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

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.