Closed-Loop Insulin Delivery Systems: Past, Present, and Future Directions

Abstract

Closed-loop (artificial pancreas) systems for automated insulin delivery have been likened to the holy grail of diabetes management. The first iterations of glucose-responsive insulin delivery were pioneered in the 1960s and 1970s, with the development of systems that used venous glucose measurements to dictate intravenous infusions of insulin and dextrose in order to maintain normoglycemia. Only recently have these bulky, bedside technologies progressed to miniaturized, wearable devices. These modern closed-loop systems use interstitial glucose sensing, subcutaneous insulin pumps, and increasingly sophisticated algorithms. As the number of commercially available hybrid closed-loop systems has grown, so too has the evidence supporting their efficacy. Future challenges in closed-loop technology include the development of fully closed-loop systems that do not require user input for meal announcements or carbohydrate counting. Another evolving avenue in research is the addition of glucagon to mitigate the risk of hypoglycemia and allow more aggressive insulin dosing.

Keywords: artificial pancreas; closed-loop systems; glycemic control; medical devices; type 1 diabetes.

Figure 1

Early closed-loop technologies: (A) Components of the Biostator (reproduced from Fogt et al., 1978); (B) A mobile version of the Biostator (reproduced from Pfeiffer 1987) (10, 11).

Figure 2

The six categories of closed-loop systems as defined by the JDRF.

Figure 3

Commercially available and in-development hybrid closed-loop systems. (A) MiniMed 670G with Guardian Link 3 sensor/transmitter. (B) Omnipod Horizon with patch-pump. (C) CamAPS FX algorithm hosted on Android. (D) Tandem t:slim X2 pump paired with Dexcom G6 sensor. (E) Diabeloop DLBG1 algorithm with Kaleido patch-pump and Dexcom G6 sensor.

Figure 4

A timeline of selected studies of closed-loop systems. CLS = closed-loop system; HCLS = hybrid closed-loop system. References: Weinzimer et al., (24), Phillip et al., (42), Russell et al., (43), Thabit et al., (26), Bergenstal et al., (27), Stewart et al., (44), Kovatchev et al., (45), El-Khatib et al., (46), Brown et al., (47), Tauschmann et al., (48), Lal et al., (32).