title: A bihormonal closed-loop artificial pancreas for type 1 diabetes.
abstract: 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 < or =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.
authors.affiliation: Department of Biomedical Engineering, Boston University and the Diabetes Unit and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
authors.forename: Firas H
authors.initials: FH
authors.lastname: El-Khatib
authors.affiliation: Department of Biomedical Engineering, Boston University and the Diabetes Unit and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Russell
authors.affiliation: Department of Biomedical Engineering, Boston University and the Diabetes Unit and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
authors.forename: David M
authors.initials: DM
authors.lastname: Nathan
authors.affiliation: Department of Biomedical Engineering, Boston University and the Diabetes Unit and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Sutherlin
authors.affiliation: Department of Biomedical Engineering, Boston University and the Diabetes Unit and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Damiano
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D016503:Drug Delivery Systems; D005260:Female; D005934:Glucagon / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D061268:Insulin Lispro; D008297:Male; D008875:Middle Aged; D019397:Pancreas, Artificial; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007328:Insulin; D061268:Insulin Lispro; D005934:Glucagon
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