Physiological Differences Between Interstitial Glucose and Blood Glucose Measured in Human Subjects

ERAY KULCU MS 1 JANET A. TAMADA PHD 1 GERARD REACH 0 RUSSELL O. POTTS PHD 1 MATTHEW J. LESHO PHD 1 0 INSERM U341, Diabetes Department, H otel-Dieu Hospital , Paris, France. City, CA 94063 1 Cygnus , Redwood City, California OBJECTIVE - This study investigated whether glucose readings from a sensor sampling in interstitial fluid differ substantially from blood glucose (BG) values measured at the same time. RESEARCH DESIGN AND METHODS - We have evaluated the relationship between BG and glucose extracted from interstitial fluid using the GlucoWatch (Cygnus, Redwood City, CA) biographer, a device that collects glucose from subcutaneous interstitial space through intact skin by application of a low electric current. We evaluated the relative change in the interstitial glucose (IG) signal (IGS) as measured by the biographer versus BG using a normalized two-point sensitivity index (NSI). RESULTS - The results show that biographer measures of IG differ in time and magnitude from the corresponding BG values. In particular, the biographer values were shifted in time due to instrumental and physiological lag. Results show an average total lag of 17.2 7.2 min for all subjects evaluated. The instrumental lag was 13.5 min, suggesting that physiological lag is 5 min. In addition, when glucose was increasing, the change in IGS was less than that in BG, while when BG was decreasing, the change in IGS was greater than that in BG. CONCLUSIONS - Similar results have been reported for other measures of IG, suggesting that differences reflect physiological variation in glucose uptake, utilization, and elimination in blood and interstitial space. This further evidence of the difference between IG and BG should be considered when interpreting glucose measurements from devices that sample interstitial fluid. - G (IG) may differ substantially from when IG was measured by a microdialysis lucose measured in interstitial fluid ferences. Similar results were obtained blood glucose (BG) values mea- technique and compared with BG (2). sured at the same time. Reach et al. (1) The purpose of this study was to inevaluated dynamic changes in IG in rats vestigate whether these differences obusing an implanted glucose sensor. Their served in interstitial fluid glucose sensors results showed that IG was lower than BG can also be observed using an iontowhen glucose was increasing, yet IG and phoretic, transdermal glucose sensor. We BG were similar when glucose was declin- have evaluated the relationship between ing. They developed a physiological BG and glucose extracted from interstitial push-pull model to describe these dif- fluid using a GlucoWatch (Cygnus, Redwood City, CA) biographer. This is an Food and Drug Administration approved device used to detect trends and track patterns in glucose levels (35). It works through a process called reverse iontophoresis (6), which allows the biographer to collect glucose samples from subcutaneous interstitial space through intact skin by application of a low-level electric current. When current is applied, glucose molecules are pulled through the skin, along with charged molecules (positive and negative ions) and the surrounding medium (water). The ions migrate to gel collection discs placed at the anode () and cathode () in a single-use AutoSensor. The glucose molecules are then collected in these discs for analysis. The gel collection discs contain the enzyme glucose oxidase. As glucose enters the discs, it reacts with the glucose oxidase in the gel and forms hydrogen peroxide. A biosensor in contact with each gel collection disc detects the hydrogen peroxide generating a current. This current is integrated, producing a signal in units of electric charge, nanoCoulombs (nC). The biographer uses a calibration value entered by the patient to convert the signal into a glucose measurement. The singlepoint calibration is performed with a traditional BG meter after a 3-h warm-up period. RESEARCH DESIGN AND METHODS Data from existing clinical studies were used for this analysis (5). The studies consisted of diabetic (type 1 and insulin-treated type 2) subjects, each wearing one or two biographers. Informed consent was obtained from all subjects. A total of 59 wear periods were chosen solely on the basis of significant BG excursion throughout the day and sufficient available biographer data to perform time lag analyses. The data were from studies in a controlled clinical setting (28 wear periods) and a simulated home environment (31 wear periods). The investigator induced mild hyper- and hypoglycemia during the studies (between 40 and 450 mg/dl). The 59 biographer wear periods were from 51 unique subjects. There were eight subjects who provided data from two wear periods. There were 22 men and 29 women, and 32 subjects with type 1 diabetes and 19 with type 2 diabetes. The means SD of other descriptive statistics were as follows: age 52 12 years, HbA1c (prestudy) 7.7 1.6%, and BMI 28.6 4.6 kg/m2. Time lag The effect of time lag can potentially confound the assessment of interstitial and BG differences. However, when frequent BG and biographer data are available, it is possible to calculate the time lag between the two measurements and eliminate it. To estimate time lag, IG values were linearly interpolated to yield values every minute. BG readings were taken twice per hour using a HemoCue (Aktiebolaget Leo, Helsingborg, Sweden) analyzer. The time shift required to match the biographer and BG values was then determined using a method similar to cross-correlation analysis, where the biographer glucose data were shifted in time with respect to the BG data until maximal overlap was obtained. This analysis yielded an average total lag of 17.2 7.2 min for the biographer glucose relative to the BG value. A similar value was obtained previously (2). The total lag is a sum of the instruFigure 3 A plot of NSI versus BG1 for decreasing glucose values. The regression line (NSI 1.3821 0.0005 BG1, r 0.023, n 489) is also shown. mental and physiological lag. The instrumental lag arises from biographers measurement method, which produces a glucose value every 20 min by averaging two 10-min values. Each 10-min period consists of 3 min of glucose collection and 7 min of glucose detection. Thus glucose is collected from 20 to 17 min and 10 to 7 min, relative to the biographer value. This leads to an average instrumental lag of 13.5 min. The physiological lag represents the time required for BG to diffuse from capillaries into the interstitial space. The physiological lag associated with the biographer, therefore, is the difference of total lag and instrumental lag. In this case, it was 3.7 min (2), which is in agreement with previously published estimates of time lag between BG and IG (8). For the following analysis, this value was approximated as 5 min. (This analysis used 1-min interpolation of values, so this approximation i (...truncated)