You need to move forward, and therefore must occasionally have a foot on the gas (insulin). The gas pedal failing, causing you to stop moving forward, is not urgently dangerous (hyperglycemia). However, if your brakes (glucagon) can sometimes fail completely, that could cause you to die almost immediately if you're moving too fast toward danger (extreme hypoglycemia). Given this situation where brakes are unreliable, do you want your automated control system to rely on them and push you to dangerous speeds?

Even in this framing, it still feels like an extraordinarily valuable addition, and relatively low risk. It's also, of course, more to add to the patient's maintenance, but might help them or their caregivers sleep at night.

I agree with all that you've said, and this point in particular is extremely important. It's also the reason I moved from a DIY system like the one mentioned here, to a commercial system, once the latter was available. There is simply less hardware and software to juggle with the commercial system. There are fewer knobs, bells, and whistles, meaning I might not be able to tweak things to be in as tight control as might be possible with a DIY system (though with risks!), but overall it's been "good enough" for me, and greatly reduces the cognitive burden of having T1D. My experience clearly doesn't match everyone's, but considering I'm typically someone who loves to tinker, and has plenty of T1D experience (engineer, 34 years with T1D), I'm sure I'm far from the only one that feels this way. My glycemic control isn't significantly better than it was when I did it via constant monitoring and mental math, but the cognitive and emotional burden is much lower.

Failure detection is via alarms to trigger patient action based on the continuous glucose monitor (which has a different set of reliability issues) as well as patient symptoms.

Hypoglycemia becomes symptomatic long before blood sugar is low enough to result in death or serious debilitation and T1D patients know their symptoms well. The risks are not nearly as dramatic as you're suggesting as one isn't/shouldn't be relying on glucagon to prevent severe hypoglycemia, I don't think any system is designed or being conceived to operate in such conditions.

Hypoglycemia isn't really much of a problem anymore with current CGMs and pumps.

There is a what seems to be a significant number of people who don't "feel their lows."

> Hypoglycemia isn't really much of a problem anymore with current CGMs and pumps.

Current CGM's can still require hours of "warm up", and many current pumps still must be removed for things like swimming so they don't get penetrated with water.

Severe hypoglycemia to the point of what was described (death) is not reported in any of the recent device studies.

Level 2 or moderate hypoglycemia, very different from death, is reported at < 0.5% in recent closed loop system studies.

> Current CGM's can still require hours of "warm up", and many current pumps still must be removed for things like swimming so they don't get penetrated with water.

Current CGMs are water resistant but conveniently one is also not administering insulin while swimming either. The bionic pancreas is also dependent on CGMs and has the same limitations.

I'm really not sure what point you're getting at. Hypoglycemia is not what's being improved upon with current advancements, it's time in target.

Are there large-scale studies that show this for a dual hormone control algorithm (the context of this thread)?

Bihormonal pumps do not mean continuous infusions of both insulin and glucagon. The pumps pulse insulin when you're high and glucagon when you're low. They're not both administered at the same time or continuously infused in a "balanced state".

The context in this thread:

> However, if your brakes (glucagon) can sometimes fail completely

A bihormonal system would not result in more insulin being administered than an insulin-only system for a given blood sugar, if the glucagon pump fails we would have an insulin-only system where we have plenty of safety data. There is no mechanism by which a bihormonal system has higher risk of hypoglycemia than existing closed loop insulin system.

> In this case, you could be more aggressive in either direction of pushing BG, because you have a safety net.

Often times in an acute setting, yes. However patients who have had diabetes (T1 or T2) for a long time often lose a lot of their hypoglycemia sensitivity and symptoms. It's not nearly that simple.

How quickly does a glucagon shot trigger GNG and how quickly can GNG raise glucose levels?

Really happy to see that there are people now working on both gradients!

All the well-tested pumps (Tandem, Omnipod, Medtronic) are insulin-delivery only.

Tandem is working on a dual chambered pump.

https://diatribe.org/jdrf-and-tandem-diabetes-care-announce-...

It'll be a while before we see highly reliable and well-tested dual-reservoir systems is my bet.

The complexities of balancing insulin and glucagon in a two-pump system are also high. And the feedback loop from sensors that detect BGL aren't super fast. My kid's Dexcom works on a 5 minute sample loop now. So you can't make decisions fast and when you do, you can't course correct a bad decision quickly.

I love that people are working on this stuff. The folks at https://wearenotwaiting.net/ are amazing and we even use NightScout here, but the fragility of the systems are stark and it'll be a ways to go before it's not just the brave pioneers pushing these frontiers for T1Ds.

>I would have thought by now they'd have hacked 2 patch-pump AIDs to work simultaneously.

As you pointed out, the problem is not really hardware. It could technically be done in a straightforward way using two independently controlled insulin pumps, but the complexity and risk of the whole operation goes way up if you are taking way more insulin. Taking a bunch of insulin and glucagon at the same time is not necessarily a great idea either - they don't just annihilate each other without consequence and you could end up with secondary effects like gaining a bunch of weight.

>Because this feels like a holy grail / functional cure

Unfortunately it is not; even dual hormone systems have problems keeping up w/ the kinetics of glucose absorption and to address this there is also research into tri-hormonal systems, w/ amylin as the third hormone. In any case you will still need some a-priori info about meals and planned activities, though less so than with a single hormone system. Integration of exogenous data sources to provide this info to the APS is what we are working on at Replica.

Also, hate to be the bearer of bad news but beta bionics has shelved their dual hormone ambitions for now; their prototype device soon to be released is insulin-only. On the bright side there is a small Dutch company whose tech predates beta-bionics. They sell a dual hormone device and will give it to you for a ton of $ (and probably have you sign a bunch of waivers): https://www.inredadiabetic.nl/en/discover-the-ap/

Not necessarily, at least not via patient input. In the albeit small Inreda studies manual announcement of exercise and meals wasn't required (or an option). Medtronic also has a meal prediction algorithm on their newest offering that's a step towards a fully automated process and currently more or less obviates carb counting but isn't at the point where you don't have to announce a meal (yet).

Rather than integrating external data sources the algorithms are predicting based on historical glucose levels and/or insulin administration and it seems to be working.

https://jamanetwork.com/journals/jamasurgery/article-abstrac...

None of the systems claiming you don't have to do anything in terms of meal announcement are _working_ in the sense of achieving euglycemic parity, which should be the goal. I can say with certainty that the cgm logs from people who don't announce meals on the Inreda device do not look like they are from non-diabetics: there are still often large post-prandial spikes. Inreda likely does better than any single hormone system, but the problem is not solved in any sense.

I'm not going as far as to claim Medtronic's approach (I believe the only one commercially available with so-called meal prediction based on historical CGM and offers full correction boluses) is the optimal one, just that it is an approach that is at least very good (~80% time in target) and while it still requires meal announcements it's just the first step of what they're trying to do. Clearly we can expect further iterations of these algorithms as the technology matures.

> Inreda uses two identical CGMs for noise reduction purposes just so they can get clean data with less of a lag.

Just giving an example that this is possible without external input or data, your statement was that you will need a-priori information which is not necessarily the case. Whether such a system is optimal is a different question.

I haven't seen the raw data and highly doubt enough of it even exists for anyone to make a claim whether or not such a system can be optimized to the point necessary.

> None of the systems claiming you don't have to do anything in terms of meal announcement are _working_ in the sense of achieving euglycemic parity, which should be the goal.

For clarity to any less knowledgeable readers while time spent in euglycemia is a very important outcome measure it cannot come at the expense of severe hypoglycemia or severe hyperglycemia/diabetic ketoacidosis (i.e. an algorithm that improves euglycemia to 95% but has a 2% severe hypo time is less acceptable than 80% euglycemia and 0.5% severe hypo.)

To my knowledge no system on the market/generally available right now is claiming to be completely input free. The closest to my knowledge is again the MiniMed 780G discussed in my first point which will assuredly be iterated on.

Also to be clear I'm not being dismissive of what your company is working on, it's a very interesting and novel approach. It may even be necessary to achieve the optimal product. I look forward to reading about your results when you publish them. I'm just presenting alternatives and a brief overview of what other approaches are for HN readers who are likely unfamiliar with the topic being discussed.

For the record, when I say "Euglycemic Parity" what I really mean is a sort of Turing test (not time in range), where a data-driven Endocrinologist is asked to tell the difference between CGM records from a non-diabetic, and CGM records from a diabetic equipped with some control system. Passing this test should be our long term goal IMO and we will probably have to bring many techniques to bear to eventually achieve it.

The difference between how quickly food and insulin hit your bloodstream make it seem like there is no way to "algorithm your way out of" meal announcements. Food hits almost immediately, and with variable strength depending on macronutrients in it, and insulin takes ~15 minutes to start working, and peaks at 1 hour, with no concern about BG levels. Can you square these 2 for me and make it make sense?

1. Time in severe hypoglycemia - ideally 0%

2. Time in severe hyperglycemia/diabetic ketoacidosis - ideally 0%

3. Time in euglycemia (also called time in target) - clinical target is >70% and for reference the median healthy non-diabetic is in target ~90-95% of the time.

Closed loop systems are very good at #1 and #2 as it takes a while for levels to get to the severe state and insulin can be administered (or withheld) based on CGM.

When we talk about algorithming out of meal announcements it's whether historical patient-specific blood glucose levels and insulin administrations (i.e. a surrogate for what you eat and when) combined with CGM can keep #3 acceptable, not necessarily optimal. Medtronic is using this approach and their newest model more or less eliminates the need for accurate carb-counting but they still require meal announcements. The hope/idea is that this can potentially be eliminated with further iterations.

Another important thing to keep in mind that is sometimes lost in these discussions is that we don't treat numbers we treat patients (i.e. what are the clinical outcomes). Generally speaking, we assume the closer to normal the better but we don't have actual data about how much an extra X% outside of target ranges matters in terms of clinical outcomes and complication rates. We only really started getting this data with CGM and complications in these mild states would require very large cohorts and long (10-20 year) follow-ups to detect differences as they're likely to also be mild.

So while you're absolutely correct regarding the limitations and that an algorithm cannot outperform accurate carb-counting and meal announcements the missing piece is that it may be sufficient. Particularly if said algorithms result in improved time-in-target for patients who aren't good at managing their diabetes and find meal announcements cumbersome.

I totally get that we "treat the patient" -- that's sort of what I'm hinting at with the demographics. But, in my opinion this thing you said:

> we don't have actual data about how much an extra X% outside of target ranges matters in terms of clinical outcomes and complication rates. We only really started getting this data with CGM and complications in these mild states would require very large cohorts and long (10-20 year) follow-ups to detect differences as they're likely to also be mild.

... is not the same as saying "we know that 70% TIR is safe to live with no complications". I don't think any of the guidelines are that confident, because there's not enough evidence yet. Consider this study (discussed at [1]):

> Overall, increasing time spent with glucose levels in the target range of 70–180 mg/dL (3.9–9.9 mmol/L) was associated with decreasing risk for microvascular complications. For instance, 50.0% of the 10 individuals in the lowest category for TIR (<40%) had at least one microvascular complication, compared with just 27.3% of the 99 people in the highest category for TIR (≥70%).

> Moreover, El Malahi said that the 180 people with microvascular complications had significantly lower average TIR than the 324 individuals without, at 60.4% versus 63.9%.

This suggests to me that a difference of 4% of TIR can seriously affect long-term outcomes. And, by the way, even those with the highest TIR still had microvascular complications higher than the normal population. On top of that, we know that genetic and environmental factors may be at play.

Therefore, my monkey math is that 75%+ as a TIR goal may mean that even if the patient is an order of magnitude more vulnerable to complications, microvascular or otherwise, they have a much better shot.

And, unfortunately, the typical western diet with 3 meals a day and snacks, you have to be "good at managing diabetes" to get to 75%+ TIR. Thanks for reading my ramble.

[1] https://diabetes.medicinematters.com/easd-2020/glycemic-cont...

From Wikipedia:"A proportional–integral–derivative controller (PID controller or three-term controller) is a control loop mechanism employing feedback that is widely used in industrial control systems and a variety of other applications requiring continuously modulated control. A PID controller continuously calculates an error value e(t) as the difference between a desired setpoint (SP) and a measured process variable (PV) and applies a correction based on proportional, integral, and derivative terms (denoted P, I, and D respectively), hence the name."

Getting PID control loops to work has a lot of research behind it, but it's still hard to get right with new hardware. I would imagine a PID control loop involving organics (wetware) would be much order, and harder still a PID control loop in organics with life-threatening failures possible.

The way the Supreme Court recently changed patent law [3] for software has definitely had a positive effect for APS development. [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769814/ [2] https://patents.google.com/patent/US20150306314 [3] https://en.wikipedia.org/wiki/Alice_Corp._v._CLS_Bank_Intern...

That's good news, right? That means that everything that people now come up with has well-documented prior art?

If you need a really optimal control trajectory minimizing or maximizing for some parameter, you are willing to do the system identification necessary for it to work, and you don't much care whether an electrician can understand how it works model-based controls are much better. as /u/Communitivity mentioned so called 'model based control' (which is an umbrella of techniques) is a much more powerful tool.

Oh my gosh, this is the startup I considered starting last year when this issue became personal to me and I wrapped my brain around the complexity of insulin dosing.

There are a lot of challenges here but we absolutely need an external "brain" to correlate many data points, some trends, and reasonably estimate current insulin sensitivity.

If I was back in that position I'd go low carb high exercise from the start, and do everything I could to reduce my insulin requirements as much as possible. There are cases of new T1s coming of insulin completely, or just a low basal dose for multiple years.

Would love to see/hear more about what you're working on!

    - 1 drug, it works ok, still very patient specific.
    - 2 drugs at the same time, only if you validated correctly at least one alone before.
    - 3 at the same time: clusterfuck/total mess.

I'm a type 1 diabetic on multiple daily injections -- a pump just introduces a lot of inconvenience for me, price aside. You have to track batteries and change tubing and make sure the tubing doesn't snag on things, and unplug the machine before taking a shower or bath, and ... blah blah blah...

All I need for MDI is to carry my syringes and vial around in a cold pack (I live in the tropics, lol) and I don't need to worry about hardware beyond that.

Inreda (a Dutch company) has a CE-marked device[4] that can be clinically used but one limitation has been glucagon stability (has to be replenished daily). Tandem in the US was working on this as well but I haven't heard anything about them in a while, not sure how far along they are.

The Inreda product is still in the early stages of testing but fully functional. Small crossover trials seem promising (defined by more time in euglycemic state).

There is a competing approach with "intelligent insulin" or a self-regulating glucose sensitive insulin formulations that have different bioavailability depending on circulating glucose levels rather than relying on a monitor, this is farther out from clinical use.

One of the reasons bihormonal pumps haven't entered mainstream use yet is that it's more expensive/complicated and the current techniques of algorithmic predictions of hypoglycemic episodes and insulin delivery suspension are already very good that hypo isn't much of a problem with modern devices like Tandem's offering.

Medtronic has added a meal detection algorithm[5] that's really good too (the best on the market I'm told by my endo colleagues) and they say we're getting close to not needing carb counting anymore. This is the first such algorithm so we're not there yet.

The question then becomes how clinically useful more time in euglycemia is as the hypo episode problem is essentially solved, we'll need more data to draw any conclusions and it will take a while for this particular question as many of the outcome measures are long-term.

[1] https://pubmed.ncbi.nlm.nih.gov/28007348/

[2] https://jamanetwork.com/journals/jamasurgery/article-abstrac...

[3] https://pubmed.ncbi.nlm.nih.gov/24931572/

[4] https://www.inredadiabetic.nl/en/discover-the-ap/

[5] https://www.medtronicdiabetes.com/products/minimed-780g-insu...

Glucose-responsive insulin also seems like science fiction as this point, but would be extremely powerful tool.

I'm very familiar with one of the most popular, closed-loop system combinations in the USA and I definitely don't feel the hypoglycemia problem is anywhere near "solved". There is too much volatility dictating a person's insulin sensitivity that even today's smartest systems will regularly give too much insulin, requiring treatment, or too little, resulting in prolonged hyperglycemia.

I agree that time-in-range is incredible today with the technology, comparatively, but there's still lots and lots of room for improvement.

> I'm very familiar with one of the most popular, closed-loop system combinations in the USA and I definitely don't feel the hypoglycemia problem is anywhere near "solved".

I should have been clearer, the moderate to severe hypoglycemia (level 2 and 3) problem is essentially solved with the newest generation of closed loop systems. Hypoglycemia in general is trending towards being solved particularly with the newest Medtronic devices, both from studies and what endocrinologists are seeing.

In some of the recent studies (which again are still small as these devices are new) I've come across there are no severe hypo episodes reported and % time in moderate hypoglycemia was (picking one study) ~0.3%[2].

The belief is that further iterations of these algorithms will continue to improve this hence why I said "solved" as in there is no strong need for a large treatment paradigm shift on the basis of moderate-severe hypoglycemia.

> There is too much volatility dictating a person's insulin sensitivity that even today's smartest systems will regularly give too much insulin, requiring treatment, or too little, resulting in prolonged hyperglycemia.

Hyperglycemia is a different discussion altogether that is not addressed by insulin delivery suspension or glucagon. The MiniMed 780G is probably the most advanced system out there with minimal patient input and time in target range is being reported as ~80% which is certainly getting there.

[1] https://diabetesjournals.figshare.com/articles/figure/Fully_...

[2] https://www.nejm.org/doi/10.1056/NEJMoa2004736?url_ver=Z39.8...

Dual pumps are being worked on, but it's not yet clear that the improved glucose control justifies potential long term consequences.

Although, to go along with the cyberpunk theme ; If you want to kill a Cyborg, you just rip off his arm...

I'm thrilled to see this is happening, but the chemical inputs and various metabolic factors are far more complex than "sugar in, one hormone to lower blood glucose levels and another to correctively raise it."

Inreda: “A bi-hormonal fully closed loop system”: https://www.inredadiabetic.nl/en/home-english/

LOL, so no end then to the American insulin caravans to Canada?