Development of a fully automated closed loop artificial pancreas control system with dual pump delivery of insulin and glucagon.

Patients with diabetes have difficulty controlling their blood sugar and suffer from acute effects of hypoglycemia and long-term effects of hyperglycemia, which include disease of the eyes, kidneys and nerves/feet. In this paper, we describe a new system that is used to automatically control blood sugar in people with diabetes through the fully automated measurement of blood glucose levels and the delivery of insulin and glucagon via the subcutaneous route. When a patient's blood sugar goes too high, insulin is given to the patient to bring his/her blood sugar back to a normal level. To prevent a patient's blood sugar from going too low, the patient is given a hormone called glucagon which raises the patient's blood sugar. While other groups have described methods for automatically delivering insulin and glucagon, many of these systems still require human interaction to enter the venous blood sugar levels into the control system. This paper describes the development of a fully automated closed-loop dual sensor bi-hormonal artificial pancreas system that does not require human interaction. The system described in this paper is comprised of two sensors for measuring glucose, two pumps for independent delivery of insulin and glucagon, and a laptop computer running a custom software application that controls the sensor acquisition and insulin and glucagon delivery based on the glucose values recorded. Two control algorithms are designed into the software: (1) an algorithm that delivers insulin and glucagon according to their proportional and derivative errors and proportional and derivative gains and (2) an adaptive algorithm that adjusts the gain factors based on the patient's current insulin sensitivity as determined using a mathematical model. Results from this work may ultimately lead to development of a portable, easy to use, artificial pancreas device that can enable far better glycemic control in patients with diabetes.

Factors influencing the effectiveness of glucagon for preventing hypoglycemia.

BACKGROUND: Administration of small, intermittent doses of glucagon during closed-loop insulin delivery markedly reduces the frequency of hypoglycemia. However, in some cases, hypoglycemia occurs despite administration of glucagon in this setting. METHODS: Fourteen adult subjects with type 1 diabetes participated in 22 closed-loop studies, duration 21.5±2.0 h. The majority of subjects completed two studies, one with insulin + glucagon, given subcutaneously by algorithm during impending hypoglycemia, and one with insulin+placebo. The more accurate of two subcutaneous glucose sensors was used as the controller input. To better understand reasons for success or failure of glucagon to prevent hypoglycemia, each response to a glucagon dose over 0.5 µg/kg was analyzed (n=19 episodes). RESULTS: Hypoglycemia occurred in the hour after glucagon delivery in 37% of these episodes. In the failures, estimated insulin on board was significantly higher versus successes (5.8±0.5 versus 2.9±0.5 U, p<.001). Glucose at the time of glucagon delivery was significantly lower in failures versus successes (86±3 versus 95±3 mg/dl, p=.04). Sensor bias (glucose overestimation) was highly correlated with starting glucose (r=0.65, p=.002). Prior cumulative glucagon dose was not associated with success or failure. CONCLUSION: Glucagon may fail to prevent hypoglycemia when insulin on board is high or when glucagon delivery is delayed due to overestimation of glucose by the sensor. Improvements in sensor accuracy and delivery of larger or earlier glucagon doses when insulin on board is high may further reduce the frequency of hypoglycemia.

In vitro and in vivo evaluation of native glucagon and glucagon analog (MAR-D28) during aging: lack of cytotoxicity and preservation of hyperglycemic effect.

BACKGROUND: For automated prevention of hypoglycemia, there is a need for glucagon (or an analog) to be sufficiently stable so that it can be indwelled in a portable pump for at least 3 days. However, under some conditions, solutions of glucagon can form amyloid fibrils. Currently, the usage instructions for commercially available glucagon allow only for its immediate use. METHODS: In NIH 3T3 fibroblasts, we tested amyloid formation and cytotoxicity of solutions of native glucagon and the glucagon analog MAR-D28 after aging under different conditions for 5 days. In addition, aged native glucagon was subjected to size-exclusion chromatography (SEC). We also studied whether subcutaneous aged Novo Nordisk GlucaGen® would have normal bioactivity in octreotide-treated, anesthetized, nondiabetic pigs. RESULTS: We found no evidence of cytotoxicity from native glucagon or MAR-D28 (up to 2.5 mg/ml) at a pH of 10 in a glycine solvent. We found a mild cytotoxicity for both compounds in Tris buffer at pH 8.5. A high concentration of the commercial glucagon preparation (GlucaGen) caused marked cytotoxicity, but low pH and/or a high osmolarity probably accounted primarily for this effect. With SEC, the decline in monomeric glucagon over time was much lower when aged in glycine (pH 10) than when aged in Tris (pH 8.5) or in citrate (pH 3). Congo red staining for amyloid was very low with the glycine preparation (pH 10). In the pig studies, the hyperglycemic effect of commercially available glucagon was preserved despite aging conditions associated with marked amyloid formation. CONCLUSIONS: Under certain conditions, aqueous solutions of glucagon and MAR-D28 are stable for at least 5 days and are thus very likely to be safe in mammals. Glycine buffer at a pH of 10 appears to be optimal for avoiding cytotoxicity and amyloid fibril formation.

Continuous glucose monitoring in subjects with type 1 diabetes: improvement in accuracy by correcting for background current.

BACKGROUND: A cause of suboptimal accuracy in amperometric glucose sensors is the presence of a background current (current produced in the absence of glucose) that is not accounted for. We hypothesized that a mathematical correction for the estimated background current of a commercially available sensor would lead to greater accuracy compared to a situation in which we assumed the background current to be zero. We also tested whether increasing the frequency of sensor calibration would improve sensor accuracy. METHODS: This report includes analysis of 20 sensor datasets from seven human subjects with type 1 diabetes. Data were divided into a training set for algorithm development and a validation set on which the algorithm was tested. A range of potential background currents was tested. RESULTS: Use of the background current correction of 4 nA led to a substantial improvement in accuracy (improvement of absolute relative difference or absolute difference of 3.5-5.5 units). An increase in calibration frequency led to a modest accuracy improvement, with an optimum at every 4 h. CONCLUSIONS: Compared to no correction, a correction for the estimated background current of a commercially available glucose sensor led to greater accuracy and better detection of hypoglycemia and hyperglycemia. The accuracy-optimizing scheme presented here can be implemented in real time.

Novel use of glucagon in a closed-loop system for prevention of hypoglycemia in type 1 diabetes.

OBJECTIVE: To minimize hypoglycemia in subjects with type 1 diabetes by automated glucagon delivery in a closed-loop insulin delivery system. RESEARCH DESIGN AND METHODS: Adult subjects with type 1 diabetes underwent one closed-loop study with insulin plus placebo and one study with insulin plus glucagon, given at times of impending hypoglycemia. Seven subjects received glucagon using high-gain parameters, and six subjects received glucagon in a more prolonged manner using low-gain parameters. Blood glucose levels were measured every 10 min and insulin and glucagon infusions were adjusted every 5 min. All subjects received a portion of their usual premeal insulin after meal announcement. RESULTS: Automated glucagon plus insulin delivery, compared with placebo plus insulin, significantly reduced time spent in the hypoglycemic range (15 +/- 6 vs. 40 +/- 10 min/day, P = 0.04). Compared with placebo, high-gain glucagon delivery reduced the frequency of hypoglycemic events (1.0 +/- 0.6 vs. 2.1 +/- 0.6 events/day, P = 0.01) and the need for carbohydrate treatment (1.4 +/- 0.8 vs. 4.0 +/- 1.4 treatments/day, P = 0.01). Glucagon given with low-gain parameters did not significantly reduce hypoglycemic event frequency (P = NS) but did reduce frequency of carbohydrate treatment (P = 0.05). CONCLUSIONS: During closed-loop treatment in subjects with type 1 diabetes, high-gain pulses of glucagon decreased the frequency of hypoglycemia. Larger and longer-term studies will be required to assess the effect of ongoing glucagon treatment on overall glycemic control.

Controlled release of dexamethasone from subcutaneously-implanted biosensors in pigs: localized anti-inflammatory benefit without systemic effects.

Chronically implanted biosensors typically lose sensitivity 1-2 months after implantation, due in large part to the development of a collagen-rich capsule that prevents analytes of interest from reaching the biosensor. Corticosteroids are likely candidates for reducing collagen deposition but these compounds have many serious side effects when given over a prolonged period. One method of assessing whether or not locally released corticosteroids have a systemic effect is to measure cortisol concentrations in venous serum. We hypothesized that a very low release rate of the potent corticosteroid, dexamethasone, would lead to a localized anti-inflammatory effect without systemic effects. We found that reduction in subcutaneous granulocytes (primarily eosinophils), and to a lesser extent, reduction of macrophages served as a good local indicator of the steroid effect. When released over a 28-day period, a total dexamethasone dose of < or =0.1 mg/kg led to a consistent reduction in the number of granulocytes and macrophages found in the local vicinity of the implant without a reduction of these cells at distant tissue locations. The lack of suppression of serum cortisol with these doses confirmed that low-release rates of dexamethasone can lead to consistent local anti-inflammatory effects without distant, systemic effects. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010.