugar down. And one of the syringe makers once explored the possibility of making a "sprinkler" syringe, in which the insulin would come out of holes up and down the shaft of the needle, creating many small depots and, therefore, faster absorption.

Sphere
Volume = 4/3 ?r3
Surface = 4?r2
units of insulin* surface area
in mm squared
1 0.24
2 0.38
4 0.60
8 0.95
16 1.52
32 2.41
64 3.82
*1 unit of insulin is .01 ml

Looking at the chart, you can see that as the shot gets larger, there is less and less surface area as compared to the volume of the shot. This forces the insulin to wait longer to be absorbed, because the insulin molecules in the middle of the injected ball won't come into contact with the tissue until the insulin molecules surrounding them get absorbed first.

Another problem with large shots is variability in absorption. The larger the injected ball of insulin, the longer it will be there, and, therefore, the more unpredictable it becomes. Absorption is affected by body movement, which can hasten absorption, and by changing temperatures, both within the body and in the environment outside the body. Hot tubs, for instance, speed up absorption. If you get into a hot tub after taking a large shot, more insulin is mobilized by the heat than would be after a small shot.

I feel that all insulin users should try to understand as much as they can about this powerful, wonderful, lifesaving drug. So it is crucial to understand the mechanics of how insulin is absorbed. I hope that this little math lesson helps."

I know you guys know this. You have probably seen this article a hundred times. But my question is, it is so very easy to quote things, and say it is true, but who knows what is really happening when dosing cats on an individual basis?

I love that people help each other on the ISG's, to a certain extent, but do you really know what really happens on a day to day basis with these cats?

Also, as a side note, because I see this mentioned all the time, that "it is a hormone, not a drug' (that is injected). This would depend on the type and makeup of the insulin, but it is a drug....not saying that is bad thing per se, but I just see this said a lot (correct me if I am wrong, no problem).

And Sienne, you said not to listen to people who's spreadsheet is not up to date. I agree with you!!! And I am guilty. Dang, I am always apologizing for that.

 

Not sure what you mean here - or what your point is? Should we not help if we don't know what really happens day to day? I'm confused by that comment.

I disagree that it is a drug. see below from: http://medical-dictionary.thefreedictionary.com/exogenous insulin

Or maybe it is both, but it is definitely a hormone and acts like a hormone in the body.

 

Here's a question I haven't heard answered, or maybe I just haven't seen it answered. Why isn't it available "now"? How long until it can be used? How much later? Is is some kind of biological process that has to happen once it is injected before the body can use it? And how long will it just sit "unused"?
What has perplexed me, just from following along in some condos, is that it seems to take several days or cycles for the "shed" (that's the word that is used most often" to fill, but it seems to get drained much faster when someone has to give a shot late, or has a fur shot for instance. I don't understand the whole "timing" thing. If people like me understood the timing of how the L's work, we'd have an easier time grasping how the insulin works. I find it extremely frustrating to "not get it" even though I have been trying to for a year. I don't use them, probably never will need to, but I'd sure like to at least understand it so I can answer simple questions without sounding stupid or having to seek out someone to answer a simple question (in Health mostly).
Please don't tell me "it's an ECID thing". EVERYTHING is an ECID thing. :smile:
Sheila's explanation, I understood. But it sounds like lots of people are saying it's not right. So I'm still clueless...

Thanks,
Carl

 

Carl, I don't think it is true that "98% of the insulin I just shot is not available for use right now..." and that it "...will be waiting to be used later."

With both insulins their design creates a time release-type action in order to extend duration. To me that means they start working (getting usable monomers into the blood stream) right away, but the effect doesn't peak until sometime later - say 6-10 hours - and then it wanes over the next several hours probably well past the next shot time where THAT dose starts the process all over again.

Unfortunately, there is no way to time this out. In humans there are studies that try and present that information. Here is a chart from the Levemir product insert:

I have a PDF file of it, I assume it is available on their website.

Here are the Levemir and Lantus 24 hour "curves":

From: http://dtc.ucsf.edu/types-of-diabet...lin-therapy/types-of-insulin/insulin-analogs/

I took the levemir part of the that and overlapped it at 12 hour intervals:


Those 24 hr curves are also representing the action in humans, so the actual duration is probably less in cats - although that peak point seems to be in the right place for cats....

As previously posted in this thread, there are many factors that effect the rate of absorption so it is a matter of ECID to a certain extent. You are trying to reach an equilibrium of sorts where the dose you shoot provides the amount of circulating and available insulin, for as much of the 12 hours as possible, so the BGs are as stable as possible. The fact that we still see higher PSs and lower nadirs means there IS fading out of each dose every 12 hours.

People might be disagreeing with me, but all I am trying to do is explain how these insulins work so that anyone can understand it and then make decisions about how to change doses for their cat based on its numbers and that patterns in the numbers. I have never felt that the popular concept of a depot/shed made sense or explained what was really happening with these insulins.

(on a interesting note, if you google "how does levemir work" and look at images, there is a picture of Beau!)

 

Very interesting thread with way too much info to absorb at one read. I am bookmarking this.

Thank you all for sharing your knowledge.

Suze