Basu, Ananda

Background: Glucose sensors measure glucose concentration in the interstitial fluid (ISF), remote from blood. ISF glucose is well known to be “delayed” with respect to blood glucose (BG). However, ISF glucose is not simply a shifted-in-time version of BG but exhibits a more complex pattern. Methods: To gain insight into this problem, one can use linear systems theory. However, this may lose a more clinical readership, thus we use simulation and two case studies to convey our thinking in an easier way. In particular, we consider BG concentration measured after meal and exercise in 12 healthy volunteers, whereas ISF glucose is simulated using a well-accepted model of blood–ISF glucose kinetics, which permits calculation of the equilibration time, a parameter characterizing the system. Two metrics are defined: blood and ISF glucose difference at each time point and time to reach the same glucose value in blood and ISF. Results: The simulation performed and the two metrics show that the relationship between blood–ISF glucose profiles is more complex than a pure shift in time and that the pattern depends on both equilibration time and BG. Conclusions: In this in silico study, we have illustrated, with simple case studies, the meaning of the of ISF glucose with respect to BG. Understanding that ISF glucose is not just a shifted-in-time version but a distorted mirror of BG is important for a correct use of continuous glucose monitoring for diabetes management.

Background: The relationship between daily psychological stress and BG fluctuations in type 1 diabetes (T1DM) is unclear. More research is needed to determine if stress-related BG changes should be considered in glucose control algorithms. This study in the usual free-living environment examined relationships among routine daily stressors and BG profile measures generated from CGM readings. Methods: A total of 33 participants with T1DM on insulin pumps wore a CGM device for 1 week and recorded daily ratings of psychological stress, carbohydrates, and insulin boluses. Results: Within-subjects ANCOVAs found a significant relationship between daily stress and indices of BG variability/instability ( r = .172 to .185, P = .011 to .018, r 2 = 2.97% to 3.43%), increased % time in hypoglycemia ( r = .153, P = .036, r 2 = 2.33%) and decreased carbohydrate consumption ( r = –.157, P = .031, r 2 = 2.47%). Models accounted for more variance for individuals reporting the highest daily stress. There was no relationship between stress and mean daily glucose or low/high glucose risk indices. Conclusions: These preliminary findings suggest that naturally occurring daily stressors can be associated with increased glucose instability and hypoglycemia, as well as decreased food consumption. In addition, findings support the hypothesis that some individuals are more metabolically reactive to stress. More rigorous studies using CGM technology are needed to understand whether the impact of daily stress on BG is clinically meaningful and if it is a behavioral factor that should be considered in glucose control systems for some individuals.

Abstract Context: Early postprandial hyperglycemia and delayed hypoglycemia remain major problems in current management of type 1 diabetes (T1D). Objective: Our objective was to investigate the effects of pramlintide, known to suppress glucagon and delay gastric emptying, on postprandial glucose fluxes in T1D. Design: This was a single-center, inpatient, randomized, crossover study. Patients: Twelve patients with T1D who completed the study were analyzed. Interventions: Subjects were studied on two occasions with or without pramlintide. Triple tracer mixed-meal method and oral minimal model were used to estimate postprandial glucose turnover and insulin sensitivity (SI). Integrated liver insulin sensitivity was calculated based on glucose turnover. Plasma glucagon and insulin were measured. Main Outcome Measure: Glucose turnover and SI were the main outcome measures. Results: With pramlintide, 2-hour postprandial glucose, insulin, glucagon, glucose turnover, and SI indices showed: plasma glucose excursions were reduced (difference in incremental area under the curve [iAUC], 444.0 mMmin, P = .0003); plasma insulin concentrations were lower (difference in iAUC, 7642.0 pMmin; P = .0099); plasma glucagon excursions were lower (difference in iAUC, 1730.6 pg/mlmin; P = .0147); meal rate of glucose appearance was lower (difference in iAUC: 1196.2 μM/kg fat free mass [FFM]; P = .0316), endogenous glucose production was not different (difference in iAUC: −105.5 μM/kg FFM; P = .5842), rate of glucose disappearance was lower (difference in iAUC: 1494.2 μM/kg FFM; P = .0083). SI and liver insulin sensitivity were not different between study visits (P > .05). Conclusions: Inhibition of glucagon and gastric emptying delaying reduced 2-hour prandial glucose excursions in T1D by delaying meal rate of glucose appearance.

Background: Recent advances in accuracy and reliability of continuous glucose monitoring (CGM) devices have focused renewed interest on the use of such technology for therapeutic dosing of insulin without the need for independent confirmatory blood glucose meter measurements. An important issue that remains is the susceptibility of CGM devices to erroneous readings in the presence of common pharmacologic interferences. We report on a new method of assessing CGM sensor error to pharmacologic interferences using the example of oral administration of acetaminophen. Materials and Methods: We examined the responses of several different Food and Drug Administration–approved and commercially available CGM systems (Dexcom [San Diego, CA] Seven ® Plus™, Medtronic Diabetes [Northridge, CA] Guardian ® , and Dexcom G4 ® Platinum) to oral acetaminophen in 10 healthy volunteers without diabetes. Microdialysis catheters were placed in the abdominal subcutaneous tissue. Blood and microdialysate samples were collected periodically and analyzed for glucose and acetaminophen concentrations before and after oral ingestion of 1 g of acetaminophen. We compared the response of CGM sensors with the measured acetaminophen concentrations in the blood and interstitial fluid. Results: Although plasma glucose concentrations remained constant at approximately 90 mg/dL (approximately 5 m M ) throughout the study, CGM glucose measurements varied between approximately 85 to 400 mg/dL (from approximately 5 to 22 m M ) due to interference from the acetaminophen. The temporal profile of CGM interference followed acetaminophen concentrations measured in interstitial fluid (ISF). Conclusions: This is the first direct measurement of ISF concentrations of putative CGM interferences with simultaneous measurements of CGM performance in the presence of the interferences. The observed interference with glucose measurements in the tested CGM devices coincided temporally with appearance of acetaminophen in the ISF. The method applied here can be used to determine the susceptibility of current and future CGM systems to interference from acetaminophen or other exogenous pharmacologic agents.

Background: Quantitative assessment of the dynamic relationship between plasma and interstitial fluid (ISF) glucose and the estimation of the plasma-to-ISF delay are of major importance to determine the accuracy of subcutaneous glucose sensors, an essential component of open- and closed-loop therapeutic systems for type 1 diabetes mellitus (T1DM). The goal of this work is to develop a model of plasma-to-ISF glucose kinetics from multitracer plasma and interstitium data, obtained by microdialysis, in healthy and T1DM subjects, under fasting conditions. Materials and Methods: A specific experimental design, combining administration of multiple tracers with the microdialysis technique, was used to simultaneously frequently collect plasma and ISF data. Linear time-invariant compartmental modeling was used to describe glucose kinetics from the tracer data because the system is in steady state. Results: A two-compartment model was shown accurate and was identified from both plasma and ISF data. An “equilibration time” between plasma and ISF of 9.1 and 11.0 min (median) in healthy and T1DM subjects, respectively, was calculated. Conclusions: We have demonstrated that, in steady-state condition, the glucose plasma-to-ISF kinetics can be modeled with a linear two-compartment model and that the “equilibration time” between the two compartments can be estimated with precision. Future studies will assess plasma-to-interstitium glucose kinetics during glucose and insulin perturbations in both healthy and T1DM subjects.

Background: Understanding the effect size, variability, and underlying physiology of the dawn phenomenon is important for next-generation closed-loop control algorithms for type 1 diabetes (T1D). Subjects and Methods: We used an iterative protocol design to study 16 subjects with T1D on individualized insulin pump therapy for two successive nights. Endogenous glucose production (EGP) rates at 3 a.m. and 7 a.m. were measured with [6,6- 2 H 2 ]glucose as a single tracer, infused from midnight to 7 a.m. in all subjects. To explore possibility of tracer recycling due to prolonged [6,6- 2 H 2 ]glucose infusion, which was highly probable after preplanned interim data analyses, we infused a second tracer, [6- 3 H]glucose, from 4 a.m. to 7 a.m. in the last seven subjects to measure EGP at 7 a.m. Results: Cortisol concentrations increased during both nights, but changes in glucagon and insulin concentration were inconsistent. Although the plasma glucose concentrations rose from midnight to 7 a.m. during both nights, EGP measured with [6,6- 2 H 2 ]glucose between 3 a.m. and 7 a.m. did not differ during Night 1 but fell in Night 2. However, EGP measured with [6- 3 H]glucose at 7 a.m. was higher than that measured with [6,6- 2 H 2 ]glucose during both nights, thereby suggesting tracer recycling probably underestimating EGP calculated at 7 a.m. with [6,6- 2 H 2 ]glucose. Likewise, EGP was higher at 7 a.m. with [6- 3 H]glucose than at 3 a.m. with [6,6- 2 H 2 ]glucose during both nights. Conclusions: The data demonstrate a consistent overnight rise in glucose concentrations through increased EGP, mediated likely by rising cortisol concentrations. The observations with the dual tracer approach imply significant tracer recycling leading to underestimation of EGP measured by longer-duration tracer infusion.

Recently, a model was proposed to assess hepatic insulin sensitivity during a meal, i.e., the ability of insulin to suppress glucose production (EGP), SIP. The model was developed on EGP data obtained from a triple-tracer meal and the tracer-to-tracee clamp technique and validated against the euglycemic hyperinsulinemic clamp. The aim of this study was to assess whether SIP can be obtained from plasma concentrations measured after a single-tracer meal by incorporating the above EGP model into the oral glucose minimal model by describing both glucose production and disposal (OMMPD). Triple-tracer meal data of two databases (20 healthy and 60 healthy and prediabetic subjects) were used. Virtually model-independent EGP estimates were calculated. OMMPD was identified on exogenous and endogenous glucose concentrations, providing indices of SIP, disposal insulin sensitivity (SID), and EGP. The model fitted the data well, and SIP and SID were estimated with precision in both databases (SIP = 5.48 ± 0.54 10−4 dl·kg−1·min−1 per μU/ml and SID = 9.93 ± 2.18 10−4 dl·kg−1·min−1 per μU/ml in healthy; SIP = 5.41 ± 3.55 10−4 dl·kg−1·min−1 per μU/ml and SID = 5.34 ± 6.17 10−4 dl·kg−1·min−1 per μU/ml, in healthy and prediabetic subjects). Estimated SIP and that derived from the triple-tracer EGP model were very similar on average. Moreover, the time course of EGP normalized to basal EGP (EGPb), and EGP/EGPb agreed with the results obtained using the triple-tracer method. In this study, we have demonstrated that SIP, SID, and EGP/EGPb time course can be estimated reliably from a single-tracer meal protocol in both healthy and prediabetic subjects.

Numerous studies have used the dual-tracer method to assess postprandial glucose metabolism. The present experiments were undertaken to determine whether the marked tracer nonsteady state that occurs with the dual-tracer approach after food ingestion introduces error when it is used to simultaneously measure both meal glucose appearance (Ra meal) and endogenous glucose production (EGP). To do so, a novel triple-tracer approach was designed: 12 subjects ingested a mixed meal containing [1-13C]glucose while [6-3H]glucose and [6,6-2H2]glucose were infused intravenously in patterns that minimized the change in the plasma ratios of [6-3H]glucose to [1-13C]glucose and of [6,6-2H2]glucose to endogenous glucose, respectively. Ra meal and EGP measured with this approach were essentially model independent, since non-steady-state error was minimized by the protocol. Initial splanchnic glucose extraction (ISE) was 12.9% ± 3.4%, and suppression of EGP (EGPS) was 40.3% ± 4.1%. In contrast, when calculated with the dual-tracer one-compartment model, ISE was higher ( P < 0.05) and EGPS was lower ( P < 0.005) than observed with the triple-tracer approach. These errors could only be prevented by using time-varying volumes different for Ra meal and EGP. Analysis of the dual-tracer data with a two-compartment model reduced but did not totally avoid the problems associated with marked postprandial changes in the tracer-to-tracee ratios. We conclude that results from previous studies that have used the dual-tracer one-compartment model to measure postprandial carbohydrate metabolism need to be reevaluated and that the triple-tracer technique may provide a useful approach for doing so.

To determine if enteral delivery of glucose influences splanchnic glucose metabolism, 10 subjects were studied when glucose was either infused into the duodenum at a rate of 22 μmol · kg −1 · min −1 and supplemental glucose given intravenously or when all glucose was infused intravenously while saline was infused intraduodenally. Hormone secretion was inhibited with somatostatin, and glucose (∼8.5 mmol/l) and insulin (∼450 pmol/l) were maintained at constant but elevated levels. Intravenously infused [6,6- 2 H 2 ]glucose was used to trace the systemic appearance of intraduodenally infused [3- 3 H]glucose, whereas UDP-glucose flux (an index of hepatic glycogen synthesis) was measured using the acetaminophen glucuronide method. Despite differences in the route of glucose delivery, glucose production (3.5 ± 1.0 vs. 3.3 ± 1.0 μmol · kg −1 · min −1 ) and glucose disappearance (78.9 ± 5.7 vs. 85.0 ± 7.2 μmol · kg −1 · min −1 ) were comparable on intraduodenal and intravenous study days. Initial splanchnic glucose extraction (17.5 ± 4.4 vs. 14.5 ± 2.9%) and hepatic UDP-glucose flux (9.0 ± 2.0 vs. 10.3 ± 1.5 μmol · kg −1 · min −1 ) also did not differ on the intraduodenal and intravenous study days. These data argue against the existence of an “enteric” factor that directly (i.e., independently of circulating hormone concentrations) enhances splanchnic glucose uptake or hepatic glycogen synthesis in nondiabetic humans.