Variability in insulin action

I’m Dr. Ralph Abraham, consultant in diabetes at the London Diabetes Centre.

And today, I’d like to talk to you about the variabilities of insulin action in patients who need to take insulin for diabetes. Much of my time in consultations with patients is involved with assessing their glucose control when they’re taking insulin injections, and helping them improve it. I have patients who have absolutely immaculate blood glucose profiles, so much so that one would question whether you could detect that they actually have diabetes. And they are people who take multiple insulin injections every day. And yet, the great majority of people who use insulin have great difficulty. And despite many of them being very experienced, and putting a lot of effort, and knowledge and education programs in their practice, they still show widely varying glucose excursions, particularly after food, but also when they’re asleep.

So, if you inject the same dose of insulin into your skin, in exactly the same way, in a fresh site every day, you would expect to get an identical glucose response, but you don’t. And they’re often wildly different. So I’m going to show you a trace from a patient and this is the sort of thing that we regularly see.

And I hope you can see this in front of you now, these are four days of a patient who takes the same amount of long acting insulin every night before she goes to bed, about 11 o’clock. And can you can see that on Thursday, it’s almost as though that insulin didn’t work because her blood sugar’s rising. On Wednesday, she seems to have a very good response, and it’s coming down, so she has a normal blood sugar by four o’clock in the morning. On Tuesday, again, it seems that her insulin don’t seem to work at all. And on Monday, it seems she started over flowing state normal, which is probably what you would expect a lone acting insulin to do.

So this video today is going to take you through the possible reasons for this. And I think it’s important that every patient begins to understand why it can be more complex than perhaps your healthcare professional makes you believe.

First of all, it’s important to emphasize that once you’ve passed your first grade, with basic education, you will learn that the response of your blood glucose to insulin, and the level of your blood defects is not only related to food and your insulin dose. It’s much more complicated than that, and I want to discuss the various reasons why glucose control can be effortlessly achieved if you’re an intensive care patient in hospital getting your insulin through your vein. Not eating, normal food and being passive and lying in the bed and not doing anything. The moment you have normal living and you’re taking subcutaneous injections and eating food, all hell breaks loose.

So the same dose of subcutaneous injected insulin can have different blood glucose effects in different patients. The scientists will call it between patient variability. If you take the same insulin injected into different people, you will get completely different responses, everyone’s not the same.

Insulin resistance varies with different persons. It varies with the amount of fat you have on your abdomen. The amount of exercise you do, with your body weight, with your genes, with your stress levels. And insulin resistance is very well studied and understood in type two diabetes. And so we knew that there are genetic, weights, stress and activity factors, all of which play an important part.

However, in day to day life in one patient, that’s you. This is unlikely to be a major factor in long term control as you’re the same every day. And most of the factors that impact on an individual patient’s response to glucose do not change much from day to day. So while between patient variability might be a great importance to a pharmaceutical company, it’s less relevant to you as the patient. Now this is not the case within patient variability. Because the blood glucose response to the same insulin dose injected on different occasions can be different. And some of the factors involved, the type of insulin you use, the injection site, the technique, the temperature, the exercise level concurrently, stress levels concurrently, whether the correct dose is used every time and the time that the dose is given. So it’s not straightforward or simple.

Let’s start with the type of insulin. Once insulin is injected into the skin, unlike what happens when it’s injected into a vein directly into your blood. It congregates into groups of six molecules called X-hormones. And these are not active when they’re clumped together in groups of six. They have to dissociate in the skin into single molecules before they can be absorbed and become biologically active. This actually slows down the action of insulin in the skin. And the speed at which this dissociation happens is influenced by heat and blood flow. So there’s a world of difference between sitting on a beach in the Caribbean and skiing in the Alps in the middle of winter, you absorption is going to be several orders of magnitude difference.

Blood flow also influences insulin absorption. If blood flow is stimulated by exercise, then you’re going to get faster insulin. Actually preventing the dissociation of X-hormones, or even preventing the formation X-hormones is an avenue of approach pharmaceutical companies are using in order to change the absorption characteristics of insulin. So there is variability and absorption.

And what is not widely appreciated is exactly how big this is. It can be up to 25% within patients and actually as much as 50% between patients. Well, that’s enormous, that’s huge. The variability is higher for some insulins, and over the last 30 or 40 years insulin manufacturers have improved the characteristics of insulins so that this between patient variability is not so extensive. Older isophane insulins and lente insulins which some of you may remember  were very, very poor. But even soluble insulins, and non-soluble insulins medicines vary between 21% and 44% between patients, and 13% to 20% within a single patient. The best long acting insulin currently is Detemir, which is better than Glargine and which is better than the older isophane insulins. But of course, with this improved reliability comes a shorter duration of action. And there’s variability in the action of these insulins, which vary according to injection technique, the angle at which the needle goes into the skin, varying rates of food absorption, vary from one person to another, and which vary between different types of food.

What are the factors that influence the action of insulin in the skin? One of the most important is insulin sensitivity. When I said that we’re all very variable in our response, one of the reasons is the varying degrees of insulin resistance, that means the varying ways in which a person responds to a given dose of insulin. The most powerful is the level of underlying insulin resistance or it’s converse insulin sensitivity. This is affected by time of day, by concomitant hormone levels, by your wight, by exercise levels, hormone levels. Cortisol and adrenaline are stress hormones, they go up if you’re ill. So when you’re ill, you need more insulin than when you’re not hill. When you’re stressed, you need more insulin, than when you’re not stressed. And at the time of the menses and after the menopause, female hormone levels are at their lowest. And therefore, there’s a huge difference between insulin requirements in the middle of the menstrual cycle, and at the end insulin absorption itself is influenced by patient related factors and the properties of the insulin you use. So the patient related factors are where you inject. Most patients thought a long time ago, will do their insulin injection in a parallel, you’ve got to see my arm here, of their arm.

Got the screen so that you can see what happens when my arm is here is pushed into say my tummy or into my leg, and the radius of the arm determines where the insulin injection goes because it’s most convenient. But the result of that is that the person puts the injection into the same spot every time. And if you’ve done that for 30 years, you’ll find your skin is hard, and bruised, and insulin doesn’t get absorbed from there.

So you’ve got to use fresh site injection. Your depth of injection is important, although much less important now that we have four millimeter, and even most people will use five millimeter needles. So your injection is nearly always into subcutaneous tissue. But if it is into muscle because you have no subcutaneous tissue which is very thin, then of course, the insulin is absorbed much faster.

And again, temperature is very, very important. As I explained, if you live in a hot tropical country, absorption is much faster than it is perhaps in a temperate country. So when I have patients who showed me different responses to insulin when they come from back home, which is a hot tropical country, and then they show me what’s happening to them in London, you’ve got to understand that ambient temperature plays a big row. Massage, lots of patients have massage. Orthostatic movement, where they are upright or they are lying down or influence absorption and dispersion of the insulin from its depot where it has been injected.

A long time ago, we used to have types of insulin that required shaking and mixing properly, this was never or rarely done properly by patients. And fortunately, this is not a problem. We have much at the moment in the current day. Even the introduction of pens took away a huge error in dosing which used to occur with syringes. If people used to have to take small amounts of insulin and they had a cataract, they could never be sure that their insulin dose from time to time wouldn’t vary by 100% or 200%, or 300%.

And I do hope that with voice memos, with control with smartphones, that even if people were poorly sighted, they could guarantee that with modern technology dosing would be accurate and we would never have to worry about the fact that somebody thought they were taking six units of insulin that might have been taking anything between 2 and 20 units of insulin.

So once you’ve got rid of the bubbles, once you’re sure that you know that the right amount of insulin is being taken, once you know that you need a fresh sight and temperatures controlled. Do you still get errors? And yes, you do. And these errors really are probably not controlled. And it’s very important that patients realize that maybe they shouldn’t seek for … , because technically once you injection to the skin, you introduce error, and if you’re going to avoid that error, you actually have to change where insulin is injected, and how it’s injected.

So does any of this matter, was it just another search for perfection from your diabetes doctor? I’m afraid it does matter. There’s been a lot of research into the differences between populations that have great variability in their glucose excursions. You know that that glucose ups and downs look like the MLS, and comparing them with patients are very obsessive about their diabetes and have virtually flat glucose preference. Variability in sciences is often assessed as a coefficient of variation. And if you take the fasting glucose, so you’re taking out of the equation, different amounts of food taken by patients, then there’s lots of evidence that mortality statistics are much less in patients whose fasting glucose is less variable. So it clearly matters to be able to get less variability in your glucose responses. The best way of doing that is going to be with continuous insulin infusions and a closed loop solution. That means wearing a sensor and a pump all the time and that’s the way modern diabetes is going.

But for those of you who don’t want to change or cannot change, unable to change, it’s important that you understand how complex glucose responses to an insulin injections are. And how injections into the skin are a proxy approximation to what happens in a normal person whose insulin is secreted from the pancreas, goes directly to the liver in the bloodstream, and doesn’t have any of the problems that people who do injections of insulin have. So don’t be too hard on yourself, understand that you can do lots to help yourself. But lots also comes down to the method and way in which insulin is injected into the skin. So Thank you for listening to me, stuck around for a while here.