Continuous Subcutaneous Insulin Delivery Systems: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Viviana Elian
,
Violeta Popovici
,
Emma-Adriana Ozon
,
Adina Magdalena Musuc
,
Ancuța Cătălina Fița
,
Emilia Rusu
,
Gabriela Radulian
,
Dumitru Lupuliasa
An insulin pump is an electronic device that releases rapid insulin according to the body’s daily needs. Insulin pumps deliver insulin in two primary ways: A continuous infusion of small amounts of rapid insulin throughout the day and night (basal rate) and A one-time dose of rapid-acting insulin for meals or high blood glucose correction (bolus).
  • type 1 diabetes mellitus
  • insulin
  • diabetes management
  • technology
  • continuous glucose monitoring systems
  • insulin pumps

1. Introduction

The ideal individuals for insulin pump use are:
  • People with Type 1 Diabetes (T1DM) or insulin-dependent Type 2 diabetes (T2DM);
  • People with multiple-day injections of insulin;
  • People who can assess appropriate blood glucose control;
  • Capable of performing insulin pump therapy initiation and maintenance;
  • Able to maintain frequent contact with the healthcare team;
  • Able to consider insulin pumps as a tool to improve diabetes care;
  • Capable of accurately calculating carbohydrates and insulin bolus;
  • Individuals with critical clinical conditions who have serious difficulties controlling glycemic targets, despite intensive treatment and monitoring;
  • With substantially decompensated diabetes (frequent severe hypoglycemia and/or hyperglycemia);
  • Other associated conditions: extreme insulin sensitivity, gastroparesis, pregnancy, variable schedules or work shifts, significant “dawn phenomenon”, high insulin dose therapy, or severe insulin resistance.

2. Conventional Insulin Pumps

An insulin pump is a small digital device that ensures a continuous infusion of rapid-acting insulin (CSII). The infusion set is inserted into the subcutaneous tissue and fixed on the skin with an adhesive. In most insulin pumps, the infusion set connects to the pump by plastic tubing. Insulin infuses from the pump through the tubing to the infusion set cannula and into the subcutaneous tissue. The most common devices are displayed in Table 1.
Table 1. Comparison between various commercially available CSII pumps.
  AccuChek Spirit Combo Medtronic Paradigm 522/722 Medtronic 720G Omipod Patch Pump Cellnovo Insulin Pump Dana
Diabecare R
Producer Roche Pharma Medtronic Medtronic Insulet Corporation Cellnovo Sooil
Weight (g) 80 100 105   30 51
Dimensions (mm) 80 × 56 × 20 51 × 79 × 20 96 × 53 × 25 Pod: 41 × 61 × 18
PDA: 66 × 110 × 26		 NA 54 × 75 × 19
Insulin Volume per Infusion Set (mL) 315 176-300 300 200 150 300
Basal Increments (units) 0.1 0.05 0.025 0.05 0.05 0.1
Basal Delivery minim (units) 3 10 3 3 3 3
Bolus Increments minim (units) 0.1, 0.2, 0.5, 1,2 0.1 0.025 0.05 0.05 0.1–87
Basal Rates/24 h (units) 24 48 48 48 24 48
Basal Profiles (units) 5 3 8 7 20 4
Bolus Calculator On separate device Yes Yes Yes Yes Yes
Multiple Bolus-type Options Yes Yes Yes Yes Yes Yes
NA = not available.

2. Insulin Patch Pumps (PPs)

Some insulin pumps are directly attached to the skin (patch insulin pumps). A hand device controls insulin delivery in a PP; however, some devices also allow at least some functionality via the PP. The simple forms of PPs intended for insulin therapy aim to be small and disposable, and easy to handle and carry. There are three categories of PPs: PPs with reduced features, fully equipped PPs, and PPs suitable for automatic insulin delivery (AID) systems.
The reduced-features PP delivers only basal insulin. A fully equipped PP delivers a variable amount of basal insulin over 24 h and has a bolus button that permits prandial insulin to be given in two-unit increments daily.
Full-featured electromechanical patch pumps generally have an electromechanical structure with an electronic controller. These are all full-featured pumps with different basal rates, individually controllable bolus amounts, and additional means of bolus delivery.
PPs are small, easy to use, and discreet to wear. Moreover, they can interact with the CGM and AID systems’ algorithms. 

3. Sensor-Augmented Pump (SAP)

An SAP is a CSII that can integrate data from a CGM system. Glycemia is displayed on the pump in real time. It is used by the pump algorithm to automatically stop the basal insulin infusion (for up to 2 h) as a response to detected/predicted hypoglycemia. Then, the basal insulin infusion is released at the previously programmed rate. This feature helps diminish moderate-to-severe hypoglycemia, especially during nighttime, and reach better glycemic control [1]. SAPs are known as open-loop systems [2].
There are two types of SAPT available on the market:
▪
Low-glucose suspend (SAPT-LGS): Suspends basal rate when hypoglycemia occurs.
▪
Predictive low-glucose management (SAPT-PLGM): Can suspend basal rate before hypoglycemia occurs.
SAP can reduce hypoglycemia by 40–50% (<70 mg/dL) without an increase in glycosylated hemoglobin [3][4][5][6].

4. Closed-Loop Insulin Systems (Artificial Pancreas)

A CGM could become a part of a CSII through an algorithm, generating a closed-loop insulin system. It is a substantially improved system, adjusting insulin delivery in response to real-time sensor glucose levels and other inputs, such as meal intake. Control algorithms can modulate the insulin needs’ variability between and within individual users, considering CGM accuracy limitations and insulin delivery imprecision [7].
The three main components of a closed-loop system are:
▪
Glucose measuring device (CGM);
▪
Control device for BG analysis and insulin dosing regulation (computer/microprocessor);
▪
Insulin infusion device (insulin pump).
The control algorithms are continuously adapted to physiological changes with real-time adjustment of closed-loop control parameters.
Various control algorithms were developed [8]: model predictive iterative learning control (MPC) [9][10][11], proportional integral derivative (PID) controllers [12][13], and fuzzy logic control approaches [14][15].
The closed-loop system functions as a pancreas that controls BG levels. Thus, the closed-loop insulin system is known as the artificial pancreas (AP) [16]. When an AP system requires counting and registering the carbohydrate amount from mealtime, it is called a “hybrid” [17] because a part of insulin is provided automatically, and another is infused based on the reported information.
In 2016, the FDA approved the first hybrid closed-loop system [18]. It automatically gives a suitable amount of short-acting insulin at a basal rate. The patient still needs a glucose meter a few times daily, manually adjusting the insulin delivery at mealtimes and when it requires a dose correction. Nowadays, there are several FDA- and EMA-approved systems: Medtronic 770/780G, Tandem Control IQ, Omnipod 5, CamAPS, Diabeloop, etc. (Table 2).
Table 2. Comparison between various commercially available hybrid closed-loop systems [19].
  Tandem t:Slim X2 Control IQ Medtronic 780G Omnipod 5 CamAPS FX
Producer Tandem Diabetes Care,
San Diego, CA, USA		 Medtronic plc,
Dublin, Ireland		 Insulet Corporation,
Acton, MA, USA		 CamDiab Ltd.,
London, UK
Pump Tandem Medtronic Omnipod Dana, Ypsopump
CGM Dexcom G6 Guardian 3 and 4 Dexcom G6 Dexcom G6, Freestyle Libre 3
CGM duration (days) 10 7 10 10/14
Algorithm type MPC PID MPC MPC
Algorithm configuration On pump On pump On pump App on Android smartphone
Approved for ages (years) 6 and above 7 and above 2 and above 1 and above
Weight (g) 112 105 Pod 26
PDA 165		 NA
Dimensions (mm) 79 × 51 × 15 96 × 53 × 25 Pod 39 × 52 × 14.5 NA
Tubeless No No Yes No
Insulin volume per infusion set
(mL)		 300 300 85–200 300
Minimum basal increments (units) 0.001 0.025 0.05 NA
Bolus range (units) 0–25 0–25 0.05–30  
Minimum daily dose (units) 10 8 6 5
Algorithm target (mg/dL) 110–160 100 or 120 110–150 104
(80–198)
Meal detection No Yes No No
Data are available in each product’s technical specifications, adapted from https://www.pcdsociety.org/resources/details/diabetes-technology-state-art, accessed on 10 March 2023. NA = not available.
Another artificial pancreas system is known as a hormonal bionic pancreas (BP) [20][21][22]. It has the next-generation technology to deliver insulin and/or glucagon automatically rather than standard-of-care management. Therefore, BP is more effective in maintaining blood glucose levels within the normal range in T1DM people [23]. In May 2023, the Beta Bionics Inc. (Boston, MA, USA) iLet ACE Pump and iLet Dosing Decision Software pancreas system [20][22][24][25][26] received FDA approval.
Like a healthy pancreas, an utterly automated closed-loop system does not request meal announcements; it can react to BG level variations [27]. The benefits and limitations of closed-loop systems are given in Table 3.
Table 3. Benefits and limitations of closed-loop systems.
Closed-Loop Insulin Systems Benefits Closed-Loop Insulin Systems Limitations
The glucose levels can be continuously monitored. The T1DM patient regularly verifies the devices to ensure that they function correctly.
The control algorithms improve BG control, automatically regulating the amount of insulin. The user must continuously verify the CGM and infusion pump catheter, ensuring they are in a suitable place, and change them when needed.
The system helps the T1DM user avoid emerging events (hypoglycemia and hyperglycemia). The CGM accuracy should be verified, and the CGM sensor must be regularly replaced.
  The patient must count the mealtime carbohydrates and enter them into the system.
  The control software settings must be verified to ensure that the insulin infusion has a suitable amount.
  The extreme BG levels should be regulated if the system is unable.
  The pump’s algorithm could not predict exercise.

Complications

▪
Hypoglycemia occurs when a significant basal rate of insulin is delivered due to a human error in insulin pump programming or a device malfunction.
▪
Hyperglycemia is caused by programming error or device malfunction, leading to a low insulin delivery rate (battery depletion or malposition, cannula occlusion, total pump failure).
▪
If the infusion set is not changed regularly, at 3–4 days, there are irritation and infections at the place of cannula insertion.
▪
Insulin pump therapy discontinuation (18–50%) is the T1DM patient choice for various reasons: unwanted interference with the lifestyle, missing improvements in glycemic control, and infection at the insertion place. It occurs with high incidence in women, younger individuals, pregnancy, and when the patient has psychological comorbidities.

This entry is adapted from the peer-reviewed paper 10.3390/life13081663

References

  1. Berget, C.; Messer, L.H.; Forlenza, G.P. A clinical overview of insulin pump therapy for the management of diabetes: Past, present, and future of intensive therapy. Diabetes Spectr. 2019, 32, 194–204.
  2. Pohar, S.L. Subcutaneous open-loop insulin delivery for type 1 diabetes: Paradigm Real-Time System. Issues Emerg. Health Technol. 2007, 105, 1–6.
  3. Danne, T.; Kordonouri, O.; Holder, M.; Haberland, H.; Golembowski, S.; Remus, K.; Bläsig, S.; Wadien, T.; Zierow, S.; Hartmann, R.; et al. Prevention of Hypoglycemia by using low glucose suspend function in sensor-augmented pump therapy. Diabetes Technol. Ther. 2011, 13, 1129–1134.
  4. Bergenstal, R.M.; Klonoff, D.C.; Garg, S.K.; Bode, B.W.; Meredith, M.; Slover, R.H.; Ahmann, A.J.; Welsh, J.B.; Lee, S.W.; Kaufman, F.R. Threshold-Based Insulin-Pump Interruption for Reduction of Hypoglycemia. N. Engl. J. Med. 2013, 369, 224–232.
  5. Abraham, M.B.; Nicholas, J.A.; Smith, G.J.; Fairchild, J.M.; King, B.R.; Ambler, G.R.; Cameron, F.J.; Davis, E.A.; Jones, T.W. Reduction in Hypoglycemia with the predictive low-Glucose management system: A long-term randomized controlled trial in adolescents with type 1 diabetes. Diabetes Care 2018, 41, 303–310.
  6. Forlenza, G.P.; Li, Z.; Buckingham, B.A.; Pinsker, J.E.; Cengiz, E.; Paul Wadwa, R.; Ekhlaspour, L.; Church, M.M.; Weinzimer, S.A.; Jost, E.; et al. Predictive low-glucose suspend reduces Hypoglycemia in adults, adolescents, and children with type 1 diabetes in an at-home randomized crossover study: Results of the PROLOG trial. Diabetes Care 2018, 41, 2155–2161.
  7. Boughton, C.K.; Hovorka, R. New closed-loop insulin systems. Diabetologia 2021, 64, 1007–1015.
  8. Quiroz, G. The evolution of control algorithms in artificial pancreas: A historical perspective. Annu. Rev. Control 2019, 48, 222–232.
  9. Vigersky, R.A.; Huang, S.; Cordero, T.L.; Shin, J.; Lee, S.W.; Chhabra, H.; Kaufman, F.R.; Cohen, O. Improved HBA1C, total daily insulin dose, and treatment satisfaction with insulin pump therapy compared to multiple daily insulin injections in patients with type 2 diabetes irrespective of baseline C-peptide levels. Endocr. Pract. 2018, 24, 446–452.
  10. Abuin, P.; Rivadeneira, P.S.; Ferramosca, A.; González, A.H. Artificial pancreas under stable pulsatile MPC: Improving the closed-loop performance. J. Process Control 2020, 92, 246–260.
  11. Incremona, G.P.; Messori, M.; Toffanin, C.; Cobelli, C.; Magni, L. Model predictive control with integral action for artificial pancreas. Control Eng. Pract. 2018, 77, 86–94.
  12. Karpelyev, V.A.; Philippov, Y.I.; Averin, A.V.; Boyarskiy, M.D.; Gavrilov, D.A. Development and in silico validation of the pid-algorithm for the artificial pancreas with intraperitoneal insulin delivery. Diabetes Mellit. 2018, 21, 58–65.
  13. Chakrabarty, A.; Gregory, J.M.; Moore, L.M.; Williams, P.E.; Farmer, B.; Cherrington, A.D.; Lord, P.; Shelton, B.; Cohen, D.; Zisser, H.C.; et al. A new animal model of insulin-glucose dynamics in the intraperitoneal space enhances closed-loop control performance. J. Process Control 2019, 76, 62–73.
  14. Soylu, S.; Danisman, K. In silico testing of optimized Fuzzy P+D controller for artificial pancreas. Biocybern. Biomed. Eng. 2018, 38, 399–408.
  15. Mehmood, S.; Ahmad, I.; Arif, H.; Ammara, U.E.; Majeed, A. Artificial pancreas control strategies used for type 1 diabetes control and treatment: A comprehensive analysis. Appl. Syst. Innov. 2020, 3, 31.
  16. Peyser, T.; Dassau, E.; Breton, M.; Skyler, J.S. The artificial pancreas: Current status and future prospects in the management of diabetes. Ann. N. Y. Acad. Sci. 2014, 1311, 102–123.
  17. Janez, A.; Battelino, T.; Klupa, T.; Kocsis, G.; Kuricová, M.; Lalić, N.; Stoian, A.P.; Prázný, M.; Rahelić, D.; Šoupal, J.; et al. Hybrid Closed-Loop Systems for the Treatment of Type 1 Diabetes: A Collaborative, Expert Group Position Statement for Clinical Use in Central and Eastern Europe. Diabetes Ther. 2021, 12, 107–3135.
  18. De Bock, M.; Dart, J.; Roy, A.; Davey, R.; Soon, W.; Berthold, C.; Retterath, A.; Grosman, B.; Kurtz, N.; Davis, E.; et al. Exploration of the Performance of a Hybrid Closed Loop Insulin Delivery Algorithm That Includes Insulin Delivery Limits Designed to Protect Against Hypoglycemia. J. Diabetes Sci. Technol. 2017, 11, 68–73.
  19. Hybrid Closed-Loop Insulin Delivery Systems for People with Type 1 Diabetes. Available online: https://www.cadth.ca/hybrid-closed-loop-insulin-delivery-systems-people-type-1-diabetes (accessed on 14 March 2023).
  20. Elkhatib, F.; Buckingham, B.A.; Buse, J.B.; Harlan, D.M.; Magyar, K.; Ly, T.T.; Kirkman, M.S.; Malkani, S.; Thompson, M.J.; Lock, J.P.; et al. Home use of a bihormonal bionic pancreas vs. Conventional insulin pump therapy in adults with type 1 diabetes: A multicenter, randomized clinical trial. Diabetes 2016, 65, 369–380.
  21. El-Khatib, F.H.; Russell, S.J.; Magyar, K.L.; Sinha, M.; McKeon, K.; Nathan, D.M.; Damiano, E.R. Autonomous and continuous adaptation of a bihormonal bionic pancreas in adults and adolescents with type 1 diabetes. J. Clin. Endocrinol. Metab. 2014, 99, 1701–1711.
  22. Rayannavar, A.; Mitteer, L.M.; Balliro, C.A.; El-Khatib, F.H.; Lord, K.L.; Hawkes, C.P.; Ballester, L.S.; Damiano, E.R.; Russell, S.J.; De Leon, D.D. The bihormonal bionic pancreas improves glycemic control in individuals with hyperinsulinism and post pancreatectomy diabetes: A pilot study. Diabetes Care 2021, 44, 2582–2585.
  23. Beck, R.W.; Russell, S.J.; Damiano, E.R.; El-Khatib, F.H.; Ruedy, K.J.; Balliro, C.; Li, Z.; Calhoun, P. A Multicenter Randomized Trial Evaluating Fast-Acting Insulin Aspart in the Bionic Pancreas in Adults with Type 1 Diabetes. Diabetes Technol. Ther. 2022, 24, 681–696.
  24. Wszola, M.; Klak, M.; Kosowska, A.; Olkowska-Truchanowicz, J.; Tymicki, G.; Berman, A.; Bryniarski, T.; Kołodziejska, M.; Uchrynowska-Tyszkiewicz, I.; Kamiński, A. Bionic pancreas: The first results of functionality bionic tissue model with pancreatic islets. Korean J. Transplant. 2021, 35, S44.
  25. Russell, S.; Balliro, C.; Sherwood, J.; Jafri, R.; Hillard, M.; Sullivan, M.; Greaux, E.; Selagamsetty, R.; El-Khatib, F.; Damiano, E. Home use of the iLet bionic pancreas in the bihormonal configuration using dasiglucagon versus the insulin-only configuration in adults with type 1 diabetes. Diabetes Technol. Ther. 2020, 22, S97.
  26. NCT03565666. The Insulin-Only Bionic Pancreas Bridging Study. 2018. Available online: https://clinicaltrials.gov/show/NCT03565666 (accessed on 10 February 2023).
  27. Forlenza, G.P.; Messer, L.H.; Berget, C.; Wadwa, R.P.; Driscoll, K.A. Biopsychosocial Factors Associated with Satisfaction and Sustained Use of Artificial Pancreas Technology and Its Components: A Call to the Technology Field. Curr. Diab. Rep. 2018, 18, 114.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback