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.

Continuous amperometric monitoring of subcutaneous oxygen in rabbit by telemetry.

The primary objective was to develop a telemetric oxygen sensor designed for implantation in subcutaneous tissue. In the sensor, the platinum indicating electrode was covered with polythene to retard oxygen entry and avoid interference. Given the potential for large indicating electrodes to deplete oxygen in vivo, some sensors were made with very small indicating electrodes. Sensors were tested in the anesthetized rabbit at various oxygen concentrations. Animals were studied 1 and 5 days after implementation. The sensor could detect changes in oxygen in vivo. Measurements were similar at 1 and 5 days and sensors with different sized electrodes yielded similar results. This telemetric implantable amperometric sensor can detect variations in tissue oxygenation and may have applications in cardiopulmonary physiology, continuous glucose monitoring and other related fields.

Calibration of a subcutaneous amperometric glucose sensor. Part 1. Effect of measurement uncertainties on the determination of sensor sensitivity and background current.

The calibration of a continuous glucose monitoring system, i.e. the transformation of the signal I(t) generated by the glucose sensor at time (t) into an estimation of glucose concentration G(t), represents a key issue. The two-point calibration procedure consists of the determination of a sensor sensitivity S and of a background current I(o) by plotting two values of the sensor signal versus the concomitant blood glucose concentrations. The estimation of G(t) is subsequently given by G(t) = (I(t)-I(o))/S. A glucose sensor was implanted in the subcutaneous tissue of nine type 1 diabetic patients during 3 (n = 2) and 7 days (n = 7). For each individual trial, S and I(o) were determined by taking into account the values of two sets of sensor output and blood glucose concentration distant by at least 1 h, the procedure being repeated for each consecutive set of values. S and I(o) were found to be negatively correlated, the value of I(o) being sometimes negative. Theoretical analysis demonstrates that this phenomenon can be explained by the effect of measurement uncertainties on the determination of capillary glucose concentration and of sensor output.

Calibration of a subcutaneous amperometric glucose sensor implanted for 7 days in diabetic patients. Part 2. Superiority of the one-point calibration method.

UNLABELLED: Calibration, i.e. the transformation in real time of the signal I(t) generated by the glucose sensor at time t into an estimation of glucose concentration G(t), represents a key issue for the development of a continuous glucose monitoring system. OBJECTIVE: To compare two calibration procedures. In the one-point calibration, which assumes that I(o) is negligible, S is simply determined as the ratio I/G, and G(t) = I(t)/S. The two-point calibration consists in the determination of a sensor sensitivity S and of a background current I(o) by plotting two values of the sensor signal versus the concomitant blood glucose concentrations. The subsequent estimation of G(t) is given by G(t) = (I(t)-I(o))/S. RESEARCH DESIGN AND METHODS: A glucose sensor was implanted in the abdominal subcutaneous tissue of nine type 1 diabetic patients during 3 (n = 2) and 7 days (n = 7). The one-point calibration was performed a posteriori either once per day before breakfast, or twice per day before breakfast and dinner, or three times per day before each meal. The two-point calibration was performed each morning during breakfast. RESULTS: The percentages of points present in zones A and B of the Clarke Error Grid were significantly higher when the system was calibrated using the one-point calibration. Use of two one-point calibrations per day before meals was virtually as accurate as three one-point calibrations. CONCLUSION: This study demonstrates the feasibility of a simple method for calibrating a continuous glucose monitoring system.

Understanding spontaneous output fluctuations of an amperometric glucose sensor: effect of inhalation anesthesia and use of a nonenzyme containing electrode.

Implantable glucose sensors are often unstable in vivo. Possible causes include local oscillations of glucose or oxygen levels, fluctuation of interferants, and external electromagnetic interference. To better understand glucose versus nonglucose mediated fluctuations, we compared sensors fabricated with glucose oxidase versus blank electrodes without enzyme in rabbits. We also investigated the effect of general anesthesia. We used power spectral analysis to investigate transmitted signals from amperometric peroxide sensing devices 2-3 weeks after subcutaneous implantation. Fasted animals were studied for 90 minutes in the conscious state and for 90 minutes during halothane anesthesia. Animals exhibited almost no body movement during the studies. In the conscious state, enzyme active sensors demonstrated more oscillations than blank electrodes at almost all frequencies from 2 to > 8 cycles per hour. This finding suggested that the spontaneous fluctuations were secondary to local changes in glucose or oxygen. Because fluctuations were not seen in the blank electrode, periodic changes in interferant concentrations, electromyographic activity, or in external electromagnetic interference are unlikely. General inhalation anesthesia was associated with markedly reduced sensor output fluctuation at almost all frequencies in enzyme active sensors. We conclude that fluctuation of electrochemical glucose sensor output, unrelated to fluctuations in blood glucose, is likely secondary to spontaneous changes in the local concentration or vascular delivery of glucose or oxygen. Anesthesia may have stabilized blood flow, preventing normal spontaneous autoregulatory variation.

Rise in background current over time in a subcutaneous glucose sensor in the rabbit: relevance to calibration and accuracy.

In order to calibrate a continuous glucose monitor, accurate determination of the background current (I0) is necessary, in part because I0 could change over time. We compared two methods of I0 measurement: (1), extrapolation of sensor output data (as a function of glucose level) to the intercept at zero glucose and (2) direct measurement of the output of a blank anode with no enzyme coat. We implanted telemetric sensors subcutaneously in rabbits and measured their outputs during tri-level glucose clamps once per week for 5 weeks. The two methods yielded similar results. I0 rose substantially over time and this increase reached significance during week 3 by the direct method but not until week 5 by the extrapolation method. Using the direct method, I0 rose from 3.41 (0.60-8.48 nanoamperes (nA), median and range) during week 1 to 13.42 (9.1-14.3) during week 5. Using the extrapolation method, I0 rose from 0.57 (0-16.7) during week 1 to 15.3 (12.2-21.6) during week 5. We conclude that I0 can rise over time. If this rise went undetected and was assumed to be stable, a one-point calibration procedure would overestimate glycemia in the hypoglycemic range, i.e. fail to appreciate the severity of hypoglycemia. It is recommended that during validation of a chronic glucose sensor, I0 be measured sequentially over time.

Assessment of chronically implanted subcutaneous glucose sensors in dogs: the effect of surrounding fluid masses.

We developed a continuous, distributed-anode glucose sensor and now report on its use during subcutaneous implantation in dogs without diabetes. Using telemetry, we monitored sensor response to weekly administration of intravenous glucose. In a preliminary attempt to reduce fibrosis around the sensor, some sensors were designed to slowly release dexamethasone (DEX). Before implantation, in vitro sensor sensitivity was similar to values obtained after explantation (0.66 +/- 0.09 vs 1.07 +/- 0.19 nA/mM, n = 9, p = ns). Sensitivity in individual animals varied substantially over time. Average longevity of sensors was 32.1 +/- 8.6 days. Device failure was caused by leakage of fluid into, or interruption of, circuitry. Lag time during glucose ascent averaged 5.8 +/- 1.0 min. In devices that became surrounded by fluid masses, lag time during descent was greater than in devices without fluid (33.7 +/- 4.5 vs 10.7 +/- 1.6 min, p < 0.001). There was a nonsignificant tendency for longevity of the six sensors that contained DEX to be greater than the eight sensors without DEX (47.2 +/- 18.7 vs 20.8 +/- 3.6 days, p = ns). The development of fluid masses surrounding electrochemical glucose sensors prolongs lag time and probably contributes to the commonly observed instability of sensitivity over time. In future long-term implant studies, it is likely that avoidance of fluid masses will improve sensor function.

The case-conferencing project: a first step towards shared care between general practitioners and a mental health service.

OBJECTIVES: The objectives of this study were: (i) to improve general practitioners' knowledge of the mental disorders they commonly treat, and to increase their confidence in managing people with these disorders; and (ii) to increase general practitioners' familiarity with the Logan-Beaudesert Mental Health Service. METHOD: Eleven general practitioners met with psychiatrists from the Logan-Beaudesert Mental Health Service in six 2-hour sessions held at monthly intervals. Each session comprised a teaching component, a consumer interview and a case-conference. Outcomes were measured using an objective test of general practitioners' knowledge, a subjective test of their confidence in dealing with mental health problems, and satisfaction surveys for participating consumers, general practitioners and psychiatrists. RESULTS: On the objective test, the scores of 10 out of the 11 general practitioners improved (p < 0.05). On the subjective test, the ranked scores improved in nine out of the 11 cases (p < 0.05). Consumers, general practitioners and psychiatrists expressed their satisfaction with the format and content of the course. CONCLUSIONS: Having improved the knowledge of a group of general practitioners who are familiar with the functioning of the Logan-Beaudesert Mental Health Service, the stage is now set to proceed to the next step: the shared-care project.

A double-blind comparison of topical capsaicin and oral amitriptyline in painful diabetic neuropathy.

An 8-week double-blind, multicenter, parallel study compared the safety and efficacy of topical capsaicin and oral amitriptyline in patients with painful diabetic neuropathy involving the feet. Two hundred thirty-five patients were randomized to treatment with either capsaicin cream or amitriptyline capsules. Capsaicin-treated patients received inactive capsules, and amitriptyline-treated patients applied vehicle cream. A visual analogue scale of pain intensity and measurements of interference by pain with functional activities were recorded at onset and at 2-week intervals. A visual analogue scale of pain relief and physicians' global evaluation assessed changes in pain status from baseline. Topical capsaicin and oral amitriptyline produced equal and statistically significant improvements in pain over the course of the study. By the end of week 8, 76% of patients in each group experienced less pain, with a mean reduction in intensity of more than 40%. By the end of the study, the interference with daily activities by pain had diminished significantly (P = .001) in both groups, including improvements in sleeping and walking. No systemic side effects were observed in patients treated with topical capsaicin. Most patients receiving amitriptyline experienced at least one systemic side effect, ranging from somnolence (46%) to neuromuscular (23%) and cardiovascular (9%) adverse effects. Topically applied capsaicin is an equally effective but considerably safer alternative to amitriptyline for relief of the pain of diabetic neuropathy.

The contribution of insulin-dependent and insulin-independent glucose uptake to intravenous glucose tolerance in healthy human subjects.

Glucose disposal occurs by both insulin-independent and insulin-dependent mechanisms, the latter being determined by the interaction of insulin sensitivity and insulin secretion. To determine the role of insulin-independent and insulin-dependent factors in glucose tolerance, we performed intravenous glucose tolerance tests on 93 young healthy subjects (55 male, 38 female; 18-44 years of age; body mass index, 19.5-52.2 kg/m2). From these tests, we determined glucose tolerance as the glucose disappearance constant (Kg), calculated beta-cell function as the incremental insulin response to glucose for 19 min after an intravenous glucose bolus (IIR0-19), and derived an insulin sensitivity index (SI) and glucose effectiveness at basal insulin (SG) using the minimal model of glucose kinetics. To eliminate the effect of basal insulin on SG and estimate insulin-independent glucose uptake, we calculated glucose effectiveness at zero insulin (GEZI = SG - [SI x basal insulin]). Insulin-dependent glucose uptake was estimated as SI x IIR0-19, because the relationship between SI and beta-cell function has been shown to be hyperbolic. Using linear regression to determine the influence of these factors on glucose tolerance, we found that GEZI was significantly related to Kg (r = 0.70; P < 0.0001), suggesting a major contribution of insulin-independent glucose uptake to glucose disappearance. As expected, SI x IIR0-19 also correlated well with Kg (r = 0.74; P < 0.0001), confirming the importance of insulin-dependent glucose uptake to glucose tolerance. Although IIR0-19 alone correlated with Kg (r = 0.35; P = 0.0005), SI did not (r = 0.18; P > 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid detection of hyperglycaemia by a subcutaneously-implanted glucose sensor in the rat.

The relationship between the concentration of polymer in the coat of an electrochemical glucose sensor and the lag time between changes in blood glucose and sensor output was explored. Sensors designed to be highly permeable to glucose were coated with a polyurethane mixture diluted 1:6.7 (15%) in trichloroethane. Coats of those designed to be less permeable were diluted 1:2.5 (40%). The in vitro response of the 40% sensors, but not the 15% sensors, was nearly linear up to a glucose level of 56 mM. When tested in 10 rats, the response of the 15% sensors to injected glucose was much more rapid than that of the 40% sensors. The time difference between the peak blood glucose level and peak sensor output was also much smaller for the 15% sensors. In conclusion, use of an electrochemical glucose sensor with high permeability to glucose demonstrates that glucose in the intravascular space equilibrates very rapidly with the subcutaneous space.

Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function.

To determine the relationship between insulin sensitivity and beta-cell function, we quantified the insulin sensitivity index using the minimal model in 93 relatively young, apparently healthy human subjects of varying degrees of obesity (55 male, 38 female; 18-44 yr of age; body mass index 19.5-52.2 kg/m2) and with fasting glucose levels < 6.4 mM. SI was compared with measures of body adiposity and beta-cell function. Although lean individuals showed a wide range of SI, body mass index and SI were related in a curvilinear manner (P < 0.0001) so that on average, an increase in body mass index was associated generally with a lower value for SI. The relationship between the SI and the beta-cell measures was more clearly curvilinear and reciprocal for fasting insulin (P < 0.0001), first-phase insulin response (AIRglucose; P < 0.0001), glucose potentiation slope (n = 56; P < 0.005), and beta-cell secretory capacity (AIRmax; n = 43; P < 0.0001). The curvilinear relationship between SI and the beta-cell measures could not be distinguished from a hyperbola, i.e., SI x beta-cell function = constant. This hyperbolic relationship described the data significantly better than a linear function (P < 0.05). The nature of this relationship is consistent with a regulated feedback loop control system such that for any difference in SI, a proportionate reciprocal difference occurs in insulin levels and responses in subjects with similar carbohydrate tolerance. We conclude that in human subjects with normal glucose tolerance and varying degrees of obesity, beta-cell function varies quantitatively with differences in insulin sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypersensitivity of the hypothalamic-pituitary-adrenal axis to naloxone in post-traumatic stress disorder.

Naloxone, which increases endogenous corticotropin-releasing hormone (CRH) release by blocking an inhibitory opioidergic tone on the hypothalamic-pituitary-adrenal (HPA) axis, was administered in a dose-response protocol to seven healthy volunteers and 13 patients with treated posttraumatic stress disorder (PTSD). Six of the PTSD patients showed an increased hormonal response to the lowest naloxone dose (6 micrograms/kg) compared to both the control subjects and the other PTSD patients. This difference persisted on detailed subgroup analysis, although it was less marked at the highest naloxone dose (125 micrograms/kg). The responses of the other seven PTSD patients were indistinguishable from those of the control group. The greater responses of the six PTSD patients could not be explained on the basis of associated psychiatric illnesses or psychotropic drug therapy, and did not correlate with standard psychological testing or severity of PTSD. The results of this preliminary study therefore suggest that a hypersensitivity of the HPA axis to endogenous CRH stimulation may occur in PTSD.