Optimal coverage of prandial insulin requirements remains an elusive goal. The invention of rapid-acting insulin analogs (RAIAs) was a big step forward in reducing postprandial glycemic excursions in patients with diabetes in comparison with using regular human insulin; however, even with these, the physiological situation cannot be adequately mimicked. Developing ultrafast-acting insulins (UFIs)—showing an even more rapid onset of action and a shorter duration of action after subcutaneous (SC) administration—is another step forward in achieving this goal. The need for UFIs has been gradually recognized over the years, and subsequently, a number of different approaches to cover this need are in clinical development. A rapid increase in circulating insulin levels can be achieved by different measures: Modification of the primary structure of insulin molecule (as we know from RAIAs), addition of excipients that enhance the appearance in the monomeric state post-injection, or addition of enzymes that enable more free spreading of the insulin molecules in the SC tissue. Other measures to increase the insulin absorption rate increase the local blood flow nearby the insulin depot in the SC tissue, injecting the insulin intradermally or applying via another route, e.g., the lung. The development of these approaches is in different stages, from quite early stages to nearing market authorization. In time, daily practice will show if the introduction of UFIs will fulfill their clinical promise. In this review, the basic idea for UFIs will be presented and the different approaches will be briefly characterized.
PolonskyKSGivenBDVan CauterE. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest.1988;81 (2): 442–8.
2.
MonnierLLapinskiHColetteC. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: Variations with increasing levels of HbA(1c). Diabetes Care.2003;26 (3): 881–5.
3.
MonnierLColetteCBonifaceH. Contribution of postprandial glucose to chronic hyperglycaemia: From the “glucose triad” to the trilogy of “sevens”. Diabetes Metab.2006;32 Spec No 2: 2S11–6.
4.
SiegelaarSEHollemanFHoekstraJBDeVriesJH. Glucose variability; does it matter?. Endocr Rev.2010;31 (2): 171–82.
5.
De VegtFDekkerJMRuhéHGStehouwerCDNijpelsGBouterLMHeineRJ. Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: The Hoorn Study. Diabetologia.1999;42 (8): 926–31.
6.
Temelkova-KurktschievTSKoehlerCHenkelELeonhardtWFueckerKHanefeldM. Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1c level. Diabetes Care.2000;23 (12): 1830–4.
7.
McCarterRJHempeJMChalewSA. Mean blood glucose and biological variation have greater influence on HbA1c levels than glucose instability: An analysis of data from the Diabetes Control and Complications Trial. Diabetes Care.2006;29 (2): 352–5.
8.
KilpatrickESRigbyASAtkinSL. The effect of glucose variability on the risk of microvascular complications in type 1 diabetes. Diabetes Care.2006;29 (7): 1486–90.
9.
KilpatrickES. Arguments for and against the role of glucose variability in the development of diabetes complications. J Diabetes Sci Technol.2009;3 (4): 649–55.
10.
KilpatrickESRigbyASAtkinSL. Effect of glucose variability on the long-term risk of microvascular complications in type 1 diabetes. Diabetes Care.2009;32 (10): 1901–3.
11.
RazIWilsonPWStrojekKKowalskaIBozikovVGittAKJermendyGCampaigneBNKerrLMilicevicZJacoberSJ. Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: The HEART2D trial. Diabetes Care.2009;32 (3): 381–6.
12.
SupersaxoAHeinWRSteffenH. Effect of molecular weight on the lymphatic absorption of water-soluble compounds following subcutaneous administration. Pharm Res.1990;7 (2): 167–9.
13.
BrangeJOwensDRKangSVolundA. Monomeric insulins and their experimental and clinical implications. Diabetes Care.1990;13 (9): 923–54.
14.
BrangeJRibelUHansenJFDodsonGHansenMTHavelundSMelbergSGNorrisFNorrisKSnelL. Monomeric insulins obtained by protein engineering and their medical implications. Nature.1988;333 (6174): 679–82.
15.
HeinemannLHeiseTWahlLCTrautmannMEAmpudiaJStarkeAABergerM. Prandial glycaemia after a carbohydrate-rich meal in type I diabetic patients: Using the rapid acting insulin analogue [Lys(B28), Pro(B29)] human insulin. Diabet Med.1996;13 (7): 625–9.
16.
CobryEMcFannKMesserLGageVVanderWelBHortonLChaseHP. Timing of meal insulin boluses to achieve optimal postprandial glycemic control in patients with type 1 diabetes. Diabetes Technol Ther.2010;12 (3): 173–7.
17.
LuijfYMvan BonACHoekstraJBDevriesJH. Premeal injection of rapid-acting insulin reduces postprandial glycemic excursions in type 1 diabetes. Diabetes Care.2010;33 (10): 2152–5.
18.
FreckmannGPleusSHaugCBittonGNagarR. Increasing local blood flow by warming the application site: Beneficial effects on postprandial glycemic excursionsJ Diabetes Sci Technol.2012;6 (4): 780–5.
19.
DillonRS. Improved serum insulin profiles in diabetic individuals who massaged their insulin injection sites. Diabetes Care.1983;6 (4): 399–401.
20.
KelloggDLJr.In vivo mechanisms of cutaneous vasodilation and vasoconstriction in humans during thermoregulatory challenges. J Appl Physiol.2006;100 (5): 1709–18.
21.
MinsonCTBerryLTJoynerMJ. Nitric oxide and neurally mediated regulation of skin blood flow during local heating. J Appl Physiol.2001;91 (4): 1619–26.
22.
KoivistoVA. Sauna-induced acceleration in insulin absorption. Br Med J.1980;281 (6240): 621–2.
23.
SindelkaGHeinemannLBergerMFrenckWChantelauE. Effect of insulin concentration, subcutaneous fat thickness and skin temperature on subcutaneous insulin absorption in healthy subjects. Diabetologia.1994;37 (4): 377–80.
24.
RazIWeissRYegorchikovYBittonGNagarRPesachB. Effect of a local heating device on insulin and glucose pharmacokinetic profiles in an open-label, randomized, two-period, one-way crossover study in patients with type 1 diabetes using continuous subcutaneous insulin infusion. Clin Ther.2009;31 (5): 980–7.
25.
McVeyEHirschLSutterDEKapitzaCDellwegSClairJRebrinKJudgeKPettisRJ. Pharmacokinetics and postprandial glycemic excursions following insulin lispro delivered by intradermal microneedle or subcutaneous infusion. J Diabetes Sci Technol.2012;6 (4): 743–54.
26.
HarveyAJKaestnerSASutterDEHarveyNGMiksztaJAPettisRJ. Microneedle-based intradermal delivery enables rapid lymphatic uptake and distribution of protein drugs. Pharm Res.2011;28 (1): 107–16.
27.
PettisRJGinsbergBHirschLSutterDKeithSMcVeyEHarveyNGHompeschMNosekLKapitzaCHeinemannL. Intradermal microneedle delivery of insulin lispro achieves faster insulin absorption and insulin action than subcutaneous injection. Diabetes Technol Ther.2011;13 (4): 435–42.
28.
PettisRJHirschLKapitzaCNosekLHovelmannUKurthHJSutterDEHarveyNGHeinemannL. Microneedle-based intradermal versus subcutaneous administration of regular human insulin or insulin lispro: Pharmacokinetics and postprandial glycemic excursions in patients with type 1 diabetes. Diabetes Technol Ther.2011;13 (4): 443–50.
29.
GuptaJFelnerEIPrausnitzMR. Rapid pharmacokinetics of intradermal insulin administered using microneedles in type 1 diabetes subjects. Diabetes Technol Ther.2011;13 (4): 451–6.
30.
BossAHPetrucciRLorberD. Coverage of prandial insulin requirements by means of an ultra-rapid-acting inhaled insulin. J Diabetes Sci Technol.2012;6 (4): 773–9.
31.
HeinemannLHeiseT. Current status of the development of inhaled insulin. Br J Diab Vasc Dis.2004;4: 295–301.
RaveKPotockaEHeinemannLHeiseTBossAHMarinoMCostelloDChenR. Pharmacokinetics and linear exposure of AFRESA compared with the subcutaneous injection of regular human insulin. Diabetes Obes Metab.2009;11 (7): 715–20.
34.
RaveKHeiseTPfutznerABossAH. Coverage of postprandial blood glucose excursions with inhaled technosphere insulin in comparison to subcutaneously injected regular human insulin in subjects with type 2 diabetes. Diabetes Care.2007;30 (9): 2307–8.
35.
RosenstockJLorberDLGnudiLHowardCPBilheimerDWChangPCPetrucciREBossAHRichardsonPC. Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: A multicentre randomised trial. Lancet.2010;375 (9733): 2244–53.
36.
HeinemannLJacquesY. Oral insulin and buccal insulin: A critical reappraisal. J Diabetes Sci Technol.2009;3 (3): 568–84.
37.
StoteRMarburyTShiLMillerMStrangeP. Comparison pharmacokinetics of two concentrations (0.7% and 1.0%) of Nasulin, an ultra-rapid-acting intranasal insulin formulation. J Diabetes Sci Technol.2010;4 (3): 603–9.
38.
StoteRMillerMMarburyTShiLStrangeP. Enhanced absorption of Nasulin™, an ultrarapid-acting intranasal insulin formulation, using single nostril administration in normal subjects. J Diabetes Sci Technol.2011;5 (1): 113–9.
39.
HingsonRAHughesJG. Clinical studies with jet injection; a new method of drug administration. Curr Res Anesth Analg.1947;26 (6): 221–30.
40.
WellerCLinderM. Jet injection of insulin vs the syringe-and-needle method. JAMA.1966;195 (10): 844–7.
41.
TaylorRHomePDAlbertiKG. Plasma free insulin profiles after administration of insulin by jet and conventional syringe injection. Diabetes Care.1981;4 (3): 377–9.
42.
BremsethDLPassF. Delivery of insulin by jet injection: Recent observations. Diabetes Technol Ther.2001;3 (2): 225–32.
43.
MaloneJILowittSGroveNPShahSC. Comparison of insulin levels after injection by jet stream and disposable insulin syringe. Diabetes Care.1986;9 (6): 637–40.
44.
TheintzGESizonenkoPC. Risks of jet injection of insulin in children. Eur J Pediatr.1991;150 (8): 554–6.
45.
SarnoMJBellJEdelmanSV. Pharmacokinetics and glucodynamics of rapid-, short-, and intermediate-acting insulins: Comparison of jet injection to needle syringe. Diabetes Technol Ther.2002;4 (6): 863–6.
46.
EngwerdaEEAbbinkEJTackCJde GalanBE. Improved pharmacokinetic and pharmacodynamic profile of rapid-acting insulin using needle-free jet injection technology. Diabetes Care.2011;34 (8): 1804–8.
47.
EdsbergBHerlyDHildebrandtPKühlC. Insulin bolus given by sprinkler needle: Effect on absorption and glycaemic response to a meal. Br Med J (Clin Res Ed).1987;294 (6584): 1373–6.
48.
PohlRHauserRLiMDeSouzaEFeldsteinRSeibertROzhanKKashyapNSteinerS. Ultra-rapid absorption of recombinant human insulin induced by zinc chelation and surface charge masking. J Diabetes Sci Technol.2012;6 (4): 755–63.
49.
KrasnerAPohlRSimmsPPichottaPHauserRDe SouzaE. A review of a family of ultra-rapid-acting insulins: Formulation development. J Diabetes Sci Technol.2012;6 (4): 786–96.
50.
SteinerSHompeschMPohlRSimmsPFlackeFMohrTPfutznerAHeinemannL. A novel insulin formulation with a more rapid onset of action. Diabetologia.2008;51 (9): 1602–6.
51.
HompeschMMcManusLPohlRSimmsPPfutznerABulowEFlackeFHeinemannLSteinerSS. Intra-individual variability of the metabolic effect of a novel rapid-acting insulin (VIAject) in comparison to regular human insulin. J Diabetes Sci Technol.2008;2 (4): 568–71.
52.
HeinemannLHompeschMFlackeFSimmsPPohlRAlbusKPfütznerASteinerS. Reduction of postprandial glycemic excursions in patients with type 1 diabetes: A novel human insulin formulation versus a rapid-acting insulin analog and regular human insulin. J Diabetes Sci Technol.2011;5 (3): 681–6.
53.
HeinemannLNosekLFlackeFAlbusKKrasnerAPichottaPHeiseTSteinerS. U-100, pH-Neutral formulation of VIAject(®): Faster onset of action than insulin lispro in patients with type 1 diabetes. Diabetes Obes Metab.2012;14 (3): 222–7.
54.
MuchmoreDBVaughnDE. Accelerating and improving the consistency of rapid-acting analog insulin absorption and action for both subcutaneous injection and continuous subcutaneous infusion using recombinant human hyaluronidase. J Diabetes Sci Technol.2012;6 (4): 764–72.
55.
BookbinderLHHoferAHallerMFZepedaMLKellerGALimJEEdgingtonTSShepardHMPattonJSFrostGI. A recombinant human enzyme for enhanced interstitial transport of therapeutics. J Control Release.2006;114 (2): 230–41.
56.
VaughnDEYocumRCMuchmoreDBSugarmanBJVickAMBilinskyIPFrostGI. Accelerated pharmacokinetics and glucodynamics of prandial insulins injected with recombinant human hyaluronidase. Diabetes Technol Ther.2009;11 (6): 345–52.
57.
HompeschMMuchmoreDBMorrowLVaughnDE. Accelerated insulin pharmacokinetics and improved postprandial glycemic control in patients with type 1 diabetes after coadministration of prandial insulins with hyaluronidase. Diabetes Care.2011;34 (3): 666–8.
58.
HompeschMMuchmoreDBMorrowLLudingtonEVaughnDE. Improved postprandial glycemic control in patients with type 2 diabetes from subcutaneous injection of insulin lispro with hyaluronidase. Diabetes Technol Ther.2012;14 (3): 218–24.
59.
VaughnDEMuchmoreDB. Use of recombinant human hyaluronidase to accelerate rapid insulin analogue absorption: Experience with subcutaneous injection and continuous infusion. Endocr Pract.2011;17 (6): 914–21.
60.
MorrowLMuchmoreDBLudingtonEAVaughnDEHompeschM. Reduction in intrasubject variability in the pharmacokinetic response to insulin after subcutaneous co-administration with recombinant human hyaluronidase in healthy volunteers. Diabetes Technol Ther.2011;13 (10): 1039–45.
61.
PhillipsNBWhittakerJIsmail-BeigiFWeissMA. Insulin fibrillation and protein design: Topological resistance of single-chain analogs to thermal degradation with application to a pump reservoir. J Diabetes Sci Technol.2012;6 (2): 277–88.
62.
HeinemannLOvermannHMühlhauserI. How do patients with diabetes mellitus type I handle the injection-meal interval in daily life?. Diabetes.1997;46Suppl 1: 340A.
63.
OvermannHHeinemannL. Injection-meal interval: Recommendations of diabetologists and how patients handle it. Diabetes Res Clin Pract.1999;43 (2): 137–42.
64.
HeinemannLHohmannAStarkeAARBergerM. What is the correct timing of subcutaneous injections of regular insulin to cover carbohydrate rich meals?. Horm Metab ResSuppl.1992;26: 137–9.
65.
CoatesPAIsmailISLuzioSDGriffithsIOllertonRLVolundAOwensDR. Intranasal insulin: The effects of three dose regimens on postprandial glycaemic profiles in type II diabetic subjects. Diabet Med.1995;12 (3): 235–9.
66.
RaveKBottSHeinemannLShaSBeckerRHWillavizeSAHeiseT. Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin. Diabetes Care.2005;28 (5): 1077–82.
67.
HeinemannLWeyerCRauhausMHeinrichsSHeiseT. Variability of the metabolic effect of soluble insulin and the rapid-acting insulin analog insulin aspart. Diabetes Care.1998;21 (11): 1910–4.
68.
BeckerRHFrickAD. Clinical pharmacokinetics and pharmacodynamics of insulin glulisine. Clin Pharmacokinet.2008;47 (1): 7–20.
69.
RaveKMNosekLde la PeñaASegerMErnestCS2ndHeinemannLBatyckyRPMuchmoreDB. Dose response of inhaled dry-powder insulin and dose equivalence to subcutaneous insulin lispro. Diabetes Care.2005;28 (10): 2400–5.
70.
HeiseTNosekLSpitzerHHeinemannLNiemollerEFrickADBeckerRH. Insulin glulisine: A faster onset of action compared with insulin lispro. Diabetes Obes Metab.2007;9 (5): 746–53.
71.
MudaliarSRLindbergFAJoyceMBeerdsenPStrangePLinAHenryRR. Insulin aspart (B28 asp-insulin): A fast-acting analog of human insulin: Absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects. Diabetes Care.1999;22 (9): 1501–6.
72.
RaveKHeiseTHeinemannLBossAH. Inhaled Technosphere insulin in comparison to subcutaneous regular human insulin: Time action profile and variability in subjects with type 2 diabetes. J Diabetes Sci Technol.2008;2 (2): 205–12.
73.
LuzioSDDunseathGLockettABroke-SmithTPNewRROwensDR. The glucose lowering effect of an oral insulin (Capsulin) during an isoglycaemic clamp study in persons with type 2 diabetes. Diabetes Obes Metab.2010;12 (1): 82–7.
74.
CerneaSKidronMWohlgelernterJModiPRazI. Comparison of pharmacokinetic and pharmacodynamic properties of single-dose oral insulin spray and subcutaneous insulin injection in healthy subjects using the euglycemic clamp technique. Clin Ther.2004;26 (12): 2084–91.
75.
CerneaSKidronMWohlgelernterJModiPRazI. Dose-response relationship of oral insulin spray in healthy subjects. Diabetes Care.2005;28 (6): 1353–7.
76.
HeinemannLHompeschM. Biosimilar insulins: How similar is similar?. J Diabetes Sci Technol.2011;5 (3): 741–54.
77.
MuchmoreDSharpMVaughnD. Benefits of blinded continuous glucose monitoring during a randomized clinical trial. J Diabetes Sci Technol.2011;5 (3): 676–80.
78.
BergenstalRMTamborlaneWVAhmannABuseJBDaileyGDavisSNJoyceCPerkinsBAWelshJBWilliSMWoodMA. Sensor-augmented pump therapy for A1C reduction (STAR 3) study: Results from the 6-month continuation phase. Diabetes Care.2011;34 (11): 2403–5.
