Introduction
For automated insulin delivery, closed-loop (artificial pancreas) devices have been compared to the proverbial "holy grail" of diabetes control. Intensive insulin therapy, administered as either many daily injections or continuous subcutaneous insulin infusion via the pump, is the cornerstone of treatment for type 1 diabetes. Intense insulin therapy aims to achieve tight glycemic control and lower the risk of micro- and macrovascular consequences of hyperglycemia by simulating physiological insulin release by pancreatic beta cells in a basal-bolus mode. However, the substantial burden of self-management necessary with frequent blood glucose monitoring and adjustment of insulin dosing prevents many people with type 1 diabetes from achieving adequate glycemic control. In the 1970s, insulin pumps initially entered clinical use; since then, they have become more reliable and smaller. Systems for continuous glucose monitoring (CGMS) are more precise and less invasive today.
For patients with type 1 diabetes (T1D), achieving the necessary glycaemic targets might be difficult without dealing with troublesome hypoglycemia and a significant amount of diabetes self-care. The Diabetes Control and Complications Trial demonstrated the advantages of intensive insulin therapy for lowering the risk of long-term complications, which increased the use of insulin pump therapy (continuous subcutaneous insulin infusion) to improve glycemic (blood sugar) outcomes, lower the risk of hypoglycemia (reduced blood sugar), and enhance the quality of life for those with type 1 diabetes.
What Are Early Closed-Loop Systems?
The first closed-loop insulin administration system, known as the "servomechanism for blood glucose management," included two intravenous syringe pumps containing insulin and either glucose or glucagon and an autoanalyzer for continuous blood glucose monitoring via an intravenous catheter. The insulin pump was turned on when the blood glucose level increased above the upper threshold, and the glucose or glucagon pump was turned on when it fell below the lower threshold. Both pumps were turned off when the blood glucose level was within a specified goal range.
What Are Fully Closed-Loop Systems?
The development and commercialization of various sophisticated glucose-sensing and insulin-delivery systems have increased fully closed-loop systems since the middle of the 2000s. With the advancements in technology for interstitial glucose sensors and insulin pumps, the focus shifted to the creation of a closed-loop subcutaneous-subcutaneous system. In order to encourage research into closed-loop technologies, regulatory approval of those technologies, and ultimately their deployment, the Juvenile Diabetes Research Foundation (JDRF) launched the artificial pancreas project in 2005. According to the degree of automation involved, the JDRF established six types of artificial pancreas systems at the time. All were in various phases of development, but none were commercially ready.
First Generation
1. Very Low Glucose Insulin Pump Off Pump - The pump shuts down due to very low glucose levels when the user does not react to the low glucose alarm.
2. Hypoglycemia Minimizer - Predictive hypoglycemia raises the alarm and causes the supply of insulin to stop before blood sugar levels drop.
3. Hypoglycemia and Hypoglycemia Minimizer - The difference between hypoglycemia and hypoglycemia minimizers is a characteristic that permits the dosage of insulin over high thresholds (for instance, 200 milligrams/deciliter).
Second Generation
1. Automated Basal Hybrid Closed Loop - Always in a closed loop with a mealtime manual to help with blousing.
2. Fully Automated Insulin Closed Loop - Eliminated manual mealtime clocks.
Third generation
1. Fully Automated Multi-Hormone Closed Loop - Instead of requiring human input for lunchtime boluses, hybrid systems are made to automate all insulin delivery.
Compared to other methods, closed-loop insulin delivery is more complicated. The parts of the closed-loop system communicate wirelessly and either have a control algorithm built into the insulin pump or are housed on a different device, like a smartphone. The control algorithm receives real-time glucose data from a continuous glucose monitoring device and, based on sensor glucose levels, automatically modifies the insulin infusion rate every five to ten minutes to direct insulin delivery via the insulin pump (single-hormone closed-loop systems). Within dual-hormone closed-loop systems, other hormones, such as glucagon, can also be administered in a glucose-responsive manner similarly.
One of the main advantages of closed-loop insulin delivery over sensor-augmented pump therapy is the continuous and automatic regulation of insulin delivery rates to adjust to the within-day and between-day variability of insulin demand.
What Are Hybrid Closed-Loop Systems?
Fully closed-loop devices automatically inject insulin without knowledge of meals, while hybrid closed-loop systems require users to actively begin mealtime boluses. The latter has the advantage of requiring less user involvement. Since totally closed-loop systems are ineffective in controlling blood sugar because subcutaneous insulin absorption takes longer than expected, the majority of closed-loop devices use a hybrid method. Fully closed-loop methods are linked to considerable postprandial excursions in hyperglycemia and late postprandial hypoglycemia. To enhance the effectiveness of fully closed-loop systems in controlling postprandial hyperglycemia, ultra-rapid insulin analogs or adjuncts are required.
Hybrid closed-loop systems employ a computerized algorithm to modify the basal rate of insulin and deliver corrected bolus doses in an effort to reduce hypoglycemia and hyperglycemia and keep glucose levels within the desired range.
What Are Dual Hormone Closed-Loop Systems?
The insulin-glucagon system can be approached in one of two ways:
1. Either by using tiny boluses to prevent hypoglycemia without increasing insulin delivery.
2. Or by intermittent glucagon doses to enable more aggressive insulin administration to target lower glucose levels.
Dual-hormone closed-loop systems have been demonstrated to decrease hypoglycemia, enhance mean glucose levels, and lengthen the amount of time spent in the target glycemic range when compared to standard insulin pump therapy. Single-hormone and dual-hormone closed-loop systems were compared in a 2017 meta-analysis, and the dual-hormone strategy increased time in target. The absence of stable liquid glucagon formulations is the greatest obstacle to the development and use of glucagon-containing closed-loop devices; some studies have employed glucagon cartridges that need to be changed as frequently as every eight hours, in the most recent study of the dual-chamber iLet, which includes insulin and Dasiglucagon (ready-to-use glucagon), a chemically stable synthetic glucagon analog.
Conclusion
The adoption of commercially available hybrid closed-loop systems into clinical practice for adults with type 1 diabetes is supported by extensive clinical data that automated insulin delivery devices are a safe and effective strategy. There is rising support for using the closed-loop strategy with hyperglycemic hospitalized patients and pregnant individuals. Automated insulin delivery systems must continue to improve acceptability, performance, and device burden. Understanding the training and support requirements for both users and healthcare professionals is essential for adopting the closed-loop approach as the norm of care in managing diabetes.
