Newly designed 'smart' insulin could improve type 1 diabetes treatment
sciencealert.com
sciencealert.com
From my perspective though, being a T1, what I want is an even faster acting insulin than we already have, with a shorter "on" time.
To explain: the shortest acting insulins we have right now take effect about 30 minutes after injection. Then the dose stays active for about 4 hours. So for me to react to a high blood sugar, and until I can be certain that I did not inject too much (nor too little), can take up to 4 hours.
That is almost unbearably long, especially when my blood sugar climbs through the roof, and I am not sure whether it is because my pump line was blocked. Overloading on insulin (called "stacking") to compensate for a crazy high blood sugar can be very dangerous - plus I can't think straight when my sugar is that high. Nothing sucks more than having to sit and wait for a high blood sugar to come down...
Contrast that lagged response time to eating food, especially high GI sugars such as a soft drink, orange juice, or even bread. This can spike my insulin in a matter of minutes.
All this makes matching sugar spikes with insulin response curves very hard; it is a one-side-overdamped-and-other-side-underdamped dynamic system. Any diabetic will tell you how crazy a "roller coaster ride" can be, which is what happens when you overcompensate on either end.
To get back to the topic of the 'smart' insulin: if this research can lead to an insulin that can always be in my bloodstream, ready to act when my blood sugar rises, and stop when my blood sugar falls, and if it can do this quick enough, then that would be a game changer.
> It's not for diabetes emergencies such as diabetic ketoacidosis (DKA).
So probably not great for this. Seems more like something you take during a meal to keep from going hyperglycemic and not something you take when you're having problems.
To be fair, I have only gone into DKA once, when I was diagnosed, so it was certainly an extreme - but, I would guess most people who end up in DKA also have some kind of extreme.
I share your wish in your last paragraph very much!
If we had insulin that was say.. 1000 units/mL (10x stronger) and didn't degrade as fast, then we could have some really cool and slim devices. You could also have a longer lasting pump site.
This would be the ideal - in a way it would be better than functioning pancreas - because pancreas needs a few minutes before releasing insuline and this would act instantly.
I will say this, though. The CGM (continuous glucose monitor) was one of the best things to help me regulate my blood sugars - even though insurance hates to cover it from time to time (not always - it's weird). As a person who has a tendency to suffer from extreme lows, I'm excited for this new "hinged" insulin, should it make it to market.
I couldn't agree more. I rave about my CGM, even with it's flaws.
- A little bit more confidence that I'll know when my blood is low, especially when sleeping
- Being able to check my blood sugar with 0 effort. I don't even mind poking holes in my fingers that much, but the difference between "get up, go downstairs, test blood, come back, get back into what I was doing" and "look at my phone" is HUGE. I "check my blood" dozens of times a day now, because it takes no effort.
- The chart, being able to see where my blood has been every 5 minutes over the past timeframe, is fantastic. I can see not only where it is but how it got there.
- Because I check my blood so often, I've gotten a better "feel" for how my blood is impacted by different things.
- Being able to go online and see the graphs of my blood sugar over timesframes over months... Once again, it just adds more information to understanding of my body and blood sugars.
The CGM "transforms", in every sense of the word, my ability to regulate my blood sugars.
Direct PDF link: https://www.pnas.org/content/pnas/118/30/e2103518118.full.pd...
The sciencealert page is a digest of the author’s university’s digest. The papers themselves are usually much better material. Quite understandable in my experience.
That said, as someone in a relationship with autoimmune diabetes, I hope this work comes to fruition. It’s obviously a good idea to try to research and develop this further.
As the article explains, the main risk of insulin use is hypoglycemia, which is essentially the result of an insulin overdose. When you dose insulin, you have to carefully match it to the carbohydrates you subsequently consume and the glucose your liver secretes. Too little insulin and you will have high blood glucose, too much and you will suffer low glucose. Highs are uncomfortable and risky long term, but lows are very uncomfortable and immediately dangerous.
For insulin to stop working once your glucose got to 75-80 would be perfect. If the insulin also stayed there and activated as soon as your glucose went up, that might be even better than having a fully functional pancreas.
It would be cool!, but I’d go for the pancreas: As far as I know, the pancreas releases insulin in pulses. Each pulse 3-5 minutes after the other? The pulses seem to matter. Supposedly the loading-unloading cycle on the insulin receptor seems to help prevent insulin resistance. (It does somehow make intuitive sense to “shake” cells’ sensors a bit to help them stay on target.)
Another thing is C-peptide. It’s a “byproduct” of the insulin protein folding in the pancreatic cell. I believe C-peptide is now known to be a biologically active control molecule with antiinflammatory properties.
Source: The Wikipedia page on insulin iirc. I an only a layman and may be severely mistaken about all of this.
Sure, it's complex.
People with type 1 don't have any insulin production at all, and typically get it in large doses (syringe) that absorb slowly or dripped out from a pump. With no endogenous production, we do not make c-peptide (it's a protein or something cleaved off of pro-insulin in the body's synthesis of insulin. Levels are measured in blood tests to determine your level of insulin production - after honeymoon period, type 1s produce no insulin and therefore no c-peptide).
I’m intimately familiar with Type 1 diabetes. I find the nuances of what the pancreas does to be quite fascinating, and the closer we get to understanding what matters and to replicating it, the better.
I believe that one wants the pulsatile secretion as well as C-peptide.
There are some recent results on C-peptide as far as I know. I believe there is still a noteworthy amount of C-peptide after the honeymoon, and I believe it is good to try to prolong the honeymoon as long as possible to retain as much C-peptide functionality as possible.
C-peptide is an active signaling molecule. It makes sense: The body produces a complex and easily identifiable protein chain as a byproduct of the crucial insulin molecule. C-peptide is more stable than insulin itself and remains a bit longer in the body. It stands to reason that the ancient and highly-preserved evolutionary function of insulin metabolism has picked up a good use for C-peptide as a signal carrier on the way.
That pulsing secretion could be achieved with a pump. Maybe they already do it?
I have LADA, which is known for a very long, gradual honeymoon period. I've looked into the studies intended to prolong function but they involve immune suppressants, as far as I can tell, which doesn't seem like a great idea in the Covid age.
I'm not so sure about that. Insulin does more than just regulate blood glucose levels; it also affects fat metabolism, potassium levels, and many other things. If the insulin "turned off" completely we could see patients who went into ketoacidosis as a result of fasting and/or exercise.
Type 1 diabetics typically take two different insulins. One is a 'long acting' that slowly absorbs over 16-24 hours, like what would be called time-release for oral medication. This insulin provides for metabolic function and counteracts the glucose your liver unpredictably and uncontrollably releases at certain times. People with pumps drip regular insulin at a slow rate for the same effect. I assume nothing would change there.
The other type is called 'fast acting' or bolus insulin. This is taken usually in one large dose prior to meals to handle the large rise in blood glucose that follows carbohydrate consumption. The insulin we are discussing here is a replacement for fast acting insulin.
The -ideal- situation for fast acting is for it all to be consumed at the end of digestion. You want fast acting to match 1:1 with the carbohydrates you ingest, every time, with none left to cause hypoglycemia (overdose). other metabolic needs are already handle by the pump drip/long-acting. This innovation would remove the danger of overshooting the insulin dosage and causing hypoglycemia, which is huge.
Ketoacidosis is typically associated with hyperglycemia. It happens when your body has no insulin. There is what's called euglycemic ketoacidosis but it's rare. In typical ketoacidosis, your blood is very high in glucose, but lacking insulin, your cells have no way to obtain it. Since your body cannot get energy out of your blood in the normal fashion it starts to digest ketones, which acidifies the blood and creates many harmful effects.
In the situation we are discussing, when your glucose rises above 75 from food or liver secretion, the novel insulin would start working, preventing ketoacidosis.
Get another two decades of experience and then we can talk.
It's entirely possible to have blood glucose below 70 mg/dL without having "too much insulin"; healthy adults routinely fall below this level during periods of metabolic starvation. At such times, the body is in a state of ketosis -- this is normal and healthy! -- but as long as there's enough insulin (which there is, in healthy adults) this does not result in acidosis. When A.B. fasted for 382 days, his blood glucose levels stabilized around 30 mg/dL while he remained ambulant.
Ketoacidosis is not so much caused by hyperglycaemia as it is co-occuring as a result of hypoinsulinaemia.
In the meantime, I am not an expert and am quite willing to be informed. I generally assume that other people in a general discussion audience are not familiar with diabetes treatment or biology at all. If you are, that’s great.
I have not heard of healthy states of hypoglycemia before, other than that many people naturally experience it during sleep. I have a friend whose mother suffers from hypoglycemia and she suffers the same ill effects as it how 1 diabetics commonly experience. I am aware that other metabolic causes exist for blood glucose levels to be reduced besides insulin.
Do you mean metabolic ketosis, the type that people try to achieve intentionally through diet? I am aware that states of ketosis exist without acidosis, such as that one. I’m not intimately familiar with the biological details.
Yes, I am aware that ketoacidosis is caused by a complete lack of insulin, and the complete lack of insulin leads to hyperglycemia, not some other causative relationship.
I'm guessing reactive hypoglycaemia? That's caused by the body overproducing insulin in response to meals; it's also believed to be a common prologue to T2D since it "trains" the body to be less sensitive to the (over)produced insulin.
No surprise that hypoglycaemia resulting from an excess of insulin is similar to hypoglycaemia resulting from an excess of insulin!
I’m not sure what you’re trying to tell me about these edge cases of hypoglycemia. I feel like I did a reasonable job describing how it works for individuals on insulin therapy.
I have not found much in medical literature that says hypoglycemia is anything other than abnormal and dangerous condition that should be treated immediately.
This study starts out with the lines, for example, “Among otherwise healthy adults, there is a subgroup of individuals who develop symptoms of hypoglycemia during episodes of food restriction.”
https://www.nature.com/articles/1602785
It appears these medical researchers do not consider hypoglycemia during periods of fasting normal or healthy.
To be clear: I don't know a lot about insulin. I'm fortunate enough not to be diabetic. So there may have been useful advancements in insulin. The price of insulin in the US does seem to be awfully high however.
It is a common practice for pharmaceutical companies to alter the active molecule in some way, claim the new version has benefits, reset the patent timeline and stop producing the old version.
EDIT: in case it wasn't clear, if this is actually good for diabetics, that's fantastic. Insulin in the US shouldn't be as expensive as it is. I'm just seen too much profiteering (eg Epipen) by that industry.
To explain, currently your pancreas is measuring your blood sugar and producing more or less insulin to keep it at a safe level (let's call that level "100"). A type 1 diabetic has to do that process manually, measuring their blood sugar with a device and taking enough insulin via needle to keep it at 100. It's possible to overshoot and have blood sugar go far below 100, which can do real damage to cells that need sugar as an energy source. Obviously if you have to measure and adjust several times a day, every day, even a 1% human error rate is going to come up often.
This theoretical insulin would stop working if there wasn't sufficient sugar already in the blood. As another comment said, it would basically stop working if your blood sugar was below 75 or 80. Right now diabetics are at risk from blood sugar being too high OR too low. This would cut out half of that risk, and be life changing for millions of people.
Has nothing to do with price, and as always I must mention that generic insulin is abundant and readily available at low prices to anyone. I don't expect everyone to follow the details of insulin and having diabetes. But it would be nice if medical advancements could be discussed without people conflating the topics with their pet political issues.
> So there may have been useful advancements in insulin
There have been massive advancements in insulin over the past couple of decades. Today's long acting and short acting insulins are a massive improvement over the older kinds. The price of insulin in the US is a disaster (when not covered by insurance), but otherwise the quality of insulin treatment is better than it's ever been.
They aren’t. https://www.rand.org/pubs/research_reports/RRA788-1.html:
“Although the ratio of U.S. to other-country prices varied depending on the comparison country and insulin category, U.S. prices were always higher (often five to ten times higher) than those in other countries.“
“Other countries” includes Canada and Germany, so they didn’t look at particularly poor countries. The linked PDF says
“The average U.S. manufacturer price per standard unit across all insulins was $98.70, compared with $6.94 in Australia, $12.00 in Canada, $7.52 in the United Kingdom, and $8.81 across all non-U.S. OECD countries combined”
Low prices could come from either a) a robust, competitive market in producing and selling insulin or b) governmental price controls. The USA explicitly chooses not to have either. Other countries typically choose b) backed up by a threat of a) (if you're a pain in the ass over our negotiated price controls, we'll go source a large supply of insulin from somewhere else).
That’s either a gross misunderstanding or deliberate misinformation. There is both price negotiations and significant rebates negotiated by pharmacy benefits managers who will often make 75% of the profit on the sale of the drugs back as rebates. They then distribute that back to insurers and other parties. Sadly those enormous rebates don’t seem to reach or benefit the patients.
Only for folks using the latest and greatest in closed-loop pump therapy is there even an approximation of the pancreas function to elevate insulin levels in response to elevated blood glucose levels, and even then its too slow to be effective. Diabetics that want to closely manage their blood glucose levels have to carefully plan how they eat and how active they are, modulo sickness, periods/etc.
If it was possible to have a latent insulin bolus floating around the bloodstream that could react to gluecose directly, it could provide an important buffer and possibly even a wonderfully passive approach to therapy vs. the ridiculous dance that patients undergo today.