Slama, Michael

While the triple tracer isotope dilution method has enabled accurate estimation of carbohydrate turnover after a mixed meal, use of the simple carbohydrate glucose as the carbohydrate source limits its translational applicability to everyday meals that typically contain complex carbohydrates. Hence, utilizing the natural enrichment of [13C]polysaccharide in commercially available grains, we devised a novel tracer method to measure postprandial complex carbohydrate turnover and indices of insulin action and β-cell function and compared the parameters to those obtained after a simple carbohydrate containing mixed meal. We studied healthy volunteers after either rice ( n = 8) or sorghum ( n = 8) and glucose ( n = 16) containing mixed meals and modified the triple tracer technique to calculate carbohydrate turnover. All meals were matched for calories and macronutrient composition. Rates of meal glucose appearance (2,658 ± 736 vs. 4,487 ± 909 μM·kg−1·2 h−1), endogenous glucose production (−835 ± 283 vs. −1,123 ± 323 μM·kg−1·2 h−1) and glucose disappearance (1,829 ± 807 vs. 3,606 ± 839 μM·kg−1·2 h−1) differed ( P < 0.01) between complex and simple carbohydrate containing meals, respectively. Interestingly, there were significant increase in indices of insulin sensitivity (32.5 ± 3.5 vs. 25.6 ± 3.2 10−5(dl·kg−1·min−2)/pM, P = 0.006) and β-cell responsivity (disposition index: 1,817 ± 234 vs. 1,236 ± 159 10−14(dl·kg−1·min−2)/pM, P < 0.005) with complex than simple carbohydrate meals. We present a novel triple tracer approach to estimate postprandial turnover of complex carbohydrate containing mixed meals. We also report higher insulin sensitivity and β-cell responsivity with complex than with simple carbohydrates in mixed meals of identical calorie and macronutrient compositions in healthy adults.

Background: Reliability of continuous glucose monitors (CGM) is a prerequisite for therapeutic dosing of insulin without the need for confirmatory blood glucose meter measurements. Interference of CGMs with commonly prescribed substances has not been extensively evaluated. Methods: We sought to undertake a novel pilot study to determine the susceptibility of FDA-approved CGM systems (Medtronic Guardian Sof-Sensor, Dexcom G4 Platinum) to erroneous readings in the presence of common medications. CGMs were placed on the abdomen of healthy subjects 48 hours prior to study. Subjects were admitted to the Clinical Research Trials Unit (CRTU) on the evening before study and fed a standard supper. The following morning, an oral medication was administered in the fasted state and blood was sampled for 9 hours. CGM values were compared to ambient glucose (measured with YSI) to observe variations in CGM readings. Microdialysis catheters were also placed in the abdomen to sample interstitial fluid (ISF) for drug concentrations. Results: Nineteen healthy drug-naïve subjects without diabetes participated in the study. A drug/substance was tested up to a maximum of nine times on separate occasions. Comparison of CGM glucose patterns to actual plasma glucose concentrations show several drugs, including lisinopril, albuterol, and acetaminophen, appear to interfere with commonly used CGM devices. Wine also interfered with CGM readings. Conclusions: We conclude there is some evidence of CGM interference with lisinopril, albuterol, acetaminophen, atenolol, and red wine. Future studies are required to address interference with newer sensors being approved or in the process of approval.

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 and Objective: The premise of effective closed-loop insulin therapy for type 1 diabetes (T1D) relies on the accuracy of continuous interstitial fluid glucose sensing that represents the crucial afferent arm of such a system. An important determinant of sensor accuracy is the physiological time lag of glucose transport from the vascular to the interstitial space. The purpose of current studies was to determine the physiological time lag of glucose transport from the vascular to the abdominal subcutaneous interstitial space in T1D. Method: Four microdialysis catheters were inserted into the abdominal subcutaneous space in 6 T1D subjects under overnight fasted conditions. Plasma glucose was maintained at 113.7 ± 6.3 mg/dl using a continuous intravenous insulin infusion. After sequential intravenous bolus administrations of glucose isotopes, timed plasma and interstitial fluid samples were collected chronologically and analyzed for tracer enrichments. Results: We observed a median (range) time lag of tracer appearance (time to detection) into the interstitial space after intravenous bolus of 6.8 (4.8-9.8) minutes, with all participants having detectable values by 9.8 minutes. Conclusions: We conclude that in the overnight fasted state in T1D adults, the delay of glucose appearance from the vascular to the interstitial space is less than 10 minutes, thereby implying that this minimal physiological time lag should not be a major impediment to the development of an effective closed-loop control system for T1D.

The accuracy of continuous interstitial fluid (ISF) glucose sensing is an essential component of current and emerging open- and closed-loop systems for type 1 diabetes. An important determinant of sensor accuracy is the physiological time lag of glucose transport from the vascular to the interstitial space. We performed the first direct measurement of this phenomenon to our knowledge in eight healthy subjects under an overnight fasted condition. Microdialysis catheters were inserted into the abdominal subcutaneous space. After intravenous bolus administrations of glucose tracers, timed samples of plasma and ISF were collected sequentially and analyzed for tracer enrichments. After accounting for catheter dead space and assay noise, the mean time lag of tracer appearance in the interstitial space was 5.3–6.2 min. We conclude that in the overnight fasted state in healthy adults, the physiological delay of glucose transport from the vascular to the interstitial space is 5–6 min. Physiological delay between blood glucose and ISF glucose, therefore, should not be an obstacle to sensor accuracy in overnight or fasting-state closed-loop systems of insulin delivery or open-loop therapy assessment for type 1 diabetes.