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Concept: sub-20-minute glucose-responsive mealtime insulin

The single biggest unlock for unannounced-meal automation — a mealtime insulin that starts working within minutes, peaks in under 20, clears with a short tail, and ideally is glucose-responsive (active only when glucose is high). No such insulin exists yet; the closest in-human result is a 3.2-fold glucose switch shown only in animals.

What we should buildconceptualultra-rapidmealtimeconceptglucose-responsive

The scorecard

Onset speed98

Mealtime convention (faster onset = better): target onset within a few minutes, approaching first-phase insulin secretion from a healthy pancreas, which begins within ~1-2 min of a glucose rise.[7]

Time to peak97

Mealtime convention (faster peak = better): explicit design goal is a sub-20-minute peak — roughly 3-5x faster than today's ultra-rapid analogs, whose glucose-lowering peaks at ~90-130 min.[6]

Short tail92

Mealtime convention (shorter tail = better): aim is fast clearance or a glucose-responsive shut-off, which would largely eliminate insulin stacking and late post-meal lows; today's analogs still tail 5-7 h.[3]

Consistency60

Aspirational: predictable absorption is unproven for any sub-20-min route, and the one glucose-responsive insulin tested in people (MK-2640) failed to show a glucose-dependent effect — real-world consistency is the key risk.[2]

Exercise flexibility90

Aspirational: glucose-responsive activity would in principle dial itself down as glucose falls during exercise — the NNC2215 prototype protected against hypoglycemia in animals — transforming exercise safety if it translates to people.[1]

Access & cost30

Access convention (cheaper/more available = better): nonexistent as a product, so currently inaccessible; a novel patented molecule would likely launch at premium brand pricing with no biosimilar for years.[3]

Insulins are scored relative to their role peers (see tags: rapid, ultra-rapid, basal, inhaled). A basal insulin's onset score compares it to other basals, not to mealtime insulins.

Editor’s take

This is the advocacy entry we would fund first. A true sub-20-minute insulin would make today's "good enough" closed-loop algorithms feel superhuman overnight, and genuine glucose-responsiveness is the prerequisite for ever dropping meal announcements entirely. We score it as a target, not a product — the in-human evidence is still essentially zero.

The full picture

This is not a product — it is a target, and one of the clearest statements of what the Type 1 field should be building. It is a mealtime (prandial / bolus) insulin concept: the dose you would take to cover a meal, the role today filled by rapid and ultra-rapid analogs.1 Two properties define it. First, speed: begin working within a few minutes and reach peak effect in under 20 minutes. Second, ideally, glucose-responsiveness ("smart" insulin): a molecule that stays inert until glucose rises, then activates — a built-in safety net against lows.2

Why these numbers? A healthy pancreas releases a rapid first-phase insulin burst within roughly 1-2 minutes of glucose rising.3 By contrast, today's fastest approved analog (faster aspart, Fiasp) only reaches its glucose-lowering peak at about 90-133 minutes and tails for 5-7 hours.4 That multi-hour gap between eating and insulin action is the heaviest physical lag an automated insulin-delivery system has to predict around — and the reason hybrid closed-loop systems still ask you to announce meals. A sub-20-minute insulin would shrink that lag three- to five-fold.4

PK/PD target (aspirational). Onset: minutes. Time-to-peak: under 20 minutes. Duration / tail: short — fast clearance, or a glucose-responsive shut-off that ends action as glucose normalizes. There is no published human PK/PD curve, because no such insulin exists yet; these are design goals, not measured values.2

Has anyone built it? Pieces, not the whole. MK-2640 (Merck) was the first glucose-responsive insulin tested in people: in 16 adults with type 1 diabetes, the intravenous analog failed to show a glucose-dependent effect, and it was about 25-fold less potent than regular insulin — the program did not advance.5 In 2024, NNC2215 (Novo Nordisk, with Carbometrics) showed a genuine molecular glucose switch — insulin-receptor affinity rose 3.2-fold as glucose went from 3 to 20 mM, and it protected pigs and rats against hypoglycemia — but it has been tested only in animals.6 Separately, glucose-responsive polymer and oral-reservoir systems have normalized glucose for a day in mice and pigs without causing lows, again preclinically.7 Authoritative reviews group all of this into three strategies — CGM-linked closed loops (already real), glucose-responsive polymers, and mechanism-based molecular modifications — and conclude that no intrinsic glucose-responsive insulin analog has reached the clinic or been approved.8

Absorption variability and exercise. A faster route would not automatically be a more consistent route — predictable day-to-day absorption is unproven for any sub-20-minute chemistry, and MK-2640's failure shows how hard the consistency bar is.5 The flip side is the prize: a truly glucose-responsive insulin would, in principle, dial itself down as glucose falls during activity, which is exactly the hypoglycemia protection NNC2215 demonstrated in animals.6

Delivery, approvals, access. Undefined — no regulator has reviewed such a product, and there is no price, region, or biosimilar to report. (For reference that a fast route is physically possible: inhaled technosphere insulin already reaches peak serum levels in ~12-15 minutes, though its glucose-lowering still peaks later and the route has its own drawbacks.)9

What's coming. This is an active, funded frontier. The Type 1 Diabetes Grand Challenge (Diabetes UK, the Steve Morgan Foundation, and Breakthrough T1D) has committed £15 million specifically to ultra-rapid and glucose-responsive "smart" insulins, explicitly so closed-loop systems can react without manual meal and exercise entry.10 Breakthrough T1D (formerly JDRF) is funding glucose-responsive insulin work toward clinical trials.11 We keep this record as a concept to hold the goal visible and to score every real insulin against the curve we actually want — see the insulin-speed gap.

References

  1. Jarosinski MA, Dhayalan B, Rege N, et al. 'Smart' insulin-delivery technologies and intrinsic glucose-responsive insulin analogues. Diabetologia (2021). https://doi.org/10.1007/s00125-021-05422-6 ↩

  2. Jarosinski MA, Dhayalan B, Rege N, et al. 'Smart' insulin-delivery technologies and intrinsic glucose-responsive insulin analogues. Diabetologia (2021). https://doi.org/10.1007/s00125-021-05422-6 ↩ ↩2

  3. Caumo A, Luzi L. First-phase insulin secretion: does it exist in real life? Considerations on shape and function. Am J Physiol Endocrinol Metab (2004). https://doi.org/10.1152/ajpendo.00139.2003 ↩

  4. Novo Nordisk. FIASP (insulin aspart injection) US Prescribing Information — Clinical Pharmacology. https://www.novo-pi.com/fiasp.pdf ↩ ↩2

  5. Krug AW, Visser SAG, Tsai K, et al. Clinical Evaluation of MK-2640: An Insulin Analog With Glucose-Responsive Properties. Clin Pharmacol Ther (2019). https://doi.org/10.1002/cpt.1215 ↩ ↩2

  6. Hoeg-Jensen T, Kruse T, Brand CL, et al. Glucose-sensitive insulin with attenuation of hypoglycaemia. Nature (2024). https://doi.org/10.1038/s41586-024-08042-3 ↩ ↩2

  7. Ji K, Wei X, Kahkoska AR, et al. An orally administered glucose-responsive polymeric complex for high-efficiency and safe delivery of insulin in mice and pigs. Nat Nanotechnol (2024). https://doi.org/10.1038/s41565-024-01764-5 ↩

  8. Wang J, Wang Z, Yu J, Kahkoska AR, Buse JB, Gu Z. Glucose-Responsive Insulin and Delivery Systems: Innovation and Translation. Adv Mater (2020). https://doi.org/10.1002/adma.201902004 ↩

  9. Goldberg T, Wong E. Afrezza (Insulin Human) Inhalation Powder: A New Inhaled Insulin for the Management of Type-1 or Type-2 Diabetes Mellitus. P T (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4634344/ ↩

  10. Type 1 Diabetes Grand Challenge. Novel Insulins (Diabetes UK · Steve Morgan Foundation · Breakthrough T1D). https://type1diabetesgrandchallenge.org.uk/the-challenges/novel-insulins/ ↩

  11. Breakthrough T1D UK. JDRF-funded smart insulin research shows promise. https://breakthrought1d.org.uk/news/jdrf-funded-smart-insulin-research-shows-promise/ ↩

Coming soon

ETA · Concept only — no such insulin exists yet; closest in-human result failed (MK-2640), best result animal-only. Actively funded frontier (e.g. £15M Type 1 Diabetes Grand Challenge), no clinical timeline.

Sources

  1. [1]Hoeg-Jensen T, Kruse T, Brand CL, et al. Glucose-sensitive insulin with attenuation of hypoglycaemia. Nature (2024) · peer-reviewed — NNC2215 (Novo Nordisk/Carbometrics). Insulin-receptor affinity rose 3.2-fold from 3 to 20 mM glucose; protected against hypoglycemia and partially covered glucose excursions in rats and pigs. Animal-only; not yet tested in humans. PMID 39415004 / PMC11499270.
  2. [2]Krug AW, Visser SAG, Tsai K, et al. Clinical Evaluation of MK-2640: An Insulin Analog With Glucose-Responsive Properties. Clin Pharmacol Ther (2019) · peer-reviewed — First-in-human glucose-responsive insulin (Merck). In 16 adults with T1D, IV MK-2640 did NOT show a glucose-dependent change in clearance; ~25-fold less potent than regular human insulin. Program did not advance. PMID 30125349.
  3. [3]Jarosinski MA, Dhayalan B, Rege N, et al. 'Smart' insulin-delivery technologies and intrinsic glucose-responsive insulin analogues. Diabetologia (2021) · peer-reviewed — Authoritative review of three GRI strategies (CGM closed-loop, glucose-responsive polymers, mechanism-based modifications). Intrinsic GRI analogues remain early-stage; none approved. PMID 33710398 / PMC8158166.
  4. [4]Wang J, Wang Z, Yu J, Kahkoska AR, Buse JB, Gu Z. Glucose-Responsive Insulin and Delivery Systems: Innovation and Translation. Adv Mater (2020) · peer-reviewed — Review of glucose-responsive moieties: glucose oxidase, phenylboronic acid, glucose-binding molecules. Translation challenges. PMID 31423670 / PMC7141789.
  5. [5]Ji K, Wei X, Kahkoska AR, et al. An orally administered glucose-responsive polymeric complex for high-efficiency and safe delivery of insulin in mice and pigs. Nat Nanotechnol (2024) · peer-reviewed — Glucose-responsive oral insulin reservoir in the liver; one-day normoglycemia without hypoglycemia in diabetic mice and pigs. Preclinical. PMID 39223256 / PMC11646558.
  6. [6]FIASP (insulin aspart injection) US Prescribing Information — Clinical Pharmacology · regulatory — Benchmark for today's fastest analog: glucose-lowering peak effect ~91-133 min, duration ~5-7 h — the lag a sub-20-min concept aims to erase.
  7. [7]Caumo A, Luzi L. First-phase insulin secretion: does it exist in real life? Considerations on shape and function. Am J Physiol Endocrinol Metab (2004) · peer-reviewed — Physiologic benchmark: a healthy pancreas mounts a rapid first-phase insulin burst within ~1-2 min of a glucose rise — the speed any 'true artificial pancreas' insulin is chasing. PMID 15308473.
  8. [8]Goldberg T, Wong E. Afrezza (Insulin Human) Inhalation Powder: A New Inhaled Insulin for the Management of Type-1 or Type-2 Diabetes Mellitus. P T (2015) · peer-reviewed — Inhaled technosphere insulin Tmax ~12-15 min (25-50 units) — proof a fast route exists, though glucose-lowering peaks later and the route has its own limits. PMC4634344.
  9. [9]Type 1 Diabetes Grand Challenge — Novel Insulins (Diabetes UK, Steve Morgan Foundation, Breakthrough T1D) · news — £15M programme funding ultra-rapid and glucose-responsive 'smart' insulins, explicitly to let closed-loop systems respond without manual meal/exercise entry.
  10. [10]Breakthrough T1D UK — JDRF-funded smart insulin research shows promise · news — Charity funding (Breakthrough T1D, formerly JDRF) for Zhen Gu's glucose-responsive oral insulin; aims to lower glucose without hypos.