Original ArticleCurrent options for obtaining glucose measurements in animal studies are limited in terms of the quality and quantity of data available. Glucometers and test strips are perhaps most commonly used. These require tail tip amputation or venipuncture, are stressful to the animal and handler, and often result in high measurement variability due to factors including measurement error, variability in the sampling process, and physiologic stress response. The use of arterial or venous cannulae can help facilitate sample collection and minimize subject and handler stress, but these require routine maintenance with blood loss and offer limited chronic patency. Options for continuous sampling for periods of a few days to 2 weeks include tethered automated blood sampling and some limited use of human continuous glucose monitors (CGMs), which have limited longevity and accuracy.Amperometric electrochemical sensors have been available for over 30 years and originated with the Clark electrode.2,3 The basic principle involves application of a reference voltage to an electrode (typically a noble metal such as platinum) to oxidize a target chemical and measure the current resulting from electron transfer to the electrode. The current is proportional to the availability of the target chemical.Many glucose sensors available today or under development are intended for use in humans with the sensor placed subcutaneously to measure glucose in interstitial fluid. These sensors are targeted at the management of diabetes where patient safety and minimal invasiveness are critical factors, thus precluding placement directly in the blood. These sensors are subject to notable biofouling due to foreign body immune response and are typically overgrown with a fibrous sheath in a matter of days. Background: Chronic continuous glucose monitoring options for animal research have been very limited due to various technical and biological challenges. We provide an evaluation of a novel telemetry device for continuous monitoring of temperature, activity, and plasma glucose levels in the arterial blood of rats for up to 2 months. Methods:In vivo testing in rats including oral glucose tolerance tests (OGTTs) and intraperitoneal glucose tolerance tests (IPGTTs) and ex vivo waterbath testing were performed to evaluate acute and chronic sensor performance. Animal studies were in accordance with the guidelines for the care and use of laboratory animals and approved by the corresponding animal care and use committees (Data Sciences International, Eli Lilly). Results:Results demonstrated the ability to record continuous measurements for 75 days or longer. Bench testing demonstrated a high degree of linearity over a range of 20-850 mg/dL with R 2 = .998 for linear fit and .999 for second order fit (n = 8 sensors). Evaluation of 6 rats over 28 days with 52 daily and OGTT test strip measurements each resulted in mean error of 3.8% and mean absolute relative difference of 16.6%. Conclusions:This device provides significant advantages in the qualit...
Euthanasia is a necessary component in research and must be conducted humanely. Currently, regulated CO2 exposure in conscious rats is acceptable, but data are divided on whether CO2 alone is more distressing than anesthesia prior to CO2. To evaluate distress in rats, we compared physiologic responses to CO2 euthanasia with and without isoflurane preanesthesia. Male Sprague–Dawley rats were implanted with telemetry devices to measure mean arterial pressure (MAP), heart rate (HR), and blood glucose. Animals recovered for 2 wk and were then exposed to either 5% isoflurane (n = 6) or 100% CO2(n = 7; calculated 30% chamber volume/min displacement) in their home cages to induce loss of consciousness. Euthanasia was then completed with CO2 in both groups. MAP and HR increased when the gas delivery lids were placed on the home cages of both groups. Both MAP and HR gradually decreased with isoflurane exposure. MAP increased and HR decreased with CO2 exposure. Glucose levels remained stable throughout the procedure, except for a small drop in conscious animals initially exposed to 100% CO2. These data suggest that both gases affect the measured parameters in a similar manner, andthat environmental factors, such as gas delivery lid placement, also change these measurements.
Until recently, preclinical and clinical work on diabetes has focused on the understanding of blood glucose elevation and its detrimental metabolic sequelae. The advent of continuous glucose monitoring (CGM) technology now allows real time monitoring of blood glucose levels as a time series, and thus the exploration of glucose dynamics at short time scales. Previous work has shown decreases in the complexity of glucose dynamics, as measured by multiscale entropy (MSE) analysis, in diabetes in humans, mice, and rats. Analyses for non-human primates (NHP) have not been reported, nor is it known if anti-diabetes compounds affect complexity of glucose dynamics. We instrumented four healthy and six diabetic rhesus monkeys with CGM probes in the carotid artery and collected glucose values at a frequency of one data point per second for the duration of the sensors’ life span. Sensors lasted between 45 and 78 days. Five of the diabetic rhesus monkeys were also administered the anti-diabetic drug liraglutide daily beginning at day 39 of the CGM monitoring period. Glucose levels fluctuated during the day in both healthy and diabetic rhesus monkeys, peaking between 12 noon – 6 pm. MSE analysis showed reduced complexity of glucose dynamics in diabetic monkeys compared to healthy animals. Although liraglutide decreased glucose levels, it did not restore complexity in diabetic monkeys consistently. Complexity varied by time of day, more strongly for healthy animals than for diabetic animals. And by dividing the monitoring period into 3-day or 1-week subperiods, we were able to estimate within-animal variability of MSE curves. Our data reveal that decreased complexity of glucose dynamics is a conserved feature of diabetes from rodents to NHPs to man.
The effect of high fat diet on glucose and food intake (FI) in pre‐diabetic ZDSD male rats was assessed using continuous glucose (CG) telemetry (DSI, model HD‐XG) and the BioDAQ FI monitoring system (Research Diets). Ten male rats, 14 weeks old were housed singly for 3 days prior to aseptic surgery to acclimate them to the FI system on control diet (Purina # 5008). All rats under isofluorane anesthesia were implanted with glucose sensor in the abdominal aorta and transmitter in the peritoneum. Animals recovered and FI returned to normal levels within 7 days at which time the glucose telemeters were turned on and measurements began. Animals were maintained on 5008 for 2 weeks at which time an OGTT was performed. Animals were then switched to a high fat diet (Research Diets # D12468) for an additional 2 weeks at which time another OGTT was performed. OGTT AUC was significantly larger in the presence of D12468 when compared to 5008 (35.5x103±1.4; 30.1x103±0.9 mg/dl x 180 min, respectively). CG monitoring allowed for visualization of the diurnal pattern that was not seen with FI and would not have been detected using twice daily sampling. DietGlucose‐Nadir(mg/dl)Glucose‐Peak(mg/dl)FI‐AM(gm/meal)FI‐ PM(gm/meal)FI‐AM(kcal/meal)FI‐PM(kcal.meal)5008103.9±3.2176.9±2.5*3.28±0.223.35±0.2311.49±0.7811.74±0.82D12468109.5±4.1246.1±6.6*,**3.25±0.323.75±0.3515.64±1.5318.04±1.61*p<0.05 AM vs PM, **p<0.05 D12468 vs 5008. Mean±SEM, n=6‐7 rats There was a significant elevation in glucose during the PM while FI was the same. When rats were switched to D12468 their glucose excursion was significantly greater, even though their FI was the similar to 5008.
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