The Artificial Pancreas: A Developing Type 1 Diabetes Innovation

Type 1 diabetes (T1D) is a disease characterized by the loss of pancreatic cells that stimulate the production of endogenous insulin. An autoimmune attack destroys β cells, limiting insulin production and resulting in unstable blood glucose levels. When glucose levels are not properly controlled, various complications can occur, leading to morbidity and eventually mortality for patients. 

Innovative approaches to provide consistent regulation of blood glucose levels are being developed to improve outcomes for patients with T1D. One of the most recent breakthroughs has been the creation of artificial pancreas (AP) technology. AP devices try to mimic the function of the pancreas using available and investigational diabetes technology.¹

Physiological Blood Sugar Regulation

In healthy people, glucose levels are regulated by the release of two hormones, insulin and glucagon, into the bloodstream.2 Insulin causes the uptake of glucose in the serum by certain tissues and suppresses the liver’s output; glucagon stimulates the liver to produce glucose and release it into the circulation.

The system is regulated by communication between islet cells in the pancreas, specifically the α and β cells, among other physiologic actions.² β cells, which control the release of insulin, are the target of autoimmune attack in T1D. Glucagon release is controlled by α cells. 

A third hormone, amylin, plays a role in glucose homeostasis during post-meal periods, promoting satiety (a feeling of fullness), slowing gastric emptying and suppressing glucagon secretion. Its action prevents glucose swings and excessive calorie intake. 

What Is an AP?

AP is also known as a “closed-loop automated insulin delivery system.”³ It consists of three components, including the following:³

• a real-time continuous glucose monitor (CGM) inserted subcutaneously, which measures glucose concentrations every five minutes and wirelessly sends information to a control algorithm device (CAD) by a transmitter;
• the CAD, which may be a personal computer, tablet, smartphone or pump device. It hosts a dosing algorithm that computes the correct amount of insulin to deliver, and adjusts the infusion rate based on predicted and current glucose levels; and
• a pump delivering insulin by a subcutaneous tube.

The small pump and infusion circuit are attached subcutaneously to the abdomen or buttocks. The needle must be replaced periodically, although newer systems have extended the period to as long as seven days.¹ 

Pumps come in two forms: tethered or patch types.¹ Tethered pumps are approximately the size of a mobile phone, deliver insulin through a tube and are worn under clothing. Patch pumps are directly attached to the body without a tube and work by remote control. 

Current iterations of AP control only basal insulin delivery, with users required to input information on meals and exercise for calculation of bolus doses. Most require carbohydrate counting to determine mealtime insulin boluses. However, hybrid closed-loop pumps are under investigation that automatically adjust the basal insulin delivery based on CGM data.

AP units currently available on the market deliver only insulin and are classified as single-hormone units. However, dual-hormone products that deliver a second hormone (such as glucagon) are being developed and show promise in improving clinical outcomes.¹ 

Artificial Pancreas vs. Standard Therapies

Outcome studies of AP use have shown the devices increase time in the desired therapeutic blood glucose range (TIR) and reduce the risk of hypo- and hyperglycemia. In one study, the AP group had a 12 percent higher TIR of 70 to 180 milligrams/deciliter (mg/dl) than the control group of children receiving standard care. The treatment effect was more pronounced (18 percent) from 10 p.m. to 6 a.m., suggesting its value during nighttime use when detection of hypoglycemia is challenging.⁴

Single-Hormone Systems

Single-hormone AP systems, which deliver only insulin, are easy to use and have a simple structure.1 However, managing glucose levels can be challenging.

The rationale for using a single-hormone AP over a typical insulin pump is to achieve tighter blood glucose control through real-time readings from the CGM. An early trial of their use showed the t:slim X2 pump improved outcomes. It increased TIR by 11 percent, reduced mean glucose levels by 13 mg/dl and reduced time in hypoglycemia by one percent over a sensor-augmented pump group. It also reduced HbA1c by 0.33 percent over six months of use compared to the control group.⁵

Challenges with the single-hormone systems include exercise-induced hypoglycemia, missed bolus doses and delayed insulin absorption. Mechanical problems with insulin delivery, delayed and variable absorption of insulin products in the subcutaneous tissue and variability in insulin action can also be issues.³

Dual Hormone Systems — Glucagon and Analogs

Dual-hormone AP systems, while still investigational, show promise in preventing rapid fluctuations in blood glucose levels.¹ They have the potential to achieve lower glucose levels, longer TIR and less hypoglycemia than insulin-only systems. They enable more stable glucose management; however, they are complex systems that require advanced skills for operation and management.⁶

The rationale behind the use of glucagon and its analogs in dual-hormone systems is that the compound is rapidly absorbed, preventing hypoglycemia more effectively than stopping an insulin infusion.⁷ Rapid-acting insulins have a duration of three to five hours and remain detectable in the plasma for a period even after they are stopped.⁸ Glucagon is a more effective choice in situations with patients experiencing rapidly dropping blood glucose levels, such as during aerobic exercise.⁹

The disadvantages of dual-hormone systems are that projected inflated costs and complexity of use may make them unsuitable for some users. The low stability of glucagon is also an issue, as cartridges must be replaced every eight to 24 hours. Analogs with longer stability windows, such as dasiglucagon, are in development; it is a ready-to-use aqueous solution that is stable in a prefilled cartridge for seven days. Other investigational options include biochaperone glucagon and nonaqueous soluble glucagon.³

Dual Hormone Systems — Amylin Analogs

Pramlintide, an analog of amylin, is also being investigated for use in dual-hormone AP systems. Deficiencies in amylin parallel those in insulin secretion and lead to poor postprandial blood glucose control and high variability.¹⁰

Studies indicate dual-hormone systems that deliver rapid-acting insulin and pramlintide improve glucose regulation compared with insulin-only systems. They increase TIR, reducing mean glucose levels and variability without increasing hypoglycemia.⁶

One disadvantage of dual-hormone systems with insulin and pramlintide is that current hormones require distinct levels of acidity to be stable and effective. This difference requires two separate cassettes and cannulas.³ However, coformulations of insulin and pramlintide are in development that are stable at similar pH levels. Patients who receive pramlintide also may experience gastrointestinal symptoms, although most are not severe.³

Future Directions

Early research is being conducted on a triple-hormone pump (insulin, glucagon, pramlintide) that would completely mimic physiological pancreatic hormone production.³ It would require use of two cartridges, one with an insulin-pramlintide coformulation and one with glucagon or an analog. It would not require user input for meals or carbohydrate counting.

Ultra-fast-acting insulins also are being developed for AP systems.³ They would better mimic the prandial insulin secretion pattern and prevent or control postprandial glucose swings. They help address insulin delivery delays in the presence of high glucose loads.

Reducing the Impact of Disease

AP therapy demonstrates the promise of improved glucose control, reduced hypoglycemic episodes and prevention of long-term complications for T1D patients. It highlights the continued research on T1D therapies to reduce the impact of this difficult disease.

Current FDA-Approved Artificial Pancreas Systems

NOTE: Tidepool Loop is an app/algorithm, rather than a pump, but works as an artificial pancreas system.