bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhaled Technosphere® Insulin in Comparison to Subcutaneous Regular Human Insulin: Time Action Profile and Variability in Subjects with Type 2 Diabetes
Authors: Rave Klaus , Heise Tim , Heinemann Lutz , Boss Anders H.
Published: January 2014

Background:

This study assessed time action profile and within- and between-subject variability of inhaled Technosphere® Insulin (TI) compared with subcutaneous regular human insulin (sc RHI).

Methods:

Thirteen subjects with type 2 diabetes (age 56 ± 7 years, body mass index 30.4 ± 3.0 kgm−2; hemoglobin A1c 6.9 ± 0.9%; mean ± SD) participated in this six-period crossover isoglycemic glucose clamp study. In randomized order, each subject received three single doses of TI and sc RHI on separate study days.

Results:

Inhalation of TI resulted in a higher maximum serum insulin concentration (858 vs 438 pmol·liter−1; p = 0.0001) and shorter intervals to maximum insulin concentration (17 vs 135 minutes; p = 0.0001) than sc RHI. Overall, 48 units of TI and 24 units of sc RHI provided comparable 3-hour insulin exposure (INS area under the curve0–3 h55.8 vs 60.0 nmol·min·liter−1, respectively). Time to maximum metabolic effect was shorter (79 vs 293 minutes; p < 0.0001), and percentage of glucose disposal during the first 3 hours was higher for TI compared with sc RHI (59 vs 27%). Within-subject variabilities of insulin exposure following inhalation of TI for 2 and 3 hours and end of study period were 19, 18, and 16% as compared with 27, 25, and 15% after sc RHI injection ( p = not significant).

Conclusion:

Technosphere Insulin has a more rapid onset of action than sc RHI. About 60% of the glucose-lowering effect of TI occurs during the first 3 hours after application. In contrast, <30% of the glucose-lowering effect of sc RHI occurs in this period. Technosphere Insulin demonstrated a lower intrasubject variability during the 3-hour postprandial period, without reaching statistical significance.
Cardiometabolic Risk Factors Assessed by a Finger Stick Dried Blood Spot Method
Authors: Kapur Sanjay , Kapur Sonia , Zava David
Published: January 2014

Background:

Cardiovascular and metabolic risk factors are gaining attention as potential indicators for intervention in the prevention and treatment of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Blood spot technology offers an efficient, convenient method to measure these risk factors in an at-risk population. Simple and convenient methods to assess cardiometabolic risk factors will allow clinicians to formulate treatment strategies for effective prevention and management of these conditions.

Method:

Insulin and high sensitivity C-reactive protein (hs-CRP) were measured in dried blood spot and corresponding serum samples using conventional commercial serum kits based on a direct sandwich ELISA technique. The triglyceride assay involved enzymatic hydrolysis of triglycerides by lipase to glycerol and free fatty acids. The glycerol produced was then measured by coupled enzyme reactions. Blood spot assays were modified from previously published methods to give improved accuracy and turnaround time.

Results:

Blood spot levels correlated well with serum levels of hs-CRP ( r = 0.99), triglycerides (fasting, r = 0.95; nonfasting, r = 0.94), and insulin (fasting, r = 0.93; nonfasting, r = 0.97).

Conclusion:

Blood spot testing for insulin, hs-CRP, and triglycerides may be helpful in the cardiometabolic screening or monitoring of patients at risk of developing CVD, T2DM, or metabolic syndrome.
Effects of Exenatide on Diabetes, Obesity, Cardiovascular Risk Factors, and Hepatic Biomarkers in Patients with Type 2 Diabetes
Authors: Nielsen Loretta L. , Okerson Ted , Holcombe John , Hoogwerf Byron
Published: January 2014

Obesity increases the risk of diabetes up to 90-fold and worsens hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease. For patients with type 2 diabetes, weight loss can trigger improvements in all these conditions and decrease the need for glucose-lowering agents. The incretin mimetic exenatide shares many glucoregulatory properties with native glucagon-like peptide-1, including enhancement of glucose-dependent insulin secretion, glucose-dependent suppression of inappropriately high glucagon secretion, slowing of gastric emptying, and reduction of food intake in patients with type 2 diabetes. Exenatide treatment was associated with progressive weight loss in the majority of patients in clinical trials. In addition, patients with elevated markers of liver injury at baseline showed improvements. Therefore, exenatide represents a unique option for adjunctive therapy for patients with type 2 diabetes not achieving adequate glycemic control on oral antidiabetic agents, especially in patients for whom weight gain would be an additional contraindication.
Insulin Pen—The “iPod” for Insulin Delivery (Why Pen Wins over Syringe)
Authors: Asamoah Ernest
Published: January 2014

Diabetes affects most aspects of everyday life and places considerable responsibility on the patient; therefore, without patient acceptance of what we offer, the therapy is unlikely to be adhered to especially when that therapy happens to be insulin injection. In 2008, almost every physician/health care provider carries new and sleek cell phones (because the newer ones are well designed and function better). Why these same providers continue to prescribe insulin via syringes in 2008 is something that I cannot fathom. Previously, some insurance companies only paid for vials and there was no other choice, but today almost all insurance pay for pens and so the “insurance reason” is no longer tenable. Since Banting and Best discovered insulin in 1921, scientists have continued to improve the types of insulin (making them mimic physiology more closely in order to minimize hypoglycemia and improve glycemic control as seen with the latest analog insulins). In the same manner, the delivery process of insulin has also continued to evolve to make it easier and more acceptable to patients. Studies have shown that patients prefer device use over traditional vials/syringes. Pen devices used to inject insulin lead to better compliance, are quicker to inject, dosing is much more accurate, and, surprisingly, are more cost effective. I challenge my colleagues to take full responsibility for what their patients use. If a provider believes in pen devices, most of his/her patients will use them. The products your patients use is a direct reflection of what you practice. Educating providers to change their beliefs and practices is key to moving American diabetic patients from syringes to pen devices.
Inhaled Insulin: Take a Deep Breath, but How?
Authors: Heinemann Lutz , Scheuch Gerhard , Heise Tim
Published: January 2014

Inhalation of insulin is the first alternative route of insulin administration, which has been developed to such a mature status that the first product (Exubera® Pfizer) was made available to the market and subsequently withdrawn as of early 2008. In view of the relatively low bioavailability of inhaled insulin and the intraindividual variability of the metabolic effect induced (which is in the range of that of subcutaneously applied regular insulin), one wonders how to improve both aspects. Unfortunately, it appears as if the impact of the inhalation maneuver on insulin deposition in the deep lung has not been studied extensively. We present some thoughts and data from an alveolar model and propose an experimental procedure that might be helpful in the quantitative evaluation of the impact of the insulin inhalation maneuver.
New Guideline Supports the Development and Evaluation of Continuous Interstitial Glucose Monitoring Devices
Authors: D'Archangelo Melissa J.
Published: January 2014

For the millions of patients who are managing diabetes, daily self-monitoring of blood glucose is a fact of life. However, the cost and inconvenience of self-monitoring have led to noncompliance by many patients. Continuous interstitial glucose monitoring (CGM) has emerged as a promising and welcome alternative to traditional glucose monitoring, which requires the patient to endure repeated finger sticks. The Clinical and Laboratory Standards Institute (CLSI) (Wayne, PA) has been working cooperatively with the Diabetes Technology Society on the development of a consensus guideline for CGM. CLSI has recently released document POCT5-P— Performance Metrics for Continuous Interstitial Glucose Monitoring; Proposed Guideline. This document specifies requirements and recommendations for methods determining analytical and clinical metrics of CGM. This guideline will support and streamline the further development and evaluation of CGM devices.
Use of a Computerized Intravenous Insulin Algorithm within a Nurse-Directed Protocol for Patients Undergoing Cardiovascular Surgery
Authors: Davidson Paul C. , Steed R. Dennis , Bode Bruce W. , Hebblewhite Harry R. , Prevosti Louis , Cheekati Vasundhara
Published: January 2014

Background:

Several studies have shown the benefits of tight glycemic control in the intensive care unit. A large hospital became concerned about certain deficiencies in the management of glucose control in conjunction with cardiovascular surgery. A multidisciplinary steering committee was formed, which implemented a glycemic protocol, the subject of this study.

Methods:

The glycemic protocol is a perioperative, nurse-directed program that incorporates the computerized intravenous (IV) insulin algorithm, Glucommander. Upon admission, hemoglobin A1c and blood glucose (BG) were tested, and patients were screened for previously diagnosed diabetes. This information was used to determine if preoperative insulin will be used, if the patient will be transitioned post-IV to subcutaneous (SC) basal-bolus insulin, and if insulin will be prescribed on discharge. IV insulin was initiated perioperatively in known diabetes cases or if one BG value >140 mg/dl or two BG values >110 mg/dl within 24 hours before or during surgery. The target range was 90 to 120 mg/dl.

Results:

In the 9 months after protocol implementation, 93% of the patients had no BG value >200 mg/dl during the first 48 hours postoperatively. In the 6 months of study data, there were 457 patients. The mean time to target range was 3.0 hours. The mean IV insulin run time was 37 hours. The mean BG value was 107 mg/dl. Only 2% of patients had transient BG <50 mg/dl, and no BG values were >40 mg/dl. Of the patients, 52% were transitioned to SC basal-bolus, and 26% were discharged on insulin.

Conclusions:

The Glucommander earned high respect from the nurses for the way it scheduled BG tests and eliminated the calculation time and calculation errors associated with manual methods. The protocol was highly effective in normalizing glucose without hypoglycemia. The multidisciplinary steering committee proved to be a good approach to implementing a glycemic protocol.
An Internet Service Supporting Quality Assessment of Inpatient Glycemic Control
Authors: Thomas Prem , Inzucchi Silvio E.
Published: January 2014

Background:

Several studies have linked the maintenance of normoglycemia in acutely ill inpatients with improved clinical outcomes. We previously proposed a few standard definitions for monitoring inpatient glycemic control, or “glucometrics.” In clinical practice, limited data management resources for developing and refining measurement protocols can slow quality improvement efforts. With regard to glucometrics, there are few baseline data regarding the quality of hospital glycemic management. Furthermore, there are no reliable methods for hospitals to gauge the progress of their quality improvement efforts.

Methods:

We built a novel Web application that calculates glucometrics on anonymized blood glucose data files uploaded by registered users. This Web site also collects many key characteristics of the users and institutions utilizing the service. This application will allow us to pool data from several institutions to calculate aggregate glucometrics, providing baseline data for quality improvement efforts and ongoing metrics for institutions to gauge their progress.

Results:

The application, accessible at http://metrics.med.yale.edu , has already drawn visitors from several countries. A number of users have registered formally, and some have begun to upload institutional glucose data. The application delivers detailed glucometrics reports to registered users, complete with visual displays. Quality improvement staff from large health systems have been the predominant users.

Conclusions:

We have created an open access Web application to facilitate quality monitoring and improvement efforts—as well as clinical research—regarding inpatient glycemic management. If employed widely, this application could help establish national performance standards for glycemic control.
In Silico Simulation of Long-Term Type 1 Diabetes Glycemic Control Treatment Outcomes
Authors: Wong Xing-Wei , Chase J. Geoffrey , Hann Christopher E. , Lotz Thomas F. , Lin Jessica , Le Compte Aaron J. , Shaw Geoffrey M.
Published: January 2014

Objectives:

The goals of this study were to develop (1) a safe and effective protocol for the clinical control of type 1 diabetes using conventional self-monitoring blood glucose (SMBG) measurements and multiple daily injections with insulin analogues, and (2) an in silico simulation tool of type 1 diabetes to predict long-term glycemic control outcomes of clinical interventions.

Methods:

The virtual patient method was used to develop a simulation tool for type 1 diabetes using data from a type 1 diabetes patient cohort ( n = 40). The tool was used to test the adaptive protocol (AC) and a conventional intensive insulin therapy (CC) against results from a representative control cohort. Optimal and suboptimal basal insulin replacements were evaluated as a function of SMBG frequency in conjunction with the (AC and CC) prandial control protocols.

Results:

In long-term glycemic control, the AC protocol significantly decreased hemoglobin A1c in conditions of suboptimal basal insulin replacement for SMBG frequencies ≥6/day, and reduced the occurrence of mild and severe hypoglycemia by 86–100% over controls, over all SMBG frequencies in conditions of optimal basal insulin.

Conclusions:

A simulation tool to predict long-term glycemic control outcomes from clinical interventions has been developed to test a novel, adaptive control protocol for type 1 diabetes. The protocol is effective and safe compared to conventional intensive insulin therapy and controls. As fear of hypoglycemia is a large psychological barrier to glycemic control, the AC protocol may represent the next evolution of intensive insulin therapy to deliver increased glycemic control with increased safety. Further clinical or experimental validation is needed to fully prove the concept.
Continuous Glucose Monitoring: Changing Diabetes Behavior in Real Time and Retrospectively
Authors: Block Jennifer M.
Published: January 2014

Results of both the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Studies supported the role of tight glucose control in reducing long-term complications of diabetes. There is further evidence that glycemic variability may be better correlated with the risk for complications than sustained hyperglycemia. These studies reinforce the need to work toward improved glucose control with minimal variability in patients with diabetes. Continuous glucose monitoring technology offers a means of obtaining a more complete picture of glucose patterns and can be used to aid in identifying trends in glycemic variability, especially overnight and after meals when blood glucose testing is not usually performed. Increased access to retrospective trends, the addition of real-time glucose alarms, and prospective trend data can be advantageous in motivating and evaluating behavior change.
Diabetes and Eating Disorders
Authors: Goebel-Fabbri Ann E.
Published: January 2014

The problem of insulin restriction is an important women's health issue in type 1 diabetes. This behavior is associated with increased rates of diabetes complications and decreased quality of life. Clinical and technological research is greatly needed to improve treatment tools and strategies for this problem. In this commentary, the author describes the scope of the problem of eating disorders and diabetes, as well as offers ideas about ways technology may be applied to help solve this complex problem.
FlexPen® and KwikPen™ Prefilled Insulin Devices: A Laboratory Evaluation of Ergonomic and Injection Force Characteristics
Authors: Ignaut Debra A. , Opincar Michael , Lenox Sheila
Published: January 2014

Background:

Advances in insulin pen technology continue to improve the usability of these devices for patients with diabetes. In this study, ergonomic features and injection force, as measured by glide force (GF) and glide force variability (GFV), were evaluated for the new Humalog® Mix75/25 KwikPen™ (KwikPen) and compared with the NovoLog® Mix 70/30 FlexPen® (FlexPen).

Methods:

Fifty prefilled insulin pen devices (25 of each type) were measured for diameter at the cartridge holder and dose window, length and weight with cap attached, and thumb reach at 30 and 60 units. GF was also determined for 100 devices (50 of each type); GFV at 30 and 60 unit doses was calculated for the plateau portion of the force curve based on the minimum and maximum force measured in that portion of the curve.

Results:

While FlexPen was lighter in weight than KwikPen, and presented a slightly smaller diameter at the cartridge holder and dose window, KwikPen had a shorter overall pen length compared to FlexPen, with a shorter thumb reach at both the 30- and 60-unit dose settings. The maximum GF for KwikPen was less than FlexPen at both the 30-unit (3.42 vs 5.36 lb, p <0.0001) and 60-unit doses (3.61 vs 5.62, p <0.0001). KwikPen GFV was lower across both doses (mean difference: −0.46 lb at 30 units, −0.44 lb at 60 units; p <0.0001 for both).

Conclusions:

While FlexPen was lighter with a slightly smaller cartridge holder and dose window diameter, KwikPen was shorter in length with less thumb reach than FlexPen. KwikPen also demonstrated lower GF and GFV, resulting in a smoother injection profile than FlexPen. These features of KwikPen's design and function may offer important advantages for the user during insulin administration.
Use of Continuous Glucose Monitoring to Estimate Insulin Requirements in Patients with Type 1 Diabetes Mellitus during a Short Course of Prednisone
Authors: Bevier Wendy C. , Zisser Howard C. , Jovanovič Lois , Finan Daniel A. , Palerm Cesar C. , Seborg Dale E. , Doyle Francis J.
Published: January 2014

Background:

Insulin requirements to maintain normoglycemia during glucocorticoid therapy and stress are often difficult to estimate. To simulate insulin resistance during stress, adults with type 1 diabetes mellitus (T1DM) were given a three-day course of prednisone.

Methods:

Ten patients (7 women, 3 men) using continuous subcutaneous insulin infusion pumps wore the Medtronic Minimed CGMS® (Northridge, CA) device. Mean (standard deviation) age was 43.1 (14.9) years, body mass index 23.9 (4.7) kg/m2, hemoglobin A1c 6.8% (1.2%), and duration of diabetes 18.7 (10.8) years. Each patient wore the CGMS for one baseline day (day 1), followed by three days of self-administered prednisone (60 mg/dl; days 2–4), and one post-prednisone day (day 5).

Results:

Analysis using Wilcoxon signed rank test (values are median [25th percentile, 75th percentile]) indicated a significant difference between day 1 and the mean of days on prednisone (days 2–4) for average glucose level (110.0 [81.0, 158.0] mg/dl vs 149.2 [137.7, 168.0] mg/dl; p = .022), area under the glucose curve and above the upper limit of 180 mg/dl per day (0.5 [0, 8.0] mg/dl·d vs 14.0 [7.7, 24.7] mg/dl·d; p = .002), and total daily insulin dose (TDI), (0.5 [0.4, 0.6] U/kg·d vs 0.9 [0.8, 1.0] U/kg·d; p = .002). In addition, the TDI was significantly different for day 1 vs day 5 (0.5 [0.4, 0.6] U/kg·d vs 0.6 [0.5, 0.8] U/kg·d; p = .002). Basal rates and insulin boluses were increased by an average of 69% (range: 30–100%) six hours after the first prednisone dose and returned to baseline amounts on the evening of day 4.

Conclusions:

For adults with T1DM, insulin requirements during prednisone induced insulin resistance may need to be increased by 70% or more to normalize blood glucose levels.
A Benchmark Data Set for Model-Based Glycemic Control in Critical Care
Authors: Chase J. Geoffrey , LeCompte Aaron , Shaw Geoffrey M. , Blakemore Amy , Wong Jason , Lin Jessica , Hann Christopher E.
Published: January 2014

Background:

Hyperglycemia is prevalent in critical care. That tight control saves lives is becoming more clear, but the “how” and “for whom” in repeating the initial results remain elusive. Model-based methods can provide tight, patient-specific control, as well as providing significant insight into the etiology and evolution of this condition. However, it is still often difficult to compare results due to lack of a common benchmark. This article puts forward a benchmark data set for critical care glycemic control in a medical intensive care unit (ICU). Based on clinical patient data from SPecialized Relative Insulin and Nutrition Tables (SPRINT) studies, it provides a benchmark for comparing and analyzing performance in model-based glycemic control.

Methods:

Data from 20 of the first 150 postpilot patients treated under SPRINT are presented. All patients had longer than a 5-day length of stay (LoS) in the Christchurch ICU. The benchmark data set matches overall patient data and glycemic control results for the entire cohort and this particular LoS >5-day group. The mortality outcome ( n = 3, 15%) also matches SPRINT results for this patient group.

Results:

Data cover 20 patients and 6372 total patient hours with an average of 339.4 hours per patient. It includes insulin and nutrition inputs along with 4182 blood glucose measurements at an average of 224.3 measurements per patient, averaging a measurement approximately every 1.5 hours (16 per day). Data are available via download in a Microsoft Excel format. A series of cumulative distribution functions and tables are used to summarize data in this article.

Conclusion:

Model-based methods can provide tighter, more adaptable “one method fits all” solutions using methods that enable patient-specific modeling and control. A benchmark data set will enable easier model and protocol development for groups lacking clinical data, as well as providing a benchmark to compare results of different protocols on a single (virtual) cohort based on real clinical data.
Using Support Vector Machines to Detect Therapeutically Incorrect Measurements by the MiniMed CGMS®
Authors: Bondia Jorge , Tarín Cristina , García-Gabin Winston , Esteve Eduardo , Fernández-Real José Manuel , Ricart Wifredo , Vehí Josep
Published: January 2014

Background:

Current continuous glucose monitors have limited accuracy mainly in the low range of glucose measurements. This lack of accuracy is a limiting factor in their clinical use and in the development of the so-called artificial pancreas. The ability to detect incorrect readings provided by continuous glucose monitors from raw data and other information supplied by the monitor itself is of utmost clinical importance. In this study, support vector machines (SVMs), a powerful statistical learning technique, were used to detect therapeutically incorrect measurements made by the Medtronic MiniMed CGMS®.

Methods:

Twenty patients were monitored for three days (first day at the hospital and two days at home) using the MiniMed CGMS. After the third day, the monitor data were downloaded to the physician's computer. During the first 12 hours, the patients stayed in the hospital, and blood samples were taken every 15 minutes for two hours after meals and every 30 minutes otherwise. Plasma glucose measurements were interpolated using a cubic method for time synchronization with simultaneous MiniMed CGMS measurements every five minutes, obtaining a total of 2281 samples. A Gaussian SVM classifier trained on the monitor's electrical signal and glucose estimation was tuned and validated using multiple runs of k-fold cross-validation. The classes considered were Clarke error grid zones A+B and C+D+E.

Results:

After ten runs of ten-fold cross-validation, an average specificity and sensitivity of 92.74% and 75.49%, respectively, were obtained (see Figure 4). The average correct rate was 91.67%.

Conclusions:

Overall, the SVM performed well, in spite of the somewhat low sensitivity. The classifier was able to detect the time intervals when the monitor's glucose profile could not be trusted due to incorrect measurements. As a result, hypoglycemic episodes missed by the monitor were detected.
Autonomie Mechanisms and Therapeutic Implications of Postural Diabetic Cardiovascular Abnormalities
Authors: Arora Rohit R. , Bulgarelli Robert J. , Ghosh-Dastidar Samanwoy , Colombo Joseph
Published: January 2014

Background:

Cardiovascular autonomic neuropathy (CAN) is a disorder of progressive autonomic dysfunction (AD) associated with diabetes and other chronic diseases. Orthostatic hypotension (OH) is one of the most incapacitating symptoms of CAN and AD. AD in OH can include sympathetic withdrawal (SW). To detect and diagnose SW, parasympathetic and sympathetic changes must be clearly differentiated from each other. This is accomplished by means of the novel autonomic nervous system (ANS) method based on the simultaneous spectral analyses of respiratory activity (RA) and heart rate variability (HRV).

Methods:

We performed autonomic profiling of 184 (142 females) consecutive, arrhythmia-free patients with type 2 diabetes using the ANX-3.0 autonomic monitoring system. The patient cohort included 86 (64 female) patients for whom an a1-agonist was the only drug changed and increased from one test to the next; 37 (33 female) for whom the a1-agonist was discontinued; and 61 (45 female) who were on an a1-agonist, but for whom no drug changes were made. The tests averaged 3.1 ± 1.4 months apart; midodrine (ProAmatine) was the a1-agonist prescribed. Of the group, 99 patients also had hypertension and 47 also had cardiovascular disease. No patient had supine hypertension.

Results:

Changes in parameters from the HRV (without respiration) and ANS methods were compared with changes in heart rate and blood pressure (BP) as measured from one test (test N) to the next (test N + 1). SW with a BP drop of less than the clinical definition may be a trend that can be an early indicator of orthostasis. In this study, patients were treated with low-dose, short-term α1-agonist (vasopressor) therapy, which tended to correct the abnormal trend of SW with a drop in BP. Included in the findings was a systolic BP trend in response to vasopressor therapy of an (expected) initial increase in BP followed by an eventual decrease in systolic BP as SW was reversed.

Conclusions:

The ANS method enables quantitative assessment of CAN by independently and simultaneously quantifying the two branches of the ANS, sympathetic and parasympathetic. The ANS method modifies standard spectral analysis of HRV (without RA analysis) by incorporating spectral analysis of RA. The ANS method appears to model the normal and abnormal responses to upright posture and changes in vasopressor therapy with greater fidelity than the HRV method. Independent, simultaneous assessment of progressive parasympathetic and sympathetic dysfunction, autonomic imbalance, and responses of the two ANS branches to therapy seems to enable early detection and early intervention. Orthostasis, by way of example, illustrates that frequent, sensitive assessments of both ANS branches can improve the negative outcomes associated with CAN.
A Subcutaneous Insulin Pharmacokinetic Model for Computer Simulation in a Diabetes Decision Support Role: Validation and Simulation
Authors: Wong Jason , Chase J. Geoffrey , Hann Christopher E. , Shaw Geoffrey M. , Lotz Thomas F. , Lin Jessica , Le Compte Aaron J.
Published: January 2014

Objective:

The goal of this study was to validate a previously derived and identified physiological subcutaneous (SC) insulin absorption model for computer simulation in a clinical diabetes decision support role using published pharmacokinetic summary measures.

Methods:

Validation was performed using maximal plasma insulin concentration (Cmax) and time to maximal concentration (tmax) pharmacokinetic summary measures. Values were either reported or estimated from 37 pharmacokinetic studies over six modeled insulin types. A validation comparison was made to equivalent pharmacokinetic summary measures calculated from model generated curves fitted to respective plasma insulin concentration data. The validation result was a measure of goodness of fit. Validation for each reported study was classified into one of four cases.

Results:

Of 37 model fits, 22 were validated on both the Cmax and the tmax summary measures. Another 6 model fits were partially validated on one measure only due to lack of reporting on the second measure with errors to reported or estimated ranges of <12%. Another 7 studies could not be validated on either measure because of inadequate reported clinical data. Finally, 2 separate model fits to data from the same study failed the validation with 90 and 71% error on tmax only, which was likely caused by protocol-based error. No model fit failed the validation on both measures.

Conclusions:

A previously derived and identified model was clinically validated for six insulin types using Cmax and tmax summary measures from published pharmacokinetic studies. Hence, this article presents a clinically valid model that accounts for multiple nonlinear effects and six different types of SC insulin in a computationally modest form suitable for use in clinical decision support.
A Pocket-Size Device to Detect Autonomic Neuropathy
Authors: Ejskjaer Niels , Fleischer Jesper , Fleischer Jacob , Jacobsen Poul Erik , Poulsen Per Logstrup , Nygaard Hans
Published: January 2014

Background:

Diabetic autonomic neuropathy (DAN) is a very frequent complication in the diabetic population (type 1 and type 2 diabetes), and patients may suffer debilitating symptoms from various organ systems. In the less symptomatic and even in the asymptomatic condition it severely impacts health. Testing for DAN is currently time-consuming and costly due to the technical setups available today, therefore the examination may not be offered regularly. The purpose of this study was to evaluate the clinical performance of a pocket-size device for detecting DAN by measuring heart rate variability (HRV).

Method:

Ten healthy young males and eight type 1 diabetes patients suffering symptomatic DAN were selected. The standardized spectral analysis equipment VariaPulse TF3® (Sima Media, Olumouc, Czechoslovakia) was used as a reference method for evaluating a prototype of the pocket-size device according to a specified protocol. HRV, inhalation/exhalation ratio (E:I) (deep breathing test), and 30:15 ratio (response going from lying to standing) were measured using both methods. Statistical calculations were performed.

Results:

The correlation between the two devices was R2 = 0.98 and R2 = 0.81 when 30:15 ratio and E:I were measured, respectively. Bland-Altman plots showed suitable agreement between the two devices, substantiated by 95% limits of agreement of the differences of ±0.014 and ±0.033 when 30:15 ratio and E:I were measured, respectively.

Conclusions:

The pocket-size device was fully interchangeable with the hitherto-used, research-based setup. It proved highly suitable for ambulatory testing of autonomic nervous function and may facilitate screening for DAN according to Danish and international recommendations.
The Implantable Peritoneal Pump—A Patient's Perspective
Authors: Witkowski Christopher J. , Saudek Christopher
Published: January 2014

A participant in a study of implantable insulin pump therapy recounts his experiences with on-and-off use of the pump over the past 18 years. Christopher Witkowski, 55, first had a pump implanted in 1990. Despite occasional difficulties over the years, Witkowski reports that his overall experience has been extremely positive. With delivery of insulin directly into the peritoneal cavity, he feels better, has more flexibility in eating, and experiences fewer insulin reactions. Witkowski expresses disappointment that the manufacturer of the pump, Medtronic, no longer plans to seek Food and Drug Administration approval for this therapy. Witkowski expresses his hope that research on the device will continue, believing that this therapy could be of benefit to millions of diabetes patients. This article is accompanied by a detailed description of the pump refill procedure by Dr. Christopher Saudek of Johns Hopkins University, current leader of the ongoing research study.
Role of Physicians in the Pharmaceutical Industry and Clinical Research Organizations: Take More Pride in Your Work
Authors: Heinemann Lutz , Hompesch Marcus
Published: January 2014

Physicians working in biopharmaceutical companies are key components in the successful development of new diagnostic and therapeutic developments. They have a high level of responsibility for the safe performance of clinical studies and for evaluating the efficacy of new potential treatments in patients. Recently, articles in highly ranked scientific journals have challenged this work. This article highlights the shortcomings of those views. In contrast, we document that the majority of the physicians working in the pharmaceutical industry provide extremely high-quality work, in part forced by the rigorous regulatory framework this work has to comply with nowadays. We promote an open (and critical!) discussion while sharing industrial views and opinions with colleagues from academia. Only by a constructive cooperation between both worlds, avoiding a black-and-white view, will we achieve an instrumental and effective way in developing new and affordable diagnostic and therapeutic tools that are truly helpful and affordable for patients. If physicians in the industry take more pride in their work, this would be helpful in fostering such an approach.
Tight Glycemic Control in the Hospital
Authors: Ellmerer Martin , Pachler Christoph , Plank Johannes
Published: January 2014

Single center randomized controlled trials could demonstrate a benefit of strict glycemic control on the mortality and morbidity outcomes for critically ill patients. Although observational studies also demonstrate a benefit of tight glucose control for patients in general wards, direct evidence is still lacking. Overall, the implementation of glucose control both in the very controlled setting of an intensive care unit and even more so in the clearly less controlled setting of a general ward has proven to be difficult. Standardization of all required working steps to establish glycemic control needs to be considered to be able to achieve safe and good blood glucose control. Recent developments from diabetes technology will have an important impact in facilitating glucose control in the hospital, although the already established workflows in hospitals will require a substantial reconsideration of diabetes-oriented technology to allow an area-wide implementation and acceptance by health care personnel.
Electromagnetic Environmental Effects Testing of Medical Devices Including Those Used for the Treatment of Diabetes
Authors: Herkert Ralph M.
Published: January 2014

Background:

Electromagnetic emissions from technologies that surround us can produce interference with implanted and externally worn medical devices. Electromagnetic environmental effects (E3) testing of medical devices at the Georgia Tech Research Institute (GTRI) began almost four decades ago and continues to incorporate new devices and new sources of electromagnetic emissions as they are developed and become available. The GTRI Medical Device Test Center provides real-world exposure fields to identify interactions and help manufacturers prevent disruptions from the environments in which their devices must function.

Methods:

Typically, the medical device is mounted in or on a torso simulator containing a saline solution that simulates the electrical characteristics of the body. The torso simulator and the device under test are then moved through the fields generated by production security and logistical system technologies using a computer-controlled positioning system. These tests are conducted with different orientations of the medical device to the electromagnetic source, simulating the way in which device wearers interact with these systems in representative situations.

Results:

Particular E3 test results measured on specific devices in the GTRI Medical Device Test Center are proprietary; however, the results of tests to date with current medical devices used for the treatment of diabetes have been encouraging. These devices have included implantable and externally worn insulin infusion pumps and continuous glucose monitoring systems from different manufacturers.

Conclusion:

Since E3 tests of diabetes treatment devices to date in the test center have centered on devices from only a few of the many current manufacturers, further testing is warranted. In addition, increased functionality, which is being added to existing devices, will create new possibilities for interference in the future.
Agreement between Glucose Trends Derived from Three Simultaneously Worn Continuous Glucose Sensors
Authors: King Allen B. , Armstrong Dana , Chu Caroline , Sharma Manoj , Price David
Published: January 2014

Background:

Sensors detect the rate and direction of glucose trend. They need to be accurate and reproducible as could be evidenced by strong agreement between multiple sensors. We evaluated this relationship through simultaneously worn glucose sensors using several methods of slope analysis.

Methods:

Ten type 1 diabetic, insulin pump-treated subjects were studied while simultaneously wearing three CGMS® Gold sensors each. Sensors were placed in the right abdomen (reference), left abdomen, and left upper arm. Sensors were calibrated and chronologically aligned. Data were only interpreted and included if there were 24 hours of data simultaneously obtained from all three sensors.

Results:

Using a two-point derived slope, increasing the duration of the trend from 5 to 60 minutes improved agreement between sensors. Using a 20-minute rolling average trend (using every 5-minute glucose value during the 20 minutes) improved the agreement to 94.3%. Finally, using whichever of the two comparator sensor rolling average trends was closest to the reference (better of two), the agreement improved to 98.2%. However, for these trend analysis methods, when the absolute reference rate of change was more than 1 mg/dl/min, the agreement decreased. Even with the best analysis approach, at an absolute reference sensor rate of change of >2 mg/dl/min, the agreement between sensors was only 40.0%.

Conclusion:

Despite several methods of analysis, trend agreement from multiple sensors diminishes as the absolute rate of change of reference glucose increases.
Effects of Pulsatile Subcutaneous Injections of Insulin Lispro on Plasma Insulin Concentration Levels
Authors: Chan Alice , Breton Marc D. , Kovatchev Boris P.
Published: January 2014

Background:

Most insulin pumps used for the treatment of diabetes perform subcutaneous insulin injections by pulses. The purpose of this work is to analyze the effects of pulsatile injections of modern insulins on plasma insulin levels compared with a continuous insulin infusion.

Method:

We simulate pulsatile implementations of a basal rate profile over a day on a type 1 diabetes mellitus patient using insulin lispro. Pulse periods were varied between 1 and 60 min, and random pump errors were included, modeled as white noise, 1/f noise, or 1/f2 noise with relative standard deviations up to 10% of the pump output.

Results:

Oscillations in plasma insulin caused by the pulsatile injections were not significant with respect to the global variations for pulse periods below 15 min. This cutoff period was found to be robust to random pump errors with standard deviations up to 10% of the pump output and hence solely determined by the insulin kinetics. Additionally, we showed that the pulse period achieving the best implementation of a continuous profile is an increasing function of the error variance for a given type of noise.

Conclusions:

Our findings support that continuous insulin infusion can be implemented by a pulsatile injection of insulin as infrequent as a pulse every 15 min without significant effects on plasma insulin levels. If clinically confirmed, this result would have important consequences on the design and in silico testing of automated insulin treatment strategies, as increased delivery intervals imply higher accuracy of insulin delivery and facilitated implementations of closed-loop control algorithms.
Review of Designing an Information Processing Ware for a Diabetic Chip
Authors: AL-Sheikh Youssef T. , Andrade Joseph D. , Millington Jared , Wong Anthony
Published: January 2014

Miniaturization of clinical chemistry analyzers can empower research conducted to better understand, diagnose, manage, and cure diseases such as diabetes. For the last decade, we have been working on the design and development of miniaturized clinical chemistry devices, including a Diabetic Chip (diabetiChip). These devices measure a small array of analytes, are small, portable, fast, easy-to-operate, and inexpensive. The chosen analytical method for the diabetiChip uses bioluminescence, which is highly sensitive and specific, and is based on photon counting and specific enzymatic reactions. Bioluminescent reactions were intentionally chosen for analyzing metabolic reactions because they use some of the central nodes of metabolism, such as adenosine triphosphate. Operations of the diabetiChip's information processing ware are the focus of this paper; we show the feasibility of using a set of kinase-containing enzymatic reactions of a firefly bioluminescence-coupled glucose assay in designing the diabetiChip. We have developed and tested the feasibility of the glucose assay; the assay's analytical detection limits (before sample dilution) were 5–185 μM. Uncertainty associated with reporting a 100 μM concentration was about ± 5 μM. The results show that an FFL bioluminescent-coupled glucose assay is promising in terms of reducing sample volume and cost. The concept of GlucoFaces™ in visualizing measurements of the diabetiChip is also discussed.
An Analysis of How to Measure Glucose during Glucose Clamps: Are Glucose Meters Ready for Research?
Authors: Hompesch Marcus , Rave Klaus
Published: January 2014

This article provides a perspective on the challenges of appropriate glucose measurement in the context of glucose clamp experiments. In a first step, the core outcome parameters of a clamp experiment, the blood glucose target level, and the glucose infusion rate will be identified. The relation of these core parameters to glucose measurement are discussed. From there, the core quality parameters of glucose measurement within a clinical research setting are identified and assessed in light of their practical implications, with a specific consideration of the work presented by Cohen et al. in this issue of the Journal of Diabetes Science and Technology.
Understanding and Improving Management of Inpatient Diabetes Mellitus: The Mayo Clinic Arizona Experience
Authors: Cook Curtiss B. , Zimmerman Richard S. , Gauthier Susanne M. , Castro Janna C. , Jameson Kimberly A. , Littman Stephanie D. , Magallanez Janice M.
Published: January 2014

We present an overview of strategies our institution has taken to understand the state of its inpatient diabetes management. We first describe how we utilized information systems to assess inpatient glycemic control and insulin management in noncritically ill patients and discuss our findings regarding mean bedside glucose levels, the prevalence and frequency hypoglycemic and hyperglycemic events, the patterns of insulin therapy, and evidence of inpatient clinical inertia. We also review the development of a survey to determine practitioner attitudes and beliefs about inpatient diabetes. Results of this survey study found that, in general, practitioners believed in the importance of controlling hyperglycemia but were not comfortable with many aspects of inpatient diabetes care, particularly with the use of insulin. Finally, we suggest steps to follow in developing a quality-improvement program for hospitals.
Percutaneous Window Chamber Method for Chronic Intravital Microscopy of Sensor—Tissue Interactions
Authors: Koschwanez Heidi E. , Klitzman Bruce , Reichert W. Monty
Published: January 2014

Background:

A dorsal, two-sided skin-fold window chamber model was employed previously by Gough in glucose sensor research to characterize poorly understood physiological factors affecting sensor performance. We have extended this work by developing a percutaneous one-sided window chamber model for the rodent dorsum that offers both a larger subcutaneous area and a less restrictive tissue space than previous animal models.

Method

A surgical procedure for implanting a sensor into the subcutis beneath an acrylic window (15 mm diameter) is presented. Methods to quantify changes in the microvascular network and red blood cell perfusion around the sensors using noninvasive intravital microscopy and laser Doppler flowmetry are described. The feasibility of combining interstitial glucose monitoring from an implanted sensor with intravital fluorescence microscopy was explored using a bolus injection of fluorescein and dextrose to observe real-time mass transport of a small molecule at the sensor-tissue interface.

Results:

The percutaneous window chamber provides an excellent model for assessing the influence of different sensor modifications, such as surface morphologies, on neovascularization using real-time monitoring of the microvascular network and tissue perfusion. However, the tissue response to an implanted sensor was variable, and some sensors migrated entirely out of the field of view and could not be observed adequately.

Conclusions:

A percutaneous optical window provides direct, real-time images of the development and dynamics of microvascular networks, microvessel patency, and fibrotic encapsulation at the tissue—sensor interface. Additionally, observing microvessels following combined bolus injections of a fluorescent dye and glucose in the local sensor environment demonstrated a valuable technique to visualize mass transport at the sensor surface.
A Review of the Management of Implanted Medical Devices for Diabetes: Trends and Directions
Authors: Edman Carl , Drinan Darrel
Published: January 2014

The management of diabetes is progressing rapidly from the use of traditional finger sticks for glucose monitoring and multiple daily injections of insulin to more user-friendly devices and approaches. These advances hold the promise of freeing persons with diabetes from the need for continued daily compliance, thereby improving their quality of life and improving control of their underlying diabetes. An underlying theme to solutions based on percutaneous or fully implanted devices is that the useful lifetime of such devices is often limited by the body's foreign body response. This review briefly outlines general factors associated with point-in-time needle stick approaches to the growing use of short-term percutaneous implants (≤7 days) to the challenges of more extended devices, both technical and regulatory, faced by developers of these devices.