bluuebunny/crossref_metadata_2025 huggingface dataset:
Closed-Loop Artificial Pancreas Using Subcutaneous Glucose Sensing and Insulin Delivery and a Model Predictive Control Algorithm: The Virginia Experience
Authors: Clarke William L. , Anderson Stacey , Breton Marc , Patek Stephen , Kashmer Laurissa , Kovatchev Boris
Published: January 2014

Background:

Recent progress in the development of clinically accurate continuous glucose monitors (CGMs), automated continuous insulin infusion pumps, and control algorithms for calculating insulin doses from CGM data have enabled the development of prototypes of subcutaneous closed-loop systems for controlling blood glucose (BG) levels in type 1 diabetes. The use of a new personalized model predictive control (MPC) algorithm to determine insulin doses to achieve and maintain BG levels between 70 and 140 mg/dl overnight and to control postprandial BG levels is presented.

Methods:

Eight adults with type 1 diabetes were studied twice, once using their personal open-loop systems to control BG overnight and for 4 h following a standardized meal and once using a closed-loop system that utilizes the MPC algorithm to control BG overnight and for 4 h following a standardized meal. Average BG levels, percentage of time within BG target of 70–140 mg/dl, number of hypoglycemia episodes, and postprandial BG excursions during both study periods were compared.

Results:

With closed-loop control, once BG levels achieved the target range (70–140 mg/dl), they remained within that range throughout the night in seven of the eight subjects. One subject developed a BG level of 65 mg/dl, which was signaled by the CGM trend analysis, and the MPC algorithm directed the discontinuance of the insulin infusion. The number of overnight hypoglycemic events was significantly reduced ( p = .011) with closed-loop control. Postprandial BG excursions were similar during closed-loop and open-loop control

Conclusion:

Model predictive closed-loop control of BG levels can be achieved overnight and following a standardized breakfast meal. This “artificial pancreas” controls BG levels as effectively as patient-directed open-loop control following a morning meal but is significantly superior to open-loop control in preventing overnight hypoglycemia.
Control to Range for Diabetes: Functionality and Modular Architecture
Authors: Kovatchev Boris , Patek Stephen , Dassau Eyal , Doyle Francis J. , Magni Lalo , De Nicolao Giuseppe , Cobelli Claudio ,   Juvenile Diabetes Research Foundation Artificial Pancreas Consortium
Published: January 2014

Background:

Closed-loop control of type 1 diabetes is receiving increasing attention due to advancement in glucose sensor and insulin pump technology. Here the function and structure of a class of control algorithms designed to exert control to range, defined as insulin treatment optimizing glycemia within a predefined target range by preventing extreme glucose fluctuations, are studied.

Methods:

The main contribution of the article is definition of a modular architecture for control to range. Emphasis is on system specifications rather than algorithmic realization. The key system architecture elements are two interacting modules: range correction module, which assesses the risk for incipient hyper- or hypoglycemia and adjusts insulin rate accordingly, and safety supervision module, which assesses the risk for hypoglycemia and attenuates or discontinues insulin delivery when necessary. The novel engineering concept of range correction module is that algorithm action is relative to a nominal open-loop strategy—a predefined combination of basal rate and boluses believed to be optimal under nominal conditions.

Results:

A proof of concept of the feasibility of our control-to-range strategy is illustrated by using a prototypal implementation tested in silico on patient use cases. These functional and architectural distinctions provide several advantages, including (i) significant insulin delivery corrections are only made if relevant risks are detected; (ii) drawbacks of integral action are avoided, e.g., undershoots with consequent hypoglycemic risks; (iii) a simple linear model is sufficient and complex algorithmic constraints are replaced by safety supervision; and (iv) the nominal profile provides straightforward individualization for each patient.

Conclusions:

We believe that the modular control-to-range system is the best approach to incremental development, regulatory approval, industrial deployment, and clinical acceptance of closed-loop control for diabetes.
A Novel Adaptive Basal Therapy Based on the Value and Rate of Change of Blood Glucose
Authors: Wang Youqing , Percival Matthew W. , Dassau Eyal , Zisser Howard C. , Jovanovič Lois , Doyle Francis J.
Published: January 2014

Background:

Modern insulin pump therapy for type 1 diabetes mellitus offers the freedom to program several basal profiles that may accommodate diurnal variability in insulin sensitivity and activity level. However, these basal profiles do not change even if a pending hypoglycemic or hyperglycemic event is foreseen. New insulin pumps could receive a direct feed of glucose values from a continuous glucose monitoring (CGM) system and could enable dynamic basal adaptation to improve glycemic control.

Method:

The proposed method is a two-step procedure. After the design of an initial basal profile, an adaptation of the basal rate is suggested as a gain multiplier based on the current CGM glucose value and its rate of change (ROC). Taking the glucose value and its ROC as axes, a two-dimensional plane is divided into a nine-zone mosaic, where each zone is given a predefined basal multiplier; for example, a basal multiplier of zero indicates a recommendation to shut off the pump.

Results:

The proposed therapy was evaluated on 20 in silico subjects (ten adults and ten adolescents) in the Food and Drug Administration-approved UVa/Padova simulator. Compared with conventional basal therapy, the proposed basal adjustment improved the percentage of glucose levels that stayed in the range of 60–180 mg/dl for all 20 subjects. In addition, the adaptive basal therapy reduced the average blood glucose index values.

Conclusions:

The proposed therapy provides the flexibility to account for insulin sensitivity variations that may result from stress and/or physical activities. Because of its simplicity, the proposed method could be embedded in a chip in a future artificial pancreatic β cell or used in a “smart” insulin pump.
Serum Insulin Aspart Concentrations following High-Dose Insulin Aspart Administered Directly into the Duodenum of Healthy Subjects: An Open-Labeled, Single-Blinded, and Uncontrolled Exploratory Trial
Authors: Ihlo Charlotte A. , Aksglæde Karin Bak , Laursen Torben , Lauritzen Torsten , Christiansen Jens Sandahl
Published: January 2014

Objective:

The goal of this study was to determine the bioavailability of high-dose insulin aspart administered directly into the duodenum of healthy subjects.

Methods:

In a pilot study, four subjects each received four escalating doses of a 1-ml solution of insulin aspart (100, 300, 600, and 1000 IU, respectively) directly into the duodenum. In the following main study, eight subjects each received two identical doses of insulin aspart of 1000 IU, in 4- and 8-ml solutions, respectively, directly into the duodenum. Subjects in the main study also received an intravenous and a subcutaneous injection of 4 to 6 IU of insulin aspart.

Results:

A considerable number of samples and, in some cases, consecutive samples revealed significantly increased concentrations of serum insulin aspart. Despite the significant serum insulin aspart concentrations, no significant changes of plasma glucose were measured. Moreover, no significant suppression of endogenous insulin secretion was detected, as assessed by the levels of serum human insulin.

Conclusions:

Administration of high-dose insulin aspart directly into the duodenum of healthy subjects resulted in significantly increased serum insulin aspart concentrations in a high number of consecutive samples using a specific enzyme-linked immunosorbent assay. However, no significant changes in the levels of plasma glucose or serum human insulin were observed. Thus, the study did not provide any evidence of biological activity of the original insulin aspart molecule after high-dose administration directly into the duodenum.
An Overview of Hypoglycemia in the Critically Ill
Authors: Lacherade Jean-Claude , Jacqueminet Sophie , Preiser Jean-Charles
Published: January 2014

Hypoglycemia is a common and serious problem among patients with diabetes mellitus. It is also perceived as the most important obstacle to tight glucose control using intensive insulin therapy in critically ill patients. Because glucose is an obligatory metabolic fuel for the brain, hypoglycemia always represents an emergency that signals the inability of the brain to meet its energy needs. When left untreated, hypoglycemia can result in permanent brain damage and ultimately, death. In the context of critical illness that limits endogenous glucose production and increases glucose utilization, inadequate nutrition, or insufficient provision of glucose, intensive insulin therapy is the most frequent cause of hypoglycemia. Neurogenic and neuroglycopenic symptoms of hypoglycemia can remain unknown because of the underlying critical illness and sedation. Thus, close and reliable monitoring of the glycemic level is crucial in detecting hypoglycemia. In prospective randomized controlled studies comparing the effects of two glucose regimens, intensive insulin therapy aimed to reach strict glucose control (<110 mg/dl) but increased the incidence of severe hypoglycemia (<40 mg/dl) by four- to sixfold. Severe hypoglycemia is statistically associated with adverse outcomes in intensive care unit patients, although a direct causal relationship has not been demonstrated.
Perioperative Blood Glucose Monitoring in the General Surgical Population
Authors: Raju Tejal A. , Torjman Marc C. , Goldberg Michael E.
Published: January 2014

Several studies have shown a relationship between poor outcome and uncontrolled blood glucose (BG) in cardiac, neurosurgical, critical care, and general surgical patients. A major study showed that tight glycemic control (80–110mg/dl) was related to increased mortality. Based on evidence from controlled studies, the American Diabetes Association, and the Society of Thoracic Surgeons, maintaining intraoperative BG levels in the 140–180 mg/dl range seems appropriate. Optimization of the patient's preoperative medications and the use of insulin infusions, as well as surgical and anesthetic technique, are important factors for achieving desirable perioperative BG control. Minimizing BG variability during surgery should be part of the glycemic control strategy. Advances in real-time glucose monitoring may soon benefit hospitalized diabetes and nondiabetes patients.
Reducing Glycemic Variability in Intensive Care Unit Patients: A New Therapeutic Target?
Authors: Egi Moritoki , Bellomo Rinaldo
Published: January 2014

Acute hyperglycemia is common in critically ill patients. Strict control of blood glucose (BG) concentration has been considered important because hyperglycemia is associated independently with increased intensive care unit mortality. After intensive insulin therapy was reported to reduce mortality in selected surgical critically ill patients, lowering of BG levels was recommended as a means of improving patient outcomes. However, a large multicenter multination study has found that intensive insulin therapy increased mortality significantly. A difference in variability of BG control may be one possible explanation why the effect of intensive insulin therapy varied from beneficial to harmful. Several studies have confirmed significant associations between variability of BG levels and patient outcomes. Decreasing the variability of the BG concentration may be an important dimension of glucose management. If reducing swings in the BG concentration is a major biologic mechanism behind the putative benefits of glucose control, it may not be necessary to pursue lower glucose levels with their attendant risk of hypoglycemia.
Clinical Need for Continuous Glucose Monitoring in the Hospital
Authors: Joseph Jeffrey I , Hipszer Brian , Mraovic Boris , Chervoneva Inna , Joseph Mark , Grunwald Zvi
Published: January 2014

Automation and standardization of the glucose measurement process have the potential to greatly improve glycemic control, clinical outcome, and safety while reducing cost. The resources required to monitor glycemia in hospitalized patients have thus far limited the implementation of intensive glucose management to patients in critical care units. Numerous available and up-and-coming technologies are targeted for the hospital patient population. Advantages and limitations of these devices are discussed herewith in.
Glycemic Control in the Medical Intensive Care Unit
Authors: Kovalaske Michelle A. , Gandhi Gunjan Y.
Published: January 2014

Hyperglycemia in the critically ill is a well-known phenomenon, even in those without known diabetes. The stress response is due to a complex interplay between counter-regulatory hormones, cytokines, and changes in insulin sensitivity. Illness/infection, overfeeding, medications (e.g., corticosteroids), insufficient insulin, and/or volume depletion can be additional contributors. Acute hyperglycemia can adversely affect fluid balance (through glycosuria and dehydration), immune and endothelial function, inflammation, and outcome. While there are several insulin infusion protocols that are able to safely and effectively treat hyperglycemia, the bulk of accumulated evidence does not support a causal relationship between acute hyperglycemia and adverse outcomes in the medical intensive care unit. Meta-analysis of randomized controlled trials suggests there is no benefit to tightening glucose control to normal levels compared to a reasonable and achievable goal of 140 to 180 mg/dl. There is a significantly increased risk of hypoglycemia. Although there is some evidence that patients without known diabetes have worse outcomes than those with known diabetes, more recent evidence is conflicting. Glycemic control in critically ill patients should not be neglected, as studies have not tested tight versus no/poor control, but tight versus good control. A moderate approach to managing critical illness hyperglycemia seems most prudent at this juncture. Future research should ascertain whether there are certain subgroups of patients that would benefit from tighter glycemic goals. It also remains to be seen if tight glucose control is beneficial once hypoglycemia is minimized with technological advances such as continuous glucose monitoring systems.
An Overview of Glycemic Control in the Coronary Care Unit with Recommendations for Clinical Management
Authors: Kosiborod Mikhail , Deedwania Prakash
Published: January 2014

The observation that elevated glucose occurs frequently in the setting of acute myocardial infarction was made decades ago. Since then numerous studies have documented that hyperglycemia is a powerful risk factor for increased mortality and in-hospital complications in patients with acute coronary syndromes. While some questions in this field have been answered in prior investigations, many critical gaps in knowledge continue to exist and remain subjects of intense debate. This review summarizes what is known about the relationship between hyperglycemia, glucose control, and outcomes in critically ill patients with acute coronary syndromes, addresses the gaps in knowledge and controversies, and offers general recommendations regarding glucose management in the coronary care unit.
A Semilogarithmic Scale for Glucose Provides a Balanced View of Hyperglycemia and Hypoglycemia
Authors: Rodbard David
Published: January 2014

Objective:

It would be desirable to improve the ability of physicians and patients to identify hypoglycemic episodes when viewing displays of glucose by date, time of day, or day of the week.

Research Design and Methods:

A logarithmic scale is utilized for display of glucose versus date and time of day using a range of 40 to 400 mg/dl. Several plausible alternatives are considered for transformation of the glucose data.

Result:

Use of a semilogarithmic plot triples the percentage of the vertical axis allocated to hypoglycemia (e.g., 40–80 mg/dl) from 10% to 30.1% while compressing the hyperglycemic region. The log scale improves the symmetry of the glucose distribution. Transformations were evaluated corresponding to the Schlichtkrull M100 value, the high blood glucose index/low blood glucose index of Kovatchev and associates, an index of glycemic control developed by the present author, and the GRADE score of Hill and coworkers. Results are similar for all four transformations. This approach is applicable both to self-monitoring of blood glucose (SMBG) and continuous glucose monitoring (CGM). Based on preliminary results, it is proposed that the log transform could potentially facilitate analysis of glucose patterns and may facilitate rapid and consistent detection and appreciation of the severity and consistency of hypoglycemic episodes, even in the presence of complex overlapping patterns commonly observed in both SMBG and CGM glucose profiles.

Conclusion:

Display of glucose on a logarithmic scale can potentially improve the accuracy of analysis and interpretation of popular methods for graphic display of glucose values. Device manufacturers should consider including options for semilogarithmic display of glucose on SMBG meters, CGM sensors, and software for retrospective analyses of glucose data.
Plasma-Generating Glucose Monitor Accuracy Demonstrated in an Animal Model
Authors: Magarian Peggy , Sterling Bernhard
Published: January 2014

Introduction:

Four randomized controlled trials have compared mortality and morbidity of tight glycemic control versus conventional glucose for intensive care unit (ICU) patients. Two trials showed a positive outcome. However, one single-center trial and a large multicenter trial had negative results. The positive trials used accurate portable lab analyzers. The negative trial allowed the use of meters. The portable analyzer measures in filtered plasma, minimizing the interference effects. OptiScan Biomedical Corporation is developing a continuous glucose monitor using centrifuged plasma and mid-infrared spectroscopy for use in ICU medicine. The OptiScanner draws approximately 0.1 ml of blood every 15 min and creates a centrifuged plasma sample. Internal quality control minimizes sample preparation error. Interference adjustment using this technique has been presented at the Society of Critical Care Medicine in separate studies since 2006.

Method:

A good laboratory practice study was conducted on three Yorkshire pigs using a central venous catheter over 6 h while performing a glucose challenge. Matching Yellow Springs Instrument glucose readings were obtained.

Results:

Some 95.7% of the predicted values were in the Clarke Error Grid A zone and 4.3% in the B zone. Of those in the B zone, all were within 3.3% of the A zone boundaries. The coefficient of determination ( R2) was 0.993. The coefficient of variance was 5.02%. Animal necropsy and blood panels demonstrated safety.

Conclusion:

The OptiScanner investigational device performed safely and accurately in an animal model. Human studies using the device will begin soon.
Health Technologies for Monitoring and Managing Diabetes: A Systematic Review
Authors: Russell-Minda Elizabeth , Jutai Jeffrey , Speechley Mark , Bradley Kaitlin , Chudyk Anna , Petrella Robert
Published: January 2014

Background:

The primary objective of this review was to determine the strength of evidence for the effectiveness of self-monitoring devices and technologies for individuals with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) based on specific health-related outcome measures. Self-monitoring devices included those that assist patients with managing diabetes and preventing cardiovascular complications (CVCs). A secondary objective was to explore issues of feasibility, usability, and compliance among patients and providers.

Methods:

Study criteria included individuals ≥14 years and youth (7–14 years) with T1DM or T2DM, intervention with a self-monitoring device, assessment of clinical outcomes with the device, literature in English, and ≥10 participants. Relevant published literature was searched from 1985 to 2008. Randomized controlled trials and observational studies were included. Data were extracted for clinical outcomes, feasibility and compliance methods, and results. Selected studies were independently evaluated with a validated instrument for assessing methodological quality.

Results:

Eighteen trials were selected. Predominant types of device interventions included self-monitoring of blood glucose, pedometers, and cell phone or wireless technologies. Feasibility and compliance were measured in the majority of studies.

Conclusions:

Self-monitoring of blood glucose continues to be an effective tool for the management of diabetes. Wireless technologies can improve diabetes self-care, and pedometers are effective lifestyle modification tools. The results of this review indicate a need for additional controlled trial research on existing and novel technologies for diabetes self-monitoring, on health outcomes associated with diabetes and CVCs, and device feasibility and compliance.
Reducing Cardiometabolic Risk in Peritoneal Dialysis Patients: Role of the Dialysis Solution
Authors: Holmes Clifford J.
Published: January 2014

Peritoneal dialysis (PD) is a well-established form of therapy for stage 5 chronic kidney disease requiring renal replacement therapy. D-Glucose has been used successfully for several decades as the osmotic agent employed in dialysis solutions to achieve adequate fluid removal. The absorption of 100–200 grams of glucose per day has been suggested as potentially increasing cardiometabolic risk, particularly in patients with diabetes. Supporting and undermining evidence for this hypothesis is reviewed, with a focus on the role of glucose absorption in changes in body composition, dyslipidemia, and glycemic control in diabetic PD patients. Clinical strategies to optimize fluid removal while minimizing the metabolic impact of glucose absorption are also discussed.
Insulin Pump Therapy: What is the Evidence for Using Different Types of Boluses for Coverage of Prandial Insulin Requirements?
Authors: Heinemann Lutz
Published: January 2014

Bolus infusion of insulin along with a meal is a standard procedure with continuous subcutaneous insulin infusion. Modern insulin pumps allow applying this bolus in four different ways: infusion of the total dose at once or splitting the dose into two boluses, infusion of a part of the bolus in the usual manner plus infusion of the other part over a prolonged period of time (with a higher infusion rate than the basal rate), or infusion of the total dose in the form of an elevated basal rate. Depending on the composition of the given meal and its glycemic index, this is an attempt to match the circulating insulin levels to the rate of glucose absorption from the gut in order to minimize postprandial glycemic excursions. However, in the framework of evidence-based medicine, the benefits of this approach should be proven in appropriately designed clinical studies. Performance of meal-related studies requires careful attention to many aspects in order to allow meaningful evaluation of a given intervention (i.e., type of bolus). Critical evaluation of the clinical experimental studies and the one clinical study published about the impact of different types of boluses on postprandial metabolic control revealed fundamental shortcomings in study design and performance in these studies. Insufficient establishment of comparable preprandial glycemia and insulinemia on the different study days within and between the patients studied is one key aspect. Therefore, the recommendation made in most of these studies (i.e., use of dual-wave bolus) has to be accepted with care, until we have better evidence.
Are Type 2 Diabetes Patients Who Self-Monitor Blood Glucose Special? The Role of Confounders in the Observational ROSSO Study
Authors: Kolb Hubert , Martin Stephan , Lodwig Volker , Heinemann Lutz , Scherbaum Werner A. , Schneider Berthold
Published: January 2014

Background:

In the German multicenter, retrospective cohort study (ROSSO), those patients with type 2 diabetes who performed self-monitoring of blood glucose (SMBG) had a better long-term clinical outcome. We analyzed whether confounders accounted for the lower rate of clinical events in the SMBG cohort.

Methods:

ROSSO followed 3268 persons from diagnosis of type 2 diabetes for a mean of 6.5 years. Data were retrieved from patient files of randomly contacted primary care practices.

Results:

In total, more than 60 potential confounders were documented, including nondisease-associated parameters such as patient's health insurance, marital status, habitation, and characteristics of diabetes centers. There were only modest differences for these parameters between groups with versus without SMBG, and multiple adjustments did not weaken the association of SMBG use with better outcome (odds ratio 0.65, 95% confidence interval 0.53–0.81, p < .001). This was also true for subgroups of patients defined by type of antidiabetes treatment. Propensity score analysis confirmed the association of SMBG use with outcome. Using key baseline parameters, 813 matching pairs of patients were identified. The analysis again showed a better long-term outcome in the SMBG group (hazard ratio 0.67 p = .004).

Conclusion:

An influence of nonrecognized confounders on better outcome in the SMBG group is rendered improbable by similar results obtained with adjustments for disease-associated or disease-independent parameters, by the analysis of patient subgroups, by propensity score analysis and by performing a matched-pair analysis. The higher flexibility in pharmacological antidiabetes treatment regimens in the SMBG cohort suggests a different attitude of treating physicians and patients in association with SMBG.
Methods of Evaluating the Utility of Continuous Glucose Monitor Alerts
Authors: Kamath Apurv , Mahalingam Aarthi , Brauker James
Published: January 2014

Background:

The evaluation of continuous glucose monitor (CGM) alert performance should reflect patient use in real time. By evaluating alerts as real-time events, their ability to both detect and predict low and high blood glucose (BG) events can be examined.

Method:

True alerts (TA) were defined as a CGM alert occurring within ± 30 minutes from the beginning of a low or a high BG event. The TA time to detection was calculated as [time of CGM alert] - [beginning of event]. False alerts (FA) were defined as a BG event outside of the alert zone within ± 30 minutes from a CGM alert. Analysis was performed comparing DexCom™ SEVEN® PLUS CGM data to BG measured with a laboratory analyzer.

Results:

Of 49 low glucose events (BG <70 mg/dl), with the CGM alert set to 90 mg/dl, the TA rate was 91.8%. For 50% of TAs, the CGM alert preceded the event by at least 21 minutes. The FA rate was 25.0%. Similar results were found for high alerts.

Conclusion:

Continuous glucose monitor alerts are capable of both detecting and predicting low and high BG events. The setting of alerts entails a trade-off between predictive ability and FA rate. Realistic analysis of this trade-off will guide patients in the effective utilization of CGM.
Simulation Environment to Evaluate Closed-Loop Insulin Delivery Systems in Type 1 Diabetes
Authors: Wilinska Malgorzata E. , Chassin Ludovic J. , Acerini Carlo L. , Allen Janet M. , Dunger David B. , Hovorka Roman
Published: January 2014

Background:

Closed-loop insulin delivery systems linking subcutaneous insulin infusion to real-time continuous glucose monitoring need to be evaluated in humans, but progress can be accelerated with the use of in silico testing. We present a simulation environment designed to support the development and testing of closed-loop insulin delivery systems in type 1 diabetes mellitus (T1DM).

Methods:

The principal components of the simulation environment include a mathematical model of glucose regulation representing a virtual population with T1DM, the glucose measurement model, and the insulin delivery model. The simulation environment is highly flexible. The user can specify an experimental protocol, define a population of virtual subjects, choose glucose measurement and insulin delivery models, and specify outcome measures. The environment provides graphical as well as numerical outputs to enable a comprehensive analysis of in silico study results. The simulation environment is validated by comparing its predictions against a clinical study evaluating overnight closed-loop insulin delivery in young people with T1DM using a model predictive controller.

Results:

The simulation model of glucose regulation is described, and population values of 18 synthetic subjects are provided. The validation study demonstrated that the simulation environment was able to reproduce the population results of the clinical study conducted in young people with T1DM.

Conclusions:

Closed-loop trials in humans should be preceded and concurrently guided by highly efficient and resource-saving computer-based simulations. We demonstrate validity of population-based predictions obtained with our simulation environment.
The Food and Drug Administration is Now Preparing to Establish Tighter Performance Requirements for Blood Glucose Monitors
Authors: Klonoff David C.
Published: January 2014

On March 16 and 17, 2010, the Food and Drug Administration (FDA) presented a public meeting about blood glucose monitoring at the Gaithersberg Hilton Hotel. The meeting was intended to present expert opinions and solicit input from the public about whether to develop new regulatory policies for blood glucose monitors. The meeting was divided into three sections: (1) Clinical Accuracy Requirements for Blood Glucose Monitors, (2) Interferences and Limitations of Blood Glucose Monitors, and (3) Tight Glycemic Control. Many officials from the Center for Devices and Radiologic Health and the Office of In Vitro Diagnostic Devices, which are the parts of FDA that regulate approval of blood glucose monitors, either spoke on the agenda or attended in the audience. Approximately 300 people attended; they were mostly clinicians (such as adult endocrinologists, pediatric endocrinologists, internists, clinical chemists, intensivists, surgeons, nurses, and diabetes educators) or industry officials from companies involved in glucose monitoring, pharmaceutical products, data analysis, or regulatory consulting.
Extended Prandial Glycemic Profiles of Foods as Assessed Using Continuous Glucose Monitoring Enhance the Power of the 120-Minute Glycemic Index
Authors: Chlup Rudolf , Peterson Karolina , Zapletalová Jana , Kudlová Pavla , Seč;kař; Pavel
Published: January 2014

Background:

The glycemic index (GI) is routinely measured 120 minutes after food intake (GI120). The purpose of this prospective open label study was to assess (1) the dynamics of glycemia over the 210 minutes following food consumption and (2) the evolution of GIs based on 120-, 150-, 180-, and 210-minute glycemic profiles.

Method:

Twenty healthy subjects (mean ± SE; 21.9 ± 1.39 years of age; body mass index 23.6 ± 0.63 kg/m2; 7 men and 13 women) completed the study. Each subject consumed 10 different foods with known GI120 on three separate occasions at four different times of day according to a defined meal plan over a 9-day period; 32 meals were evaluated. The GIs for intervals of 120, 150, 180 and 210 minutes after food consumption were determined using a continuous glucose monitoring system (CGMS) to measure glycemia. The Wilcoxon signed-rank test was applied to compare the GIs.

Results:

Glycemia returned to baseline within 120 minutes for honey and tomato soup; within 210 minutes for white bread, choco-rice cookies, fish and potatoes, wafers, and meat ravioli with cheese; and later for dark chocolate, apricot dumplings, and choco-wheat cookies. The extended GIs were higher than the respective GI120s in eight of the foods.

Conclusions:

The 120-minute glycemic index fails to fully account for changes in glycemia after ingestion of a mixed meal because glycemia remains above baseline for a longer period. The CGMS is a convenient method to determine the glucose response/GIs over intervals extended up to 210 minutes, which is adequate time for the absorption of most foods.
Continuous Glucose Monitors and the Burden of Tight Glycemic Control in Critical Care: Can They Cure the Time Cost?
Authors: Signal Matthew , Pretty Christopher G. , Chase J. Geoffrey , Le Compte Aaron , Shaw Geoffrey M.
Published: January 2014

Background:

Tight glycemic control (TGC) in critical care has shown distinct benefits but has also proven to be difficult to obtain. The risk of severe hypoglycemia (<40 mg/dl) raises significant concerns for safety. Added clinical burden has also been an issue. Continuous glucose monitors (CGMs) offer frequent automated measurement and thus the possibility of using them for early detection and intervention of hypoglycemic events. Additionally, regular measurement by CGM may also be able to reduce clinical burden.

Aim:

An in silico study investigates the potential of CGM devices to reduce clinical effort in a published TGC protocol.

Methods:

This study uses retrospective clinical data from the Specialized Relative Insulin Nutrition Titration (SPRINT) TGC study covering 20 patients from a benchmark cohort. Clinically validated metabolic system models are used to generate a blood glucose (BG) profile for each patient, resulting in 33 continuous, separate BG episodes (6881 patient hours). The in silico analysis is performed with three different stochastic noise models: Two Gaussian and one first-order autoregressive. The noisy, virtual CGM BG values are filtered and used to drive the SPRINT TGC protocol. A simple threshold alarm is used to trigger glucose interventions to avert potential hypoglycemia. The Monte Carlo method was used to get robust results from the stochastic noise models.

Results:

Using SPRINT with simulated CGM noise, the BG time in an 80–110 mg/dl band was reduced no more than 4.4% to 45.2% compared to glucometer sensors. Antihypoglycemic interventions had negligible effect on time in band but eliminated all recorded hypoglycemic episodes in these simulations. Assuming 4–6 calibration measurements per day, the nonautomated clinical measurements are reduced from an average of 16 per day to as low as 4. At 2.5 min per glucometer measurement, a daily saving of ~25–30 min per patient could potentially be achieved.

Conclusions:

This paper has analyzed in silico the use of CGM sensors to provide BG input data to the SPRINT TGC protocol. A very simple algorithm was used for early hypoglycemic detection and prevention and tested with four different-sized intravenous glucose boluses. Although a small decrease in time in band (still clinically acceptable) was experienced with the addition of CGM noise, the number of hypoglycemic events was reduced. The reduction to time in band depends on the specific CGM sensor error characteristics and is thus a trade-off for reduced nursing workload. These results justify a pilot clinical trial to verify this study.
Serum Total Adiponectin is Associated with Impaired Glucose Tolerance in Asian Indian Females but Not in Males
Authors: Luo Menghua , Oza-Frank Reena , Narayan K. M. Venkat , Gokulakrishnan Kuppan , Mohan Viswanathan
Published: January 2014

Objective:

Adiponectin may play a role in the development of type 2 diabetes and cardiovascular disease (CVD). However, little is known about the relationship between adiponectin and impaired glucose tolerance (IGT). We investigated the association between adiponectin and IGT and between adiponectin and cardiovascular risk factors among subjects with IGT.

Research Design and Methods:

Subjects with normal glucose tolerance (NGT)( n = 571) and impaired glucose tolerance ( n = 167) were recruited from the Chennai Urban Rural Epidemiology Study in south India. Serum total adiponectin levels were measured using a radioimmunoassay (Linco Research, St. Charles, MO). High sensitivity C-reactive protein (hsCRP) was estimated by nephelometry.

Results:

In sex-stratified analyses, adiponectin was significantly associated with IGT in females [odds ratio (OR): 0.93, 95% confidence interval (CI): 0.872–0.991, p = 0.026] after controlling for age, waist circumference, blood pressure, alcohol consumption, smoking, lipid profile, and glycemic indices; in males there was no significant association (OR = 0.90, 95% CI: 0.798–1.012, p = 0.078). In prediabetic females, adiponectin was not associated with any CVD risk factors (age, waist circumference, blood pressure, cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, fasting glucose, fasting insulin, and insulin resistance level), but was associated negatively with 2-hour postplasma glucose levels ( r = −0.243, p < 0.05) and hsCRP ( r = −0.219, p < 0.05) after adjusting for demographic and biomedical indices. No associations with CVD risk factors were observed in males with IGT.

Conclusion:

Serum total adiponectin levels are associated with IGT, 2-hour postplasma glucose, and hsCRP in Asian Indian females but not in males.
Cinnamon: Potential Role in the Prevention of Insulin Resistance, Metabolic Syndrome, and Type 2 Diabetes
Authors: Qin Bolin , Panickar Kiran S. , Anderson Richard A.
Published: January 2014

Metabolic syndrome is associated with insulin resistance, elevated glucose and lipids, inflammation, decreased antioxidant activity, increased weight gain, and increased glycation of proteins. Cinnamon has been shown to improve all of these variables in in vitro, animal, and/or human studies. In addition, cinnamon has been shown to alleviate factors associated with Alzheimer's disease by blocking and reversing tau formation in vitro and in ischemic stroke by blocking cell swelling. In vitro studies also show that components of cinnamon control angiogenesis associated with the proliferation of cancer cells. Human studies involving control subjects and subjects with metabolic syndrome, type 2 diabetes mellitus, and polycystic ovary syndrome all show beneficial effects of whole cinnamon and/or aqueous extracts of cinnamon on glucose, insulin, insulin sensitivity, lipids, antioxidant status, blood pressure, lean body mass, and gastric emptying. However, not all studies have shown positive effects of cinnamon, and type and amount of cinnamon, as well as the type of subjects and drugs subjects are taking, are likely to affect the response to cinnamon. In summary, components of cinnamon may be important in the alleviation and prevention of the signs and symptoms of metabolic syndrome, type 2 diabetes, and cardiovascular and related diseases.
Update on Mathematical Modeling Research to Support the Development of Automated Insulin Delivery Systems
Authors: Steil Garry M. , Hipszer Brian , Reifman Jaques
Published: January 2014

One year after its initial meeting, the Glycemia Modeling Working Group reconvened during the 2009 Diabetes Technology Meeting in San Francisco, CA. The discussion, involving 39 scientists, again focused on the need for individual investigators to have access to the clinical data required to develop and refine models of glucose metabolism, the need to understand the differences among the distinct models and control algorithms, and the significance of day-to-day subject variability. The key conclusion was that model-based comparisons of different control algorithms, or the models themselves, are limited by the inability to access individual model–patient parameters. It was widely agreed that these parameters, as opposed to the average parameters that are typically reported, are necessary to perform such comparisons. However, the prevailing view was that, if investigators were to make the parameters available, it would limit their ability (and that of their institution) to benefit from the invested work in developing their models. A general agreement was reached regarding the importance of each model having an insulin pharmacokinetic/pharmacodynamic profile that is not different from profiles reported in the literature (88% of the respondents agreed that the model should have similar curves or be analyzed separately) and the importance of capturing intraday variance in insulin sensitivity (91% of the respondents indicated that this could result in changes in fasting glucose of ≥15%, with 52% of the respondents believing that the variability could effect changes of ≥30%). Seventy-six percent of the participants indicated that high-fat meals were thought to effect changes in other model parameters in addition to gastric emptying. There was also widespread consensus as to how a closed-loop controller should respond to day-to-day changes in model parameters (with 76% of the participants indicating that fasting glucose should be within 15% of target, with 30% of the participants believing that it should be at target). The group was evenly divided as to whether the glucose sensor per se continues to be the major obstacle in achieving closed-loop control. Finally, virtually all participants agreed that a future two-day workshop should be organized to compare, contrast, and understand the differences among the different models and control algorithms.
Liquid Silicone to Mitigate Plantar Pedal Pressure: A Literature Review
Authors: Bowling Frank L. , Metcalfe Stuart A. , Wu Stephanie , Boulton Andrew J. M. , Armstrong David G.
Published: January 2014

Disruption of the body's plantar fat pad can occur as a result of one of three mechanisms: simple fat pad atrophy associated with age-related degeneration, steroid use, or collagen vascular disease. Actual or relative displacement in to the underlying osseous prominences may be seen in association with structural deformity of the foot. Disease states such as diabetes may alter the normal structural integrity of soft tissues through nonenzymatic glycation leading to increased stiffness and thus reduced attenuating capacity. Fat pad atrophy, regardless of the cause, is often associated with substantial emotional, physical, productivity, and fnancial losses. In situations where the patient is sensate, the resultant skin on bone situation is extremely painful, especially when walking.
Patient Perceptions of Different Lancing Sites for Self-Monitoring of Blood Glucose: A Comparison of Fingertip Site with Palm Site Using the OneTouch® Ultra® Blood Glucose Monitoring System
Authors: Ito Takao , Kamoi Kyuzi , Minagawa Shinichi , Kimura Keita , Kobayashi Akane
Published: January 2014

Background:

Alternate-site testing (AST) for self-monitoring of blood glucose leads to improved glycemic control for treatment of diabetes mellitus. The aim of this randomized, open-label, two-period, crossover study was to compare the comfort of two different lancing sites, fingertip and palm sites, for AST in diabetes patients.

Methods:

Patients injected insulin four times a day. Self-monitoring of blood glucose was carried out more than thrice daily with fingertip measurements for at least three months using apparatuses except the OneTouch® Ultra® Blood Glucose Monitoring System (OneTouch) before examination. The comfort of two lancing sites using OneTouch were compared. In two randomized groups that used one fingertip lancing site for one week followed by the alternate lancing site for another week, patients completed 11-item questionnaires assessing usability of the site before and after each week. Each item was scored on a visual analogue scale from −100 (most negative) to +100 (most positive).

Results:

Most patients desired to continue AST, which was insignificantly different between the two lancing sites (fingertip and palm AST) in 43 diabetes patients aged 57.3 ± 13.8 years, body mass index of 23.1 ± 2.5 kg/m2, diabetes duration of 19.6 ± 9.7 years, and hemoglobin A1c of 7.4 ± 1.1%. However, patients were less ( p < .01) satisfied with using the palm lancing site as compared to the fingertip lancing site because of difficulties in inserting the needle, drawing blood samples, and applying enough blood into the test strip.

Conclusions:

These results suggest that patients desire to use the palm for AST, but more technological advances in AST of a palm site is required to reduce patient discomfort.
Proposed Clinical Application for Tuning Fuzzy Logic Controller of artificial Pancreas Utilizing a Personalization Factor
Authors: Mauseth Richard , Wang Youqing , Dassau Eyal , Kircher Robert , Matheson Donald , Zisser Howard , Jovanovič Lois , Doyle Francis J.
Published: January 2014

Background:

Physicians tailor insulin dosing based on blood glucose goals, response to insulin, compliance, lifestyle, eating habits, daily schedule, and fear of and ability to detect hypoglycemia.

Method:

We introduce a method that allows a physician to tune a fuzzy logic controller (FLC) artificial pancreas (AP) for a particular patient. It utilizes the physician's judgment and weighing of various factors. The personalization factor (PF) is a scaling of the dose produced by the FLC and is used to customize the dosing. The PF has discrete values of 1 through 5. The proposed method was developed using a database of results from 30 University of Virginia/Padova Metabolic Simulator in silico subjects (10 adults, 10 adolescents, and 10 children). Various meal sizes and timing were used to provide the physician information on which to base an initial dosing regimen and PF. Future decisions on dosing aggressiveness using the PF would be based on the patient's data at follow-up.

Results:

Three examples of a wide variation in diabetes situations are given to illustrate the physician's thought process when initially configuring the AP system for a specific patient.

Conclusions:

Fuzzy logic controllers are developed by encoding human expertise into the design of the controller. The FLC methodology allows for the real-time scaling of doses without compromising the integrity of the dosing rules matrix. The use of the PF to individualize the AP system is enabled by the fuzzy logic development methodology.
Postprandial Glycemic Excursions with the Use of a Closed-Loop Platform in Subjects with Type 1 Diabetes: A Pilot Study
Authors: van Bon Arianne C. , Hermanides Jeroen , Koops Robin , Hoekstra Joost B. L. , DeVries J. Hans
Published: January 2014

Background:

The aim of this study was to evaluate the efficacy of a proportional derivative algorithm closed-loop system to control postprandial glucose concentrations in subjects with type 1 diabetes.

Methods:

Six subjects treated with continuous subcutaneous insulin infusion received a standardized meal on three days. The first day served as control, the second day as learning experiment for the algorithm, and the third day to compare the closed loop to the control day. Venous blood glucose was measured as reference until 300 min postprandially. The artificial pancreas platform consisted of a subcutaneous continuous glucose monitor (CGM), the GlucoDay® S (Menarini Diagnostics), two D-Tron+ pumps (Disetronic Medical Systems) for subcutaneous insulin, and glucagon administration connected to a personal computer.

Results:

One subject was excluded due to technical failure of the CGM. Two of five subjects were male, mean age was 50.8 years (range 38–60), and mean hemoglobin A1c was 8.7% (range 7.0–12.2). The mean postprandial venous blood glucose concentration of day 1 was 205 mg/dl (range 94–265 mg/dl) compared with 128 mg/dl (range 128–158 mg/dl) on day 3 ( p = .14). Percentage of time spent in euglycemia postprandially on day 1 was 31% versus 60% on day 3 ( p = .08). Time spent below 3.9 mmol/liter (70 mg/dl) was 19% on day 1 compared with 11% on day 3 ( p = 1.0). Time above 10 mmol/liter (180 mg/dl) on day 1 was 60% versus 29% on day 3 ( p = .22).

Conclusion:

The artificial pancreas provided comparable postprandial glycemic control to usual care.