Meal Bolusing Challenges
One of the most frustrating and difficult aspects of managing diabetes is meal bolusing.
Even when you accurately count carbs, remember to bolus 20 to 40 minutes before the meal, and account for factors like fat and protein content, it can still be impossible to avoid that post-meal spike.
You might be right if you’ve ever felt that the tools you are using are the problem.
Current fast-acting insulins, even those touted as being super-fast acting, come up desperately short when compared to the activation speeds of insulin produced by a healthy pancreas.
Researchers from Stanford University think they may have finally developed an ultrafast acting insulin that can compete with native insulin and battle post-meal glucose spikes with the same degree of efficiency.
In this article, we’ll take a look at the problems associated with creating a truly rapid-acting insulin and how these scientists, whose research was recently published in Science Translational Medicine, have overcome these issues to make what may be the most effective mealtime insulin to date.
Insulin’s Shape Determines Its Speed of Activation
In a diabetes-free body:
- Insulin is created and stored as a hexamer–a compact unit of six insulin molecules. This polymer is very stable but inactive.
- Once blood glucose levels begin to rise, such as after a meal, these inactive hexamers are transformed into activated monomers–single insulin molecules–that can be quickly utilized by cells to move glucose out of the bloodstream.
- Insulin levels peak at around 30 minutes after a meal. This fast activation time prevents glucose from building up in the blood and typically keeps blood sugar levels below 140 mg/dL.
For people who rely on exogenous insulin to stabilize post-meal sugars, it takes much longer for insulin levels to peak.
- The fastest acting insulin currently on the market, Fiasp, begins working in as little as 15 minutes but doesn’t fully peak until 60 to 120 minutes after it is taken.
- Humalog, the most common rapid-acting insulin, takes closer to 90 minutes to peak. (You can learn more about different insulin activation times here.)
This delayed peak occurs because current insulins contain very few monomers in their makeup.
And the hexamers and dimers in their formulation must undergo activation within the body before they can start working to lower blood glucose levels, a process that takes a significant amount of time.
The Problem with Unstable Monomers
As you might have guessed, there is a reason that current insulins are made up almost exclusively of inactive insulin polymers.
Unlike polymeric insulin, monomeric insulin is unstable and will quickly breakdown if not utilized within a short period of time.
This factor isn’t an issue for insulin activated on an as-needed basis within the body, but it is a huge problem for insulin produced in a lab and stored in vials for future use.
When insulin monomers are exposed to heat, oxygen, and even chemicals found in plastics, they elongate and form clumps known as fibrils. Insulin fibrillation not only permanently deactivates these insulin molecules, but also causes blockages in pump tubing, swelling at injection sites, and other complications that further reduce the effectiveness of the insulin.
Even with a formulation that consists primarily of more stable insulin polymers, stress-tests have shown that Humalog insulin only remains stable for about 5 hours when exposed to stressed aging conditions.
If even ‘stable’ insulin is so fragile in the face of heat, oxygen, and other factors, it is easy to see why scientists have long stayed away from monomeric insulin formulations despite the obvious advantage of quicker activation times.
‘Magic Fairy Dust’ and Polymer Technology
Despite stability challenges, the idea of an insulin made entirely of activated, ready-to-use insulin monomers is a hugely appealing concept.
And that is why the researchers out of Stanford pursued their new UltraFast Absorbing insulin Lispro (UFAL).
This insulin is made entirely out of insulin monomers and has a peak activation time of 9 minutes, which equates to a four-fold decrease in the amount of time it takes for this insulin to reach peak levels within the body.
Of course, the issue with a monomeric insulin was never going to be with activation time, but with stability.
To counteract the tendency of insulin monomers to form fibrils and become inactive, the researchers started experimenting with a large number of custom polymers meant to create a barrier between the insulin monomers to prevent aggregation.
After hundreds of failed attempts, the team finally found a polymer they could add to the insulin solution that would effectively stop fibrillation without affecting the ability of the insulin to quickly lower blood sugar.
This ‘magic fairy dust’ not only prevented the quick degradation of the insulin monomers but proved to stabilize them far beyond even what is possible for hexamer insulin solutions. While Humalog destabilizes at about 5 hours under stressful conditions, this new formula remains stable for over 24 hours.
A Gamechanger for All People with Diabetes
A truly ultrafast acting insulin such as UFAL could be a gamechanger for the millions of type 1s who struggle with post-meal blood sugar spikes due to the difficulties associated with taking insulin so far ahead of eating a meal.
Every T1 person would certainly benefit from a mealtime insulin that more closely replicated the natural function of a healthy pancreas while also being more stable in the face of heat, oxygen, and other factors.
Also it would be great if children, those with cognitive and other disabilities, and people who struggle with digestive and eating disorders could take insulin after eating and still prevent dangerous blood glucose spikes.
As you would expect, this new ultrafast insulin is still a ways from hitting the market.
Early trials using pigs and rats have shown huge promise for this new monomeric insulin but more tests and eventual human trials will need to be completed before it becomes available to the public.