Randomized trial of a dual-hormone artificial pancreas with dosing adjustment during exercise compared with no adjustment and sensor-augmented pump therapy.

AIMS: To test whether adjusting insulin and glucagon in response to exercise within a dual-hormone artificial pancreas (AP) reduces exercise-related hypoglycaemia. MATERIALS AND METHODS: In random order, 21 adults with type 1 diabetes (T1D) underwent three 22-hour experimental sessions: AP with exercise dosing adjustment (APX); AP with no exercise dosing adjustment (APN); and sensor-augmented pump (SAP) therapy. After an overnight stay and 2 hours after breakfast, participants exercised for 45 minutes at 60% of their maximum heart rate, with no snack given before exercise. During APX, insulin was decreased and glucagon was increased at exercise onset, while during SAP therapy, subjects could adjust dosing before exercise. The two primary outcomes were percentage of time spent in hypoglycaemia (<3.9 mmol/L) and percentage of time spent in euglycaemia (3.9-10 mmol/L) from the start of exercise to the end of the study. RESULTS: The mean (95% confidence interval) times spent in hypoglycaemia (<3.9 mmol/L) after the start of exercise were 0.3% (-0.1, 0.7) for APX, 3.1% (0.8, 5.3) for APN, and 0.8% (0.1, 1.4) for SAP therapy. There was an absolute difference of 2.8% less time spent in hypoglycaemia for APX versus APN (p = .001) and 0.5% less time spent in hypoglycaemia for APX versus SAP therapy (p = .16). Mean time spent in euglycaemia was similar across the different sessions. CONCLUSIONS: Adjusting insulin and glucagon delivery at exercise onset within a dual-hormone AP significantly reduces hypoglycaemia compared with no adjustment and performs similarly to SAP therapy when insulin is adjusted before exercise.

Factors affecting the success of glucagon delivered during an automated closed-loop system in type 1 diabetes.

BACKGROUND: In bi-hormonal closed-loop systems for treatment of diabetes, glucagon sometimes fails to prevent hypoglycemia. We evaluated glucagon responses during several closed-loop studies to determine factors, such as gain factors, responsible for glucagon success and failure. METHODS: We extracted data from four closed-loop studies, examining blood glucose excursions over the 50min after each glucagon dose and defining hypoglycemic failure as glucose values<60 mg/dl. Secondly, we evaluated hyperglycemic excursions within the same period, where glucose was>180 mg/dl. We evaluated several factors for association with rates of hypoglycemic failure or hyperglycemic excursion. These factors included age, weight, HbA1c, duration of diabetes, gender, automation of glucagon delivery, glucagon dose, proportional and derivative errors (PE and DE), insulin on board (IOB), night vs. day delivery, and point sensor accuracy. RESULTS: We analyzed a total of 251 glucagon deliveries during 59 closed-loop experiments performed on 48 subjects. Glucagon successfully maintained glucose within target (60-180 mg/dl) in 195 (78%) of instances with 40 (16%) hypoglycemic failures and 16 (6%) hyperglycemic excursions. A multivariate logistic regression model identified PE (p<0.001), DE (p<0.001), and IOB (p<0.001) as significant determinants of success in terms of avoiding hypoglycemia. Using a model of glucagon absorption and action, simulations suggested that the success rate for glucagon would be improved by giving an additional 0.8µg/kg. CONCLUSION: We conclude that glucagon fails to prevent hypoglycemia when it is given at a low glucose threshold and when glucose is falling steeply. We also confirm that high IOB significantly increases the risk for glucagon failures. Tuning of glucagon subsystem parameters may help reduce this risk.

A review of artificial pancreas technologies with an emphasis on bi-hormonal therapy.

Since the discovery of insulin, great progress has been made to improve the accuracy and safety of automated insulin delivery systems to help patients with type 1 diabetes achieve their treatment goals without causing hypoglycaemia. In recent years, bioengineering technology has greatly advanced diabetes management, with the development of blood glucose meters, continuous glucose monitors, insulin pumps and control systems for automatic delivery of one or more hormones. New insulin analogues have improved subcutaneous absorption characteristics, but do not completely eliminate the risk of hypoglycaemia. Insulin effect is counteracted by glucagon in non-diabetic individuals, while glucagon secretion in those with type 1 diabetes is impaired. The use of glucagon in the artificial pancreas is therefore a logical and feasible option for preventing and treating hypoglycaemia. However, commercially available glucagon is not stable in aqueous solution for long periods, forming potentially cytotoxic fibrils that aggregate quickly. Therefore, a more stable formulation of glucagon is needed for long-term use and storage in a bi-hormonal pump. In addition, a model of glucagon action in type 1 diabetes is lacking, further limiting the inclusion of glucagon into systems employing model-assisted control. As a result, although several investigators have been working to help develop bi-hormonal systems for patients with type 1 diabetes, most continue to utilize single hormone systems employing only insulin. This article seeks to focus on the attributes of glucagon and its use in bi-hormonal systems.

The effect of rising vs. falling glucose level on amperometric glucose sensor lag and accuracy in Type 1 diabetes.

BACKGROUND: Because declining glucose levels should be detected quickly in persons with Type 1 diabetes, a lag between blood glucose and subcutaneous sensor glucose can be problematic. It is unclear whether the magnitude of sensor lag is lower during falling glucose than during rising glucose. METHODS: Initially, we analysed 95 data segments during which glucose changed and during which very frequent reference blood glucose monitoring was performed. However, to minimize confounding effects of noise and calibration error, we excluded data segments in which there was substantial sensor error. After these exclusions, and combination of data from duplicate sensors, there were 72 analysable data segments (36 for rising glucose, 36 for falling). We measured lag in two ways: (1) the time delay at the vertical mid-point of the glucose change (regression delay); and (2) determination of the optimal time shift required to minimize the difference between glucose sensor signals and blood glucose values drawn concurrently. RESULTS: Using the regression delay method, the mean sensor lag for rising vs. falling glucose segments was 8.9 min (95%CI 6.1-11.6) vs. 1.5 min (95%CI -2.6 to 5.5, P<0.005). Using the time shift optimization method, results were similar, with a lag that was higher for rising than for falling segments [8.3 (95%CI 5.8-10.7) vs. 1.5 min (95% CI -2.2 to 5.2), P<0.001]. Commensurate with the lag results, sensor accuracy was greater during falling than during rising glucose segments. CONCLUSIONS: In Type 1 diabetes, when noise and calibration error are minimized to reduce effects that confound delay measurement, subcutaneous glucose sensors demonstrate a shorter lag duration and greater accuracy when glucose is falling than when rising.

Evidence for the presence of components of the alternative (properdin) pathway of complement activation in respiratory secretions.

Activation of the alternative complement pathway by respiratory secretory IgA was demonstrated by incubating purified, aggregated preparations of serum and secretory IgA with neat human serum. No depletion of the early components (C1-4) was observed, but 63 and 70% of C3-9, respectively, were consumed. The C3-9-consuming capacity of heat-aggregated nasal secretions from an IgA-deficient volunteer was compared with heat-aggregated nasal secretions from a normal volunteer known to have secretory IgA. The deficient secretions consumed C3-9, whereas the IgA deficient secretions did not. Reconstitution of the nasal secretions from the IgA-deficient volunteer with purified secretory IgA produced alternative pathway activation. Factor B of the alternative complement pathway was found to be present in 16 of 18 bronchoalveolar lavage samples (BALF) from normal volunteers. Simultaneous measurement of lavage and serum albumin and Factor B concentrations rendered it unlikely that Factor B was merely a transudative product from serum in half the samples but rather suggested that it may be a component of lower respiratory tract secretions. The presence of an intact alternative complement pathway in BALF was indicated by showing that cobra venom factor and endotoxin cleaved functionally pure human C3 when mixed with BALF, but had no effect on C3 in the absence of BALF.

Comparison of proteolytic enzyme activity in pulmonary alveolar macrophages and blood leukocytes in smokers and nonsmokers.

Proteolysis (or more specifically, elastolysis) of the lung may be involved in the pathogenesis of pulmonary emphysema. To investigate the human alveolar macrophage as a potential mediator of lung damage, elastase-like esterase and protease activity was determined in these cells as well as in alveolar lavage fluid and in peripheral blood leukocytes. Bronchoalveolar lavage was used to obtain alveolar cells and fluid in normal volunteers who were divided into two groups according to cigarette smoking history, nonsmokers and smokers. Results of these studies revealed that human alveolar macrophages possess a high activity of both elastase-like esterase and protease. Furthermore, the alveolar macrophages of cigarette smokers has a significantly greater elastase-like esterase and protease activity than those of nonsmokers. When the 4- to 5-fold increase in the number of macrophages found cigaretts smokers is taken into account there was approximately 10 times more elastase-like esterase activity and 18 times more protease activity within macrophages in the alveolar spaces of cigarette smokers' lungs. This makes the alveolar macrophage a poten potential source of proteolytic enzymes in man.

Pulmonary function evaluation of the lung resection candidate: a prospective study.

In the past, preoperative pulmonary function abnormalities have identified a group of patients in danger of postoperative cardiorespiratory morbidity and mortality. We selected a group of 56 patients, each of whom had a lung mass and had demonstrated significant abnormalities in screening pulmonary function. By using temporary unilateral pulmonary artery occlusion and quantitative macroaggregate lung scanning, we then studied these patients for split pulmonary function. Those patients whose noncancerous lung had a calculated forced expiratory volume in 1 sec greater than 800 ml and a circulation that could accommodate all of the cardiac output without producing hypertension or arterial hypoxemia were offered thoracotomy. Of the 56 patients, we judged 6 to be physiologically inoperable and did not offer surgery. Another 4 patients were not offered surgery, and 4 refused surgery. Forty-two patients underwent surgical exploration-of these, 17 then had a pneumonectomy and 13, a lobectomy. Of the 30 patients resected, 6 died in surgery (4 from respiratory insufficiency). These cardiorespiratory mortality rates (neumonectomy, 17.6 per cent; lobectomy, 7.7 per cent) are lower than those reported previously when patients had equivalent pulmonary function abnormality. A follow-up of 49 of 56 patients revealed that 59 per cent of the patients undergoing either pneumonectomy or lobectomy were still living 1 to 3 years after the resection. Our results suggested that the preoperative testing of split pulmonary function permitted an attempt at surgery in patients who might otherwise be considered inoperable by history, physical examination, screening pulmonary function tests alone.

Alpha-1-antitrypsin content in the serum, alveolar macrophages, and alveolar lavage fluid of smoking and nonsmoking normal subjects.

The content of alpha-1-antitrypsin in the serum, alveolar lavage fluid, and alveolar macrophages of smokers and nonsmokers was studied. Bronchoalveolar lavage was used to obtain alveolar fluid and macrophages from normal volunteers, and alpha-1-antitrypsin and albumin were measured using the electroimmunodiffusion technique. The serum level of inhibitor was not different between the two groups, while the total lavage fliud content of alpha-1-antitrypsin was increased in the smokers. The level of alpha-1-antitrypsin was also significantly greater (P less than 0.001) in the alveolar macrophages of the smokers suggesting the possibility of chronically increased alveolar levels in the cigarette smoker as a possible protective mechanism against proteolysis.