Review

. 2025 Jul;19(4):908-923.

doi: 10.1177/19322968251335685. Epub 2025 Jul 1.

Early Stages of Automated Insulin Delivery

Howard Zisser¹, Roman Hovorka², Ananda Basu³, Tadej Battelino⁴, Charlotte K Boughton⁵, Marc D Breton⁶, Bruce A Buckingham⁷, Sue A Brown^{6

8}, Daniel R Cherñavvsky⁶, Eyal Dassau⁹, Mark D DeBoer⁶, Francis J Doyle 3rd¹⁰, Laya Ekhlaspour¹¹, Chiara Fabris⁶, Gregory P Forlenza¹², Ahmad Haidar¹³, David C Klonoff¹⁴, Boris Kovatchev⁶, Aaron J Kowalski¹⁵, Carol J Levy¹⁶, Yogish C Kudva¹⁷, David M Maahs⁷, Moshe Phillip¹⁸, Eric Renard¹⁹, Steven J Russell^{20

21}, Viral N Shah^{22

23}, Garry M Steil^{20

24}, R Paul Wadwa²⁵, Stuart A Weinzimer²⁶

Affiliations

¹ Independent Researcher, Santa Barbara, CA, USA.
² University of Cambridge, Cambridge, UK.
³ UAB Diabetes Technology Program, The University of Alabama, Birmingham, Birmingham, AL, USA.
⁴ Faculty of Medicine, University Medical Center Ljubljana, University of Ljubljana, Ljubljana, Slovenia.
⁵ Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.
⁶ Center for Diabetes Technology, The University of Virginia, Charlottesville, VA, USA.
⁷ Division of Pediatric Endocrinology, School of Medicine, Stanford University, Stanford, CA, USA.
⁸ Division of Endocrinology, The University of Virginia, Charlottesville, VA, USA.
⁹ Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA, USA.
¹⁰ School of Engineering, Brown University, Providence, RI, USA.
¹¹ Division of Endocrinology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
¹² Anschutz Medical Campus, University of Colorado, Aurora, CO, USA.
¹³ Department of Biomedical Engineering, McGill University, Montreal, QC, Canada.
¹⁴ Diabetes Research Institute, Mills-Peninsula Medical Center, San Mateo, CA, USA.
¹⁵ Breakthrough T1D, New York, NY, USA.
¹⁶ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁷ College of Medicine and Science, Mayo Clinic, Rochester, MN, USA.
¹⁸ Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
¹⁹ Institute of Functional Genmics, Montpellier University Hospital, CNRS, INSERM, University of Montpellier, Montpellier, France.
²⁰ Harvard Medical School, Harvard University, Boston, MA, USA.
²¹ Beta Bionics, Inc, Irvine, CA, USA.
²² Division of Endocrinology & Metabolism, School of Medicine, Indiana University, Indianapolis, IN, USA.
²³ Center for Diabetes and Metabolic Diseases, School of Medicine, Indiana University, Indianapolis, IN, USA.
²⁴ Boston Children's Hospital, Boston, MA, USA.
²⁵ Barbara Davis Center for Diabetes, Anschutz Medical Campus, University of Colorado, Aurora, CO, USA.
²⁶ School of Medicine, Yale University, New Haven, CT, USA.

PMID: 40590463
PMCID: PMC12213537
DOI: 10.1177/19322968251335685

Review

Early Stages of Automated Insulin Delivery

Howard Zisser et al. J Diabetes Sci Technol. 2025 Jul.

. 2025 Jul;19(4):908-923.

doi: 10.1177/19322968251335685. Epub 2025 Jul 1.

Authors

Affiliations

¹ Independent Researcher, Santa Barbara, CA, USA.
² University of Cambridge, Cambridge, UK.
³ UAB Diabetes Technology Program, The University of Alabama, Birmingham, Birmingham, AL, USA.
⁴ Faculty of Medicine, University Medical Center Ljubljana, University of Ljubljana, Ljubljana, Slovenia.
⁵ Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.
⁶ Center for Diabetes Technology, The University of Virginia, Charlottesville, VA, USA.
⁷ Division of Pediatric Endocrinology, School of Medicine, Stanford University, Stanford, CA, USA.
⁸ Division of Endocrinology, The University of Virginia, Charlottesville, VA, USA.
⁹ Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA, USA.
¹⁰ School of Engineering, Brown University, Providence, RI, USA.
¹¹ Division of Endocrinology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
¹² Anschutz Medical Campus, University of Colorado, Aurora, CO, USA.
¹³ Department of Biomedical Engineering, McGill University, Montreal, QC, Canada.
¹⁴ Diabetes Research Institute, Mills-Peninsula Medical Center, San Mateo, CA, USA.
¹⁵ Breakthrough T1D, New York, NY, USA.
¹⁶ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁷ College of Medicine and Science, Mayo Clinic, Rochester, MN, USA.
¹⁸ Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
¹⁹ Institute of Functional Genmics, Montpellier University Hospital, CNRS, INSERM, University of Montpellier, Montpellier, France.
²⁰ Harvard Medical School, Harvard University, Boston, MA, USA.
²¹ Beta Bionics, Inc, Irvine, CA, USA.
²² Division of Endocrinology & Metabolism, School of Medicine, Indiana University, Indianapolis, IN, USA.
²³ Center for Diabetes and Metabolic Diseases, School of Medicine, Indiana University, Indianapolis, IN, USA.
²⁴ Boston Children's Hospital, Boston, MA, USA.
²⁵ Barbara Davis Center for Diabetes, Anschutz Medical Campus, University of Colorado, Aurora, CO, USA.
²⁶ School of Medicine, Yale University, New Haven, CT, USA.

PMID: 40590463
PMCID: PMC12213537
DOI: 10.1177/19322968251335685

Abstract

The development of automated insulin delivery systems has seen tremendous improvements from individual components to interoperable system combinations of devices and new drugs besides insulin. The components have become progressively smaller, more accurate, and more user friendly. This article summarizes the history of the artificial pancreas from the earliest concepts to fully functional systems to research into further improvements in the future. The authors include many of the developers of this technology who received research support from the National Institute of Diabetes and Digestive and Kidney Diseases at various stages to develop these systems.

Keywords: AID; NIDDK; artificial pancreas; automated insulin delivery.

PubMed Disclaimer

Conflict of interest statement

Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: At the time of the research reported here, H.Z. was employed by Sansum Diabetes Research Institute. H.Z. was subsequently employed by Insulet, Google, and Supersapiens. He holds patents on artificial pancreas technology. H.Z. received product support from Insulet Corporation, Roche, and Dexcom during this research. The Juvenile Diabetes Research Foundation, the Helmsley Charitable Trust, and the National Institutes of Health (NIDDK) provided research funding. H.Z. has received royalty payments from patents in his portfolio that have been licensed to Insulet and Animas. R.H. has received speaker honoraria from Sandoz, Abbott Diabetes Care, and NovoNordisk, receiving consultancy fees from Abbott Diabetes Care, patents related to closed-loop, and is director at CamDiab. A.B. received research funding from Medtronic. T.B. served on advisory panels of Novo Nordisk, Sanofi, Eli Lilly, Boehringer, Medtronic, Abbott, and Indigo Diabetes. T.B. received honoraria for participating on the speaker’s bureau of Eli Lilly, Novo Nordisk, Medtronic, Abbott, Sanofi, Dexcom, Aventis, Astra Zeneca, and Roche. T.B.’s institution received research grant support from Abbott, Medtronic, Novo Nordisk, Sanofi, Novartis, Sandoz, and Zealand Pharma, Slovenian Research and Innovation Agency, the National Institutes of Health, and the European Union. C.K.B. has received consultancy fees from CamDiab, Speaker Honoraria from Ypsomed, and research support from Dexcom, Abbott Diabetes Care, YpsoMed, and CamDiab. M.D.B. report research funding through his institution from Dexcom, Tandem, and Novo Nordisk. M.D.B. reports honoraria/consulting activities with Boydsense, Roche, Sinocare, and Tandem. M.D.B. reports royalties managed by his institution from Dexcom, Lifescan, NovoNordisk, and Sanofi. B.A.B. has received research support from Medtronic Diabetes, Tandem, Insulet, Bigfoot, Dexcom, Abbott, Convatec, and Lilly. B.A.B. serves on the advisory boards for Medtronic, Tandem, Animas, Sanofi, Roche, Novo-Nordisk, Lilly, Convatec, BD, Profusa, and Glysense. S.A.B. has received research support to her institution from Dexcom, Insulet, Roche, Tandem, and Tolerion and has participated in a data management board for MannKind. D.R.C. has no disclosures relevant to this work. E.D. has received personal fees from Roche and Eli Lilly and Company; holds patents on artificial pancreas technology; and has received product support from Insulet Corporation, Tandem Diabetes Care, Roche, and Dexcom, Inc. The work presented in this article was performed as part of his academic appointment and is independent of his employment with Eli Lilly and Company. M.D.D. has received research support from Tandem, Dexcom, Medtronic. F.J.D. reports funding over the time course described in this article from the Showalter Foundation, Roche Diagnostics Corporation, the Juvenile Diabetes Research Foundation, the Helmsley Charitable Trust, and the National Institutes of Health (NIDDK). F.J.D. also reports royalty payments from patents in a portfolio that have been licensed to Insulet, Roche, and Dexcom. L.E. receives salary support through and NIDDK career development research grant. L.E.’s institution has received research support from Breakthrough T1D, Medtronic, Mannkind, and Abbott. She has served on the advisory board of Abbott, Diabetes Center Berne, Sequel, and Medtronic. She has received consulting fees from Jaeb and Tandem Diabetes Care, and has received honorarium fees from Med Learning Group (Sanofi-sponsored grant), Tandem Diabetes Care, Medtronic, and Insulet. C.F. reports receiving research support from Novo Nordisk, Dexcom, and Tandem Diabetes Care handled by the University of Virginia, and patent royalties from Novo Nordisk and Dexcom handled by the University of Virginia’s Licensing and Ventures Group. G.P.F. conducts research supported by Medtronic, Dexcom, Abbott, Tandem, Insulet, and Beta Bionics and has been a speaker/consultant/advisory board member for Medtronic, Dexcom, Abbott, Tandem, Insulet, Beta Bionics, Sequel, and Lilly. A.H. has acted as a consultant for Eli Lilly and Abbott Diabetes Care, and has received drugs, supplies, equipment, and other in-kind support from Tandem, Adocia, Dexcom, Eli Lilly, and Ypsomed. D.C.K. is a consultant for Afon, Embecta, GlucoTrack, Lifecare, Novo, Samsung, and Thirdwayv. B.K. reports research grants handled by the University of Virginia from the National Institutes of Health, Novo Nordisk, Dexcom, and Tandem Diabetes Care. In addition, B.K. has a number of patents with royalties paid to Dexcom and Novo Nordisk. A.J.K. is the Chief Executive Officer at Breakthrough T1D. C.J.L. has received research support from Tandem Diabetes, Dexcom, Abbott, and Insulet paid to my institution (within last three years). C.J.L. have served as a consultant for Tandem Diabetes and Dexcom (within the last three years). Y.C.K. is a consultant for Novo Nordisc, Tandem Diabetes Inc, Vertex pharmaceuticals. Y.C.K. has industry studies with compensation to the following employers: Medtronic, Tanem, Dexcom, Novo Nordisk, and Sanofi. Y.C.K. supported products from Dexcom, Tandem, and Insulet. D.M.M. has had research support from the NIDDK, NIH, Breakthrough T1D, and Helmsley Charitable Trust. His institution has had research support from DexCom Inc., Medtronic, Insulet, Bigfoot Biomedical, Tandem, and Roche; and he has consulted for Abbott, the Leona M. and Harry B. Helmsley Charitable Trust, Lifescan, Sanofi, Medtronic, Provention Bio, Kriya, Novo Nordisk, Eli Lilly, Insulet, Biospex, and Bayer. M.P. is an advisory board member for AstraZeneca, Eli Lilly, Mannkind, Medtronic Diabetes, Pfizer, Sanofi, DOMPE, LifeScan, Novo Nordisk, Insulet, ProventionBio, Merck, Ascensia, Bayer, embecta, and Tandem. M.P. has received consulting fee from Qulab Medical, and ProventionBio. M.P. has received research grants from Eli Lilly, Medtronic Diabetes, Novo Nordisk, Pfizer, Sanofi, DreaMed Diabetes, NG Solutions, DOMPE, Lumos, Gwave, OPKO, ProventionBio, AstraZeneca, and Omega Galil. M.P. owns stocks from DreaMed Diabetes and NG Solutions. E.R. declares consultant/speaker fees from A. Menarini Diagnostics, Abbott, Air Liquide SI, Astra-Zeneca, Becton-Dickinson, Boehringer-Ingelheim, Cellnovo, Dexcom Inc., Eli-Lilly, Hillo, Insulet Inc., Johnson & Johnson (Animas, LifeScan), Medtronic, Medirio, Novo-Nordisk, Roche, and Sanofi-Aventis and research support by Abbott, Dexcom Inc., Insulet Inc., Roche, and Tandem Diabetes Care. S.J.R. is an employee and stockholder of Beta Bionics, Inc. V.N.S.’s institution has received research support from Enable Bioscience, Zucara Therapeutics, Lilly, Cystic Fibrosis Foundation, Breakthrough T1D, and NIH. V.N.S. has received personal fees from Sanofi, Lilly, NovoNordisk, Dexcom, Tandem Diabetes Care, Insulet, Sequel Med Tech, Embecta, Genomelink, and Lumosfit for consulting, advising, or speaking; outside of this submitted work. G.M.S. was employed by Medtronic/MiniMed and was one of the original developers of the Medtronic/MiniMed closed-loop insulin delivery algorithm. G.M.S. currently works at Boston Children’s Hospital where he is developing closed-Loop insulin delivery algorithms for use in the Intensive Care Unit. G.M.S. has served as a consultant to Abbott Diabetes Care, Roche Diabetes Care, and Eli Lilly. R.P.W. conducts research funded by Medtronic, Dexcom, Abbott, Tandem Diabetes Care, Insulet, and Eli Lilly and has been a consultant for Dexcom and Tandem Diabetes Care and an advisory board member for Sequel Med Tech. S.A.W. has conducted clinical trials for Abbott Diabetes, JDRF/Breakthrough T1D, Medtronic, and Tandem; has received honoraria for consulting or speaking engagements from Abbott, Dexcom, Insulet, Medtronic, and Tandem; and has served on advisory boards for Zealand. He currently receives research support (to his institution) from Abbott Diabetes.

Figures

**Figure 1.**
In silico dynamic simulator for closed-loop control of artificial beta cell with hardware-in-the-loop.

**Figure 2.**
The first model predictive control (MPC) study using the Artificial Pancreas System (APS) on April 10, 2007, Santa Barbara, CA. On the top right, it displays APS screens, including communication linking the Omnipod, Dexcom STS-7, main APS user interface (UI), and the real-time control/prediction algorithm. On the left, APS is running on a laptop connected via cables to the personal data manager (PDM) and the Dexcom receiver, next to our first participant.

**Figure 3.**
Pediatric AID studies at diabetes camps provide the opportunity to assess new technology approaches among groups of children—allowing acquisition of data collection in a more natural habitat.

**Figure 4.**
The Diabetes Assistant (DiAs), the first mobile glucose control platform.

**Figure 5.**
An early inpatient AP system. Abbreviations: AID, automated insulin delivery; RF, radio frequency.

**Figure 6.**
An early automated insulin delivery system. Abbreviation: IV, intravenous.

**Figure 7.**
Variability of day-to-day insulin requirements as determined by closed-loop insulin delivery across different populations with diabetes. Data presented are mean with standard deviation. Reproduced from Boughton and Hovorka under the CC-BY 4.0 license (http://creativecommons.org/licenses/by/4.0/). Abbreviations: CV, coefficient of variation; IP, inpatients; OP, outpatients; T1D, type 1 diabetes; T2D, type 2 diabetes.

See this image and copyright information in PMC

References

1. Phillip M, Kowalski A, Battelino T. Type 1 diabetes: from the dream of automated insulin delivery to a fully artificial pancreas. Nat Med. 2024;30(5):1232-1234. doi: 10.1038/d41591-024-00013-5. - DOI - PubMed
1. Kadish AH. Automation control of blood sugar. I. A servomechanism for glucose monitoring and control. Am J Med Electron. 1964;3:82-86. - PubMed
1. Albisser AM, Leibel BS, Ewart TG, Davidovac Z, Botz CK, Zingg W. An artificial endocrine pancreas. Diabetes. 1974;23(5):389-396. doi: 10.2337/diab.23.5.389. - DOI - PubMed
1. Pfeiffer EF, Thum C, Clemens AH. The artificial beta cell–a continuous control of blood sugar by external regulation of insulin infusion (glucose controlled insulin infusion system). Horm Metab Res. 1974;6(5):339-342. doi: 10.1055/s-0028-1093841. - DOI - PubMed
1. Clemens AH, Chang PH, Myers RW. The development of biostator, a glucose controlled insulin infusion system (GCIIS). Horm Metab Res. 1977; suppl 7:23-33. - PubMed

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Early Stages of Automated Insulin Delivery

Affiliations

Early Stages of Automated Insulin Delivery

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Abstract

Conflict of interest statement

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