Showing papers in "Diabetes Technology & Therapeutics in 2005"

A novel approach to continuous glucose analysis utilizing glycemic variation.

Abstract: Background: Various methodologies have been proposed for analysis of continuous glucose measurements. These methods have mainly focused on the proportion of low or high glucose readings and have not attempted to analyze other dimensions of the data obtained. This study proposes an algorithm for analysis of continuous glucose data including a novel method of assessing glycemic variability. Methods: Mean blood glucose and mean of daily differences (MODD) assessed the degree that the Continuous Glucose Monitoring System (CGMS®, Medtronic MiniMed, Northridge, CA) trace was representative of the 3-month glycemic pattern. Percentages of times in low, normal, and high glucose ranges were used to assess marked glycemic excursion. Continuous overall net glycemic action (CONGA), a novel method developed by the authors, assessed intra-day glycemic variability. These methods were applied to 10 CGMS traces chosen randomly from those completed by children with type 1 diabetes from the Royal Children's Hospital, Melbour...

A critical assessment of algorithms and challenges in the development of a closed-loop artificial pancreas.

Abstract: The development of an artificial pancreas is placed in the context of the history of the field of feedback control systems, beginning with the water clock of ancient Greece, and including a discussion of current efforts in the control of complex systems. The first generation of artificial pancreas devices included two manipulated variables (insulin and glucose infusion) and nonlinear functions of the error (difference between desired and measured glucose concentration) to minimize hyperglycemia while avoiding hypoglycemia. Dynamic lags between insulin infusion and glucose measurement were relatively small for these intravenous-based systems. Advances in continuous glucose sensing, fast-acting insulin analogs, and a mature insulin pump market bring us close to commercial realization of a closed-loop artificial pancreas. Model predictive control is discussed in-depth as an approach that is well suited for a closed-loop artificial pancreas. A major challenge that remains is handling an unknown glucose distur...

Minimally invasive extraction of dermal interstitial fluid for glucose monitoring using microneedles.

Abstract: Background: Compliance with glucose monitoring by patients with diabetes is poor because of the pain and inconvenience of conventional blood collection using lancets. To improve compliance, and thereby reduce morbidity and mortality associated with poor glucose control, this study sought to develop and test minimally invasive microneedles to extract dermal interstitial fluid (ISF) for glucose monitoring. Methods: We used a thermal puller to fabricate individual or multi-needle arrays of glass microneedles with tip radii of 15–40 µm to penetrate 700–1,500 µm deep into the skin of anesthetized hairless rats or conscious, normal, adult, human subjects. After applying a vacuum of 200–500 mm Hg for 2–10 min, we extracted ISF and measured glucose concentration. These measurements were compared with glucose levels in blood collected from the tail vein of rats or finger stick on humans. Results: Using this procedure, 1–10 µL of ISF was extracted out of holes punctured in the skin using microneedles. Human subject...

Breath Ethanol and Acetone as Indicators of Serum Glucose Levels: An Initial Report

Abstract: Background: Many volatile organic compounds are present in exhaled breath and may represent by-products of endogenous biological processes. Ethanol is produced via alcoholic fermentation of glucose by gut bacteria and yeast, while acetone derives from oxidations of free fatty acids, influenced by glucose metabolism. We hypothesized that the integrated analysis of breath ethanol and acetone would provide a good approximation of the blood glucose profile during a glucose load. Methods: We collected simultaneous exhaled breath gas, ambient air, and serum glucose and insulin samples from 10 healthy volunteers at baseline and during an oral glucose tolerance test (OGTT) (ingestion of 75 g of glucose followed by 120 min of sampling). Gas samples were analyzed by gas chromatography/mass spectrometry. Results: Mean glucose values displayed a typical OGTT pattern (rapid increase, peak values at 30–60 min, and gradual return to near baseline by 120 min). Breath ethanol displayed a similar pattern early in the test,...

Quantifying temporal glucose variability in diabetes via continuous glucose monitoring: mathematical methods and clinical application.

Abstract: Background: Continuous glucose monitors (CGMs) collect detailed blood glucose (BG) time series, which carry significant information about the dynamics of BG fluctuations. In contrast, the methods for analysis of CGM data remain those developed for infrequent BG self-monitoring. As a result, important information about the temporal structure of the data is lost during the translation of raw sensor readings into clinically interpretable statistics and images. Methods: The following mathematical methods are introduced into the field of CGM data interpretation: (1) analysis of BG rate of change; (2) risk analysis using previously reported Low/High BG Indices and Poincare (lag) plot of risk associated with temporal BG variability; and (3) spatial aggregation of the process of BG fluctuations and its Markov chain visualization. The clinical application of these methods is illustrated by analysis of data of a patient with Type 1 diabetes mellitus who underwent islet transplantation and with data from clinical tr...

The development and validation of the Norfolk QOL-DN, a new measure of patients' perception of the effects of diabetes and diabetic neuropathy.

Abstract: Background: This study was designed to develop and validate a patient-reported outcomes measure, sensitive to the different features of diabetic neuropathy (DN)—small fiber, large fiber, and autonomic nerve function. Methods: The review of 1,000 structured patient interviews guided the development of 28 items pertaining specifically to the symptoms and impact of large fiber, small fiber, and autonomic nerve function. These items, in addition to 14 generic health status items and five general information items formed the 47-item Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (QOL-DN). Items were grouped according to small fiber, large fiber, and autonomic nerve function, symptoms, and activities of daily living (ADL). Scores in individual domains were aggregated to provide a total score. Item groupings were tested for their ability to distinguish between the effects of specific nerve fiber deficits in 262 subjects—81 healthy controls (C), 86 controls with diabetes (DC), and 95 patients with DN—u...

EXUBERA: pharmaceutical development of a novel product for pulmonary delivery of insulin.

Abstract: Development of a product for pulmonary delivery of insulin presented significant technology challenges for this first-in-class pharmaceutical product. These included developing (a) a chemically stabilized protein, (b) a dry powder formulation exhibiting required aerosol physical characteristics, (c) low-dose powder filling and packaging technology, and (d) a mechanical device for powder dispersal and reliable dosing to the patient. The insulin drug is formulated using a novel excipient combination to create a powder with a high glass transition temperature (Tg). The high Tg minimizes insulin mobility (thus reactivity), enabling ambient storage conditions. The formulation composition results in minimal hygroscopicity, where customized packaging produced product ruggedness to humidity. The formulated insulin powder is manufactured by spray-drying. This technology was further engineered to produce the desired reproducible powder characteristics with tight control over particle size and moisture content. A so...

The bioartificial pancreas: progress and challenges.

Abstract: Diabetes remains a devastating disease, with tremendous cost in terms of human suffering and healthcare expenditures. A bioartificial pancreas has the potential as a promising approach to preventing or reversing complications associated with this disease. Bioartificial pancreatic constructs are based on encapsulation of islet cells with a semipermeable membrane so that cells can be protected from the host's immune system. Encapsulation of islet cells eliminates the requirement of immunosuppressive drugs, and offers a possible solution to the shortage of donors as it may allow the use of animal islets or insulin-producing cells engineered from stem cells. During the past 2 decades, several major approaches for immunoprotection of islets have been studied. The microencapsulation approach is quite promising because of its improved diffusion capacity, and technical ease of transplantation. It has the potential for providing an effective long-term treatment or cure of Type 1 diabetes.

Accuracy of the modified Continuous Glucose Monitoring System (CGMS) sensor in an outpatient setting: results from a diabetes research in children network (DirecNet) study.

Abstract: OBJECTIVE We previously reported the results of an inpatient accuracy study in children with type 1 diabetes using the Continuous Glucose Monitoring System (CGMS, Medtronic MiniMed, Northridge, CA). During the course of that study, a new process was implemented for manufacturing the CGMS sensor. Accuracy from the resulting modified sensor used by only 14 children was significantly better than the original version [median relative absolute difference (RAD), 11% vs. 19%; P < 0.001]. Baseline data from a subsequent outpatient study provide an opportunity to further assess the accuracy of the modified sensor in a much larger sample of children with type 1 diabetes. RESEARCH DESIGN AND METHODS As part of a randomized trial to assess the utility of the GlucoWatch G2 Biographer (Cygnus, Inc., Redwood City, CA), 200 children with type 1 diabetes were instructed to wear a CGMS for 48-72 h in an outpatient setting at baseline. Glucose measurements from a OneTouch UltraSmart (Lifescan, Inc., Milpitas, CA) home glucose meter were downloaded and used as reference values to calculate accuracy measures. RESULTS The overall median RAD was 12%. Accuracy was better during hyperglycemia than during hypoglycemia (median RAD, 10% vs. 20%; P < 0.001) and on optimal versus non-optimal days but did not vary significantly by the number of calibrations entered. CONCLUSIONS These data confirm the improved accuracy previously reported for the modified version of the CGMS sensor.

Noninvasive and minimally invasive methods for transdermal glucose monitoring.

Abstract: Noninvasive and minimally invasive techniques for monitoring glucose via the skin are reviewed. These approaches rely either on the interaction of electromagnetic radiation with the tissue or on the extraction of fluid across the barrier. The structure and physiology of the skin make the technical realization of transdermal glucose monitoring a difficult challenge. The techniques involving transdermal fluid extraction circumvent and/or compromise the barrier function of skin's outermost and least permeable layer, the stratum corneum, by the application of physical energy. While sonophoresis and microporation methods, for example, are in relatively early-stage development, a device using reverse iontophoresis [the GlucoWatch Biographer (Cygnus, Inc., Redwood City, CA)] is already commercially available. Optical techniques to monitor glucose are truly noninvasive. The tissue is irradiated, the absorbed or scattered radiation is analyzed, and the information is processed, to provide a measure proportional to the concentration of glucose in the dermal tissue. These techniques include near-infrared and Raman spectroscopy, polarimetry, light scattering, and photoacoustic spectroscopy. By contrast, impedance spectroscopy measures changes in the dielectric properties of the tissue induced by blood glucose variation. Large-scale studies in support of efficacy of these methodologies are as yet unavailable. At present, therefore, transdermal fluid extraction technologies are offering greater promise in terms of practical and realizable devices for patient use. The truly noninvasive allure of the optical approach assures continued and intense research activity--for the moment, however, an affordable, efficient, and portable system is not on the immediate horizon.

Response to nocturnal alarms using a real-time glucose sensor.

Abstract: Background: The objective of this study was to determine how subjects responded to alarms for hypo- and hyperglycemia while they were sleeping. Research Design and Methods: Twenty subjects with type 1 diabetes (4–17 years old) were admitted to a clinical research center for approximately 24 h. Each subject wore two GlucoWatch ® G2™ Biographers (GW2B) (Cygnus, Inc., Redwood City, CA) and was videotaped using an infrared camera from 9 p.m. to 7 a.m. The videotapes were reviewed to determine if the GW2B alarms were audible on the tape and to document the subject's response to the alarms. Because many alarms can occur surrounding a change in blood glucose, GW2B alarm "events" are defined as a one or more alarms separated from previous alarms by more than 30 min. Results: Downloaded data from the biographers identified 240 individual alarms, 75% of which occurred while the subject was sleeping. Of the 240 alarms 68% were audible on the videotape. Subjects awoke to 29% of individual alarms and to 66% of alarm e...

Exenatide Improves Glycemic Control and Reduces Body Weight in Subjects with Type 2 Diabetes: A Dose-Ranging Study

Abstract: Background: Exenatide is the first of a new class of agents known as incretin mimetics that are in development for the treatment of type 2 diabetes. Exenatide has been shown to reduce fasting and postprandial glucose in patients with type 2 diabetes, as well as provide sustained reductions in hemoglobin A1c (HbA1c). This study was designed to assess the dose dependencies of the glucoregulatory effects and tolerability of exenatide when added to diet and exercise or metformin monotherapy in patients with type 2 diabetes. Methods: In this randomized, triple-blinded, placebo-controlled Phase 2 clinical trial, 156 patients were randomized to placebo or exenatide at 2.5, 5.0, 7.5, or 10.0 µg administered b.i.d. for 28 days. Results: After 28 days of therapy, exenatide was associated with significant (P < 0.0001, linear contrast testing), dose-dependent reductions in HbA1c (0.1 ± 0.1%, –0.3 ± 0.1%, –0.4 ± 0.1%, ±0.5 ± 0.0%, and –0.5 ± 0.1% for placebo and 2.5, 5.0, 7.5, and 10.0 µg b.i.d. exenatide, respectivel...

Invasiveness as a barrier to self-monitoring of blood glucose in diabetes.

Abstract: Background: This study investigated the degree to which the invasive characteristic of glucose monitoring is a barrier to self-monitoring of blood glucose (SMBG) Methods: A paper-and-pencil Measure of Invasiveness as a reason for Skipping SMBG (MISS) was created and administered to 339 people with diabetes The correlations between MISS scores and actual SMBG frequency, percent adherence to SMBG recommendations, SMBG anxiety, SMBG burden, and knowledge of the importance of glycemic control for avoiding diabetes complications were each explored Results: On a scale of 0–28, the average MISS score was M = 43 (SD = 54, range 0–28) Fully 63% (nearly two-thirds) of respondents reported skipping SMBG because of the invasiveness of the procedure MISS scores were negatively related to percent adherence to healthcare provider SMBG recommendations as measured by memory function of automated meters (Spearman's r= –047, P < 001) MISS scores were also negatively related to absolute SMBG frequency regardless of

Hypoglycemia prediction and detection using optimal estimation.

Abstract: Patients with diabetes play with a double-edged sword when it comes to deciding glucose and A1c target levels. On the one side, tight control has been shown to be crucial in avoiding long-term complications; on the other, tighter control leads to an increased risk of iatrogenic hypoglycemia, which is compounded when hypoglycemia unawareness sets in. Development of continuous glucose monitoring systems has led to the possibility of being able not only to detect hypoglycemic episodes, but to make predictions based on trends that would allow the patient to take preemptive action to entirely avoid the condition. Using an optimal estimation theory approach to hypoglycemia prediction, we demonstrate the effect of measurement sampling frequency, threshold level, and prediction horizon on the sensitivity and specificity of the predictions. We discuss how optimal estimators can be tuned to trade-off the false alarm rate with the rate of missed predicted hypoglycemic episodes. We also suggest the use of different a...

The extended Kalman filter for continuous glucose monitoring.

Abstract: Glucose monitoring is a problem with evolving solutions using sensors and data processing techniques that are continually improving. This paper presents the development and application of the extended Kalman filter to the problem of real-time estimation of blood glucose levels and is consistent with sensors based on optical, electrical, or chemical processes. The structure of the extended Kalman filter provides the capability to systematically accommodate new information as it develops. This flexibility and the potential for performance improvement are demonstrated by processing patient data files generated using the Medtronic (Northridge, CA) MiniMed continuous glucose monitoring system (CGMS).

Optimal insulin pump dosing and postprandial glycemia following a pizza meal using the continuous glucose monitoring system.

Abstract: Background: We attempted to identify an optimal insulin pump meal bolus by comparing postprandial sensor glucose values following three methods of insulin pump meal bolusing for a consistent pizza meal. Research Design and Methods: Twenty-four patients with type 1 diabetes participated in a study to compare postprandial glucose values following three meal bolus regimens for a consistent evening pizza meal. Each participant utilized the following insulin lispro regimens on consecutive evenings, and glucose values were tracked by the Continuous Glucose Monitoring System (CGMS®, Medtronic MiniMed, Northridge, CA): (a) single-wave bolus (100% of insulin given immediately); (b) 4-h dual-wave bolus (50% of insulin given immediately and 50% given over a 4-h period); and (c) 8-h dual-wave bolus (50% of insulin given immediately and 50% given over a 8-h period). Total insulin bolus amount was kept constant for each pizza meal. Results: Divergence in blood glucose among the regimens was greatest at 8–12 h. The 8-h ...

Modeling Insulin Action for Development of a Closed-Loop Artificial Pancreas

Abstract: Three models of glucose homeostasis are compared in terms of their steady-state dose–response characteristics, how they characterize glucose distribution kinetics, and how they characterize the dyn...

Run-to-run control of meal-related insulin dosing.

Abstract: Background: This study was designed to determine if it was feasible to use a run-to-run algorithm to improve postprandial glucose concentrations in individuals with type 1 diabetes mellitus (T1DM)....

Loss of defense against stress: diabetes and heat shock proteins.

Abstract: WE PROPOSE THAT DIABETES produces a vulnerable condition with impaired defenses against stress, resulting in widespread unprotected organ systems. More specifically, the ultimate natural history of diabetes and its complications is determined by the net effect of diabetes-induced inflammation, oxidation, and glycation, as well as an induced deficiency of heat shock factor-1 (HSF-1) that subsequently reduces the stress proteins that HSF-1 stimulates—heat shock proteins (Hsps) 60, 70, and 90. (Hsp 70 is also termed Hsp 72.) Furthermore, we speculate that reduced HSF-1 and Hsp levels are the result of an insulin resistance– diabetes-induced loss of membrane fluidity. The hypothesis is based on the following observations: (1) HSF-1 and Hsp levels are low in animal models of diabetes, in human subjects with diabetes, and in people with just insulin resistance. (2) Low Hsp levels lead to cells and tissues that are susceptible to injury with shortened viability. (3) Medications and lifestyles that raise Hsp levels improve diabetes complications and slow the progression of diabetes. WHAT ARE Hsps?

Targeted Glycemic Reduction in Critical Care Using Closed-Loop Control

Abstract: Background: Critically ill patients are often hyperglycemic and extremely diverse in their dynamics. Consequently, fixed protocols and sliding scales can result in error and poor control. Tight glucose control has been shown to significantly reduce mortality in critical care. An improved physiological system model of the glucose–insulin dynamics of a critical care patient is used to develop an adaptive tight glucose control protocol that accounts for variable patient dynamics, and is verified in limited clinical trials. Methods: A physiologically based two-compartment system model that accounts for time-varying insulin sensitivity, time-varying endogenous glucose removal, and two saturation kinetics mechanisms is developed. A bolus-based adaptive control protocol is developed that monitors the physiological status of a critically ill patient, enabling tight glycemic regulation to preset glycemic targets. The model and protocol are verified in three, 5–h preliminary proof-of-concept clinical trials. Ethics...

The use of two continuous glucose sensors during and after surgery.

Abstract: Background: Maintaining plasma glucose between 80 and 120 mg/dL is beneficial for patients admitted to a surgical intensive care unit, but requires frequent glucose monitoring to ensure adequacy of treatment and detection of hypoglycemia. We examined whether continuous glucose sensing is feasible and reliable during and after major surgical procedures using two commercially available sensors. Methods: Eight patients undergoing abdominal surgery were studied. A CGMS® device (Medtronic MiniMed, Northridge, CA) and a GlucoDay® device (A. Menarini Diagnostics, Florence, Italy) were placed in the shoulder region, and a second GlucoDay device was placed in the upper leg. Blood glucose was measured every 15 min for a total duration of 12 h. Results: Technical failure of the CGMS was observed peroperatively more frequently than postoperatively (66% of all time points vs. 18%, P < 0.001). Technical failure of the GlucoDay device occurred most frequently in the GlucoDay placed in the upper leg (64% vs. 17%, P < 0.0...

Nanoporous alumina capsules for cellular macroencapsulation: transport and biocompatibility.

Abstract: Background: Currently, the most widely used treatment for diabetes is the daily subcutaneous injection of recombinant human insulin. Daily injections, however, cannot match the physiological biphas...

British internet-derived patient information on diabetes mellitus: is it readable?

Abstract: Background: Sizeable proportions of Western populations have limited language and math skills, making it difficult for them to fully and safely understand and act upon online health information. Methods: We used the Flesch Reading Ease and Flesch–Kincaid Grade Level formulae to test the readability of 20 representative Web documents from 15 trustworthy sites/providers of British origin, providing consumer information on diabetes mellitus. Results: The corresponding average and median U.K. reading ages of the tested material were found to be 14.2 and 14.65 years of age, respectively (range, 11–16.9 years). The most readable pages in our study (about one-third of all tested pages) had a Flesch Reading Ease score above 60 (range, 60.4–73.3) and a Flesch–Kincaid Grade Level of 8.0 or lower (range, 6.0–8.0), corresponding to a U.K. reading age of 11–13 years. These readability levels are well above the estimated reading age of the U.K. population in general (9 years). Conclusions: These results point to a chro...

Insulin pump therapy in preschool children with type 1 diabetes mellitus improves glycemic control and decreases glucose excursions and the risk of hypoglycemia.

Abstract: Background: Hypoglycemia in preschool children limits the effectiveness of insulin therapy. Continuous subcutaneous insulin infusion (CSII) is not widely used in this group. Objectives: This study was designed (1) to test the hypothesis that compared with twice-daily insulin injection, CSII decreases the SD of the mean daily blood glucose (BG) and improves glycemic control and (2) to evaluate the effect of CSII on parental anxiety using the Parental Stress Index (PSI) scale. Methods: Ten subjects <6 years of age and receiving insulin injections were recruited. Each underwent two 72-h CGMS® (Medtronic Minimed, Northridge, CA) monitoring periods and then was started on CSII and re-monitored 3 and 6 months later. We assessed the effects of CSII on the mean BG and SD of BG values, A1c, PSI scores, and number, distribution, and duration of hypoglycemic episodes. Results: Pooled pre- and post-CSII data were compared. There was a 22% decrease in the BG variability (mean ± SD 93 ± 19 mg/dL vs. 72 ± 5 mg/dL; P = 0...

Memory of insulin pumps and their record as a source of information about insulin therapy in children and adolescents with type 1 diabetes.

Abstract: Background: This study was designed to provide information regarding basal and bolus insulin dosage in children and adolescents using continuous subcutaneous insulin infusion (CSII) and to evaluate the safety and efficacy of the CSII method in youths. Patients and Methods: Data from 100 patients (1.6–18 years old) were collected during scheduled visits in an outpatient clinic. The mean duration of diabetes was 4.57 years (range 0.6–16 years), and mean duration of CSII therapy was 1.75 years (range 0.5–3.0 years). Each child had his or her insulin doses reviewed using the Medtronic MiniMed (Northridge, CA) Pumps&Meters software program. At each visit glycosylated hemoglobin (HbA1c) values and growth parameters (weight and height) were assessed, and episodes of severe hypoglycemia and ketoacidosis were recorded. Results: The mean HbA1c value in our study group was 7.63 ± 0.09% (range, 5.15–12.5%). Statistically significant better metabolic control was found in children under 10 years of age, in children wit...

A computational model to define the molecular causes of type 2 diabetes mellitus.

Abstract: Background: Metabolic abnormalities associated with type 2 diabetes mellitus (DM2) are caused in part by inadequate insulin action and resulting changes in gene expression in the skeletal muscle. Two recent, independent studies of human skeletal muscle biopsies from ethnically diverse DM2 patients have identified coordinated reductions in the expression of the oxidative phosphorylation (OXPHOS) genes. Whether these reductions are a consequence or a cause of impaired insulin sensitivity remains an open question. Methods: To address this question and to define the underlying molecular causes consistent with the expression changes reported in the muscle studies, we created a large-scale computable model to analyze the molecular actions and effects of insulin on muscle gene expression. The model enables computer-aided reasoning using over 210,000 molecular relationships assembled from the DM2 literature. Results: We integrated the data from these muscle biopsy studies into the model and used computer-aided ca...

Biocompatibility of an electrochemical sensor for continuous glucose monitoring in subcutaneous tissue.

Abstract: Background: The continuous monitoring of glucose allows for tighter control of the glucose concentration and thus may prevent hyper- and hypoglycemia as well as long-term complications of diabetes. While most current systems depend on the transport of fluid to a glucose sensor outside the body, we investigate the possibility of implanting a reagent-based sensor directly into the skin. In this manuscript, the biocompatibility of an electrochemical sensor for continuous glucose monitoring was assessed in vitro and in vivo. Methods: Cytotoxicity was investigated in vitro using agar diffusion testing. In vivo biocompatibility was assessed by means of histomorphological examination of the surrounding tissue 10 days after sensor implantation in rats. Results: The grade of cytotoxicity of the individual sensor components in vitro was between none and mild based on agar diffusion testing. The complete sensor also showed no cytotoxic effects when coated with the co-polymer MPC (2-methacryloyloxyethyl phosphorylcho...