A Feasibility Study of Bihormonal Closed-Loop Blood Glucose Control Using Dual Subcutaneous Infusion of Insulin and Glucagon in Ambulatory Diabetic Swine

• Published in: Journal of diabetes science and technology Vol. 3; no. 4; pp. 789 - 803
• Main Authors: El-Khatib, Firas H., Jiang, John, Damiano, Edward R.
• Format: Journal Article
• Language: English
• Published: United States Diabetes Technology Society 01.07.2009
• Subjects: Algorithms; Animals; Blood Glucose - drug effects; Blood Glucose Self-Monitoring; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - drug therapy; Feasibility Studies; Glucagon - administration & dosage; Glucagon - therapeutic use; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - therapeutic use; Infusions, Subcutaneous; Insulin - administration & dosage; Insulin - therapeutic use; Monitoring, Ambulatory; Original; Swine
• ISSN: 1932-2968; 1932-3107; 1932-3107
• DOI: 10.1177/193229680900300428

We sought to test the feasibility and efficacy of bihormonal closed-loop blood glucose (BG) control that utilizes subcutaneous (SC) infusion of insulin and glucagon, a model-predictive control algorithm for determining insulin dosing, and a proportional-derivative control algorithm for determining glucagon dosing. Thirteen closed-loop experiments (approximately 7-27 h in length) were conducted in six ambulatory diabetic pigs weighing 26-50 kg. In all experiments, venous BG was sampled through a central line in the vena cava. Efficacy was evaluated in terms of the controller's ability to regulate BG in response to large meal disturbances ( approximately 5 g of carbohydrate per kilogram of body mass per meal) based only on regular frequent venous BG sampling and requiring only the subject's weight for initialization. Closed-loop results demonstrated successful BG regulation to normoglycemic range, with average insulin-to-carbohydrate ratios between approximately 1:20 and 1:40 U/g. The total insulin bolus doses averaged approximately 6 U for a meal containing approximately 6 g per kilogram body mass. Mean BG values in two 24 h experiments were approximately 142 and approximately 155 mg/dl, with the total daily dose (TDD) of insulin being approximately 0.8-1.0 U per kilogram of body mass and the TDD of glucagon being approximately 0.02-0.05 mg. Results also affirmed the efficacy of SC doses of glucagon in staving off episodic hypoglycemia. We demonstrate the feasibility of bihormonal closed-loop BG regulation using a control system that employs SC infusion of insulin and glucagon as governed by an algorithm that reacts only to BG without any feed-forward information regarding carbohydrate consumption or physical activity. As such, this study can reasonably be regarded as the first practical implementation of an artificial endocrine pancreas that has a hormonally derived counterregulatory capability.