A Bihormonal Closed-Loop Artificial Pancreas for Type 1 Diabetes

An algorithm continuously delivers appropriate insulin and glucagon doses to diabetic patients, maintaining their blood glucose at near-normal values, even after high-carbohydrate meals. Using Math to Treat Diabetes: Automated Blood Glucose Control People with Type 1 diabetes become experts at monitoring their own blood glucose levels, self-injecting insulin daily to compensate for the loss of their pancreatic islet cells. This lifelong vigilance is difficult, and stable blood glucose can often be elusive. An artificial pancreas would be a welcome development. El-Khatib and colleagues have now taken the first steps toward developing such a device and have shown that their system can keep blood glucose within an acceptable range, even after carbohydrate-rich meals. Their artificial “pancreas,” really a closed-loop control system, is composed of a continuous blood sugar monitor, hormone pumps, and a laptop running a computer program that allows the two pumps to communicate and calculate how much hormone the patient needs at any given time. As in a real pancreas, two hormones with opposing actions on blood sugar—insulin and glucagon—were delivered into the subjects’ bloodstream. The computer algorithm incorporated a pharmacokinetic model for insulin so that it could accurately account for the decay of insulin levels in the blood. Of the 11 subjects, who were followed for 27 hours, six maintained a desirable mean blood glucose concentration of 140 mg/dl with no decreases. For the other five subjects, their slower insulin absorption required adjustment of the pharmacokinetic model to maintain stable a blood glucose concentration, but once this was done, they too showed no hypoglycemia. Although in these experiments the algorithm was executed on a laptop computer, the device could eventually run on a computer chip as part of a fully wearable, portable artificial pancreas system. Such a device would provide better control of diabetics’ blood glucose concentrations and improve their quality of life. Automated control of blood glucose (BG) concentration is a long-sought goal for type 1 diabetes therapy. We have developed a closed-loop control system that uses frequent measurements of BG concentration along with subcutaneous delivery of both the fast-acting insulin analog lispro and glucagon (to imitate normal physiology) as directed by a computer algorithm. The algorithm responded only to BG concentrations and incorporated a pharmacokinetic model for lispro. Eleven subjects with type 1 diabetes and no endogenous insulin secretion were studied in 27-hour experiments, which included three carbohydrate-rich meals. In six subjects, the closed-loop system achieved a mean BG concentration of 140 mg/dl, which is below the mean BG concentration target of ≤154 mg/dl recommended by the American Diabetes Association. There were no instances of treatment-requiring hypoglycemia. Five other subjects exhibited hypoglycemia that required treatment; however, these individuals had slower lispro absorption kinetics than the six subjects that did not become hypoglycemic. The time-to-peak plasma lispro concentrations of subjects that exhibited hypoglycemia ranged from 71 to 191 min (mean, 117 ± 48 min) versus 56 to 72 min (mean, 64 ± 6 min) in the group that did not become hypoglycemic (aggregate mean of 84 min versus 31 min longer than the algorithm’s assumption of 33 min, P = 0.07). In an additional set of experiments, adjustment of the algorithm’s pharmacokinetic parameters (time-to-peak plasma lispro concentration set to 65 min) prevented hypoglycemia in both groups while achieving an aggregate mean BG concentration of 164 mg/dl. These results demonstrate the feasibility of safe BG control by a bihormonal artificial endocrine pancreas.