bluuebunny/crossref_metadata_2025 huggingface dataset:
Microneedle-Based Automated Therapy for Diabetes Mellitus
Authors: Khanna Puneet , Strom Joel A. , Malone John I. , Bhansali Shekhar
Published: January 2014

This article discusses the use of microneedles in automated diabetes therapy systems. Advanced bioengineered systems have the potential to close the loop between diagnostic and therapeutic elements of diabetes treatment, thus constituting a “smart” system. Prevalent insulin therapies, and most glucose sensing techniques, involve the transfer of physical entities through the skin. Micromachined needles (microneedles) can achieve this in a noninvasive or minimally invasive manner while contributing various other technological merits. The dynamics of autonomous diabetes therapy systems include highly complex interdependencies between the various physical and biological entities involved, thus warranting multidisciplinary research initiatives. The iterative development of a noninvasive, bioengineered interface such as microneedles necessitates a better understanding of the human skin, its molecular architecture as a polymer film, and its role as a functional biological unit. This review addresses application-specific requirements of a microneedle-based interface system specifically for autonomous diabetes therapy. Key design issues and related parametric interdependencies specific to this application are discussed.
Body Composition Methods: Comparisons and Interpretation
Authors: Duren Dana L. , Sherwood Richard J. , Czerwinski Stefan A. , Lee Miryoung , Choh Audrey C. , Siervogel Roger M. , Chumlea Wm. Cameron
Published: January 2014

The incidence of obesity in the United States and other developed countries is epidemic. Because the prevalence of comorbidities to obesity, such as type 2 diabetes, has also increased, it is clear there is a great need to monitor and treat obesity and its comorbidities. Body composition assessments vary in precision and in the target tissue of interest. The most common assessments are anthropometric and include weight, stature, abdominal circumference, and skinfold measurements. More complex methods include bioelectrical impedance, dual-energy X-ray absorptiometry, body density, and total body water estimates. There is no single universally recommended method for body composition assessment in the obese, but each modality has benefits and drawbacks. We present here the most common methods and provide guidelines by way of examples to assist the clinician/researcher in choosing methods appropriate to their situation.
Reliability of Lightguide Spectrophotometry (O2C®) for the Investigation of Skin Tissue Microvascular Blood Flow and Tissue Oxygen Supply in Diabetic and Nondiabetic Subjects
Authors: Forst Thomas , Hohberg Cloth , Tarakci Eda , Forst Senait , Kann Peter , Pfützner Andreas
Published: January 2014

Background and Aims:

Skin microvascular assessment has progressed to an important evaluation in patients with diabetes mellitus. This study was done to evaluate a new device using micro-lightguide spectrophotometry in the assessment of skin microvascular function.

Material and Methods:

Twenty nondiabetic subjects (age 46.6 ± 14.8 years; mean ± SD) and 20 diabetic patients (age 59.4 ± 8.4 years) participated in repeated microvascular measurements using micro-lightguide spectrophotometry. This technique allows simultaneous, noninvasive measurement of microvascular blood flow and hemoglobin oxygenation (SO2) at the same anatomical area in different tissue layers. A skin probe was placed on nonhairy skin at the thenar eminence of the left hand for the measurement of SO2, and the postischemic reactive hyperemia response (PRH) was measured in skin and underlying muscle tissue.

Results:

Repeated measurements in PRH revealed a good correlation at the superficial skin layer ( r = 0.97, p < 0.0001) with a coefficient of variation at 9.2 ± 1.7% and at the superficial muscle layer ( r = 0.80, p < 0.0002) with a coefficient of variation at 9.7 ± 1.5%. A slightly weaker correlation was observed for the SO2 measurement at the skin layer ( r = 0.69 ± p < 0.0001) with a coefficient of variation at 17.5 ± 3.8% and at the muscle layer ( r = 0.48; p = 0.0016) with a coefficient of variation at 18.1 ± 10.5%.

Conclusions:

Lightguide spectrophotometry is an easy, noninvasive, and reliable method for simultaneous measurement of superficial microvascular blood flow by laser Doppler fluxmetry and skin oxygenation by spectrophotometry. Further studies are required to clarify the validity of these measures in special patient populations such as diabetes mellitus with specified microvascular complications.
Are All Clinical Studies Sponsored by Industry Not Valid?
Authors: Heinemann Lutz
Published: January 2014

Industry-sponsored studies have such a bad reputation that some journals require an additional statistical analysis by an independent statistician. This commentary discusses some of the reasons why academic people tend to believe that “academic” science is better than industry-driven science. Most likely, when it comes to publications, the risk of fraud exists in both worlds as the pressure to publish “significant” data is prevalent in both worlds. In contrast to the academic world, the level of control by regulatory bodies for industry-sponsored studies is much higher. Therefore, the quality of industry-driven studies is high, at least when it comes to the quality of data. One of the main reasons why academic people are so skeptical about the pharmaceutical industry is a lack of knowledge about the work done in industry. It is as demanding and scientific as in other industries. In turn, many physicians working in the pharmaceutical industry have low self-esteem. Also, the pharmaceutical industry should improve its self-presentation adequately to get rid of its bad image. There is a clear need for more communication between both worlds in order to better understand the mutual difficulties and needs.
Signal-Response Modeling of Partial Hormone Feedback Networks
Authors: Johnson Michael L. , Veldhuis Paula P. , Evans William S.
Published: January 2014

Background:

Endocrine feedback control networks are typically complex and contain multiple hormones, pools, and compartments. The hormones themselves commonly interact via multiple pathways and targets within the networks, and a complete description of such relationships may involve hundreds of parameters. In addition, it is often difficult, if not impossible, to collect experimental data pertaining to every component within the network. Therefore, the complete simultaneous analysis of such networks is challenging. Nevertheless, an understanding of these networks is critical for furthering our knowledge of hormonal regulation in both physiologic and pathophysiologic conditions.

Methods:

We propose a novel approach for the analysis of dose-response relationships of subsets of hormonal feedback networks. The algorithm and signal-response quantification (SRQuant) software is based on convolution integrals, and tests whether several discretely measured input signals can be individually delayed, spread in time, transformed, combined, and discretely convolved with an elimination function to predict the time course of the concentration of an output hormone. Signal-response quantification is applied to examples from the endocrine literature to demonstrate its applicability to the analysis of the different endocrine networks.

Results:

In one example, SRQuant determines the dose-response relationship by which one hormone regulates another, highlighting its advantages over other traditional methods. In a second example, for the first time (to the best of our knowledge), we show that the secretion of glucagon may be jointly controlled by the β and the δ cells.

Conclusion:

We have developed a novel convolution integral-based approach, algorithm, and software (SRQuant) for the analysis of dose-response relationships within subsets of complex endocrine feedback control networks.
In Silico Preclinical Trials: A Proof of Concept in Closed-Loop Control of Type 1 Diabetes
Authors: Kovatchev Boris P. , Breton Marc , Dalla Man Chiara , Cobelli Claudio
Published: January 2014

Arguably, a minimally invasive system using subcutaneous (s.c.) continuous glucose monitoring (CGM) and s.c. insulin delivery via insulin pump would be a most feasible step to closed-loop control in type 1 diabetes mellitus (T1DM). Consequently, diabetes technology is focusing on developing an artificial pancreas using control algorithms to link CGM with s.c. insulin delivery. The future development of the artificial pancreas will be greatly accelerated by employing mathematical modeling and computer simulation. Realistic computer simulation is capable of providing invaluable information about the safety and the limitations of closed-loop control algorithms, guiding clinical studies, and out-ruling ineffective control scenarios in a cost-effective manner. Thus computer simulation testing of closed-loop control algorithms is regarded as a prerequisite to clinical trials of the artificial pancreas.

In this paper, we present a system for in silico testing of control algorithms that has three principal components: (1) a large cohort of n = 300 simulated “subjects” ( n = 100 adults, 100 adolescents, and 100 children) based on real individuals' data and spanning the observed variability of key metabolic parameters in the general population of people with T1DM; (2) a simulator of CGM sensor errors representative of Freestyle Navigator™, Guardian RT, or Dexcom™ STS™, 7-day sensor; and (3) a simulator of discrete s.c. insulin delivery via OmniPod Insulin Management System or Deltec Cozmo® insulin pump.

The system has been shown to represent adequate glucose fluctuations in T1DM observed during meal challenges, and has been accepted by the Food and Drug Administration as a substitute to animal trials in the preclinical testing of closed-loop control strategies.
Treatment with Sitagliptin or Metformin Does Not Increase Body Weight despite Predicted Reductions in Urinary Glucose Excretion
Authors: Waters Steven B. , Topp Brian G. , Siler Scott Q. , Alexander Charles M.
Published: January 2014

Background:

We used a mathematical model to estimate the contribution of urinary glucose excretion (UGE) to reported changes in body weight (BW) following oral antihyperglycemic agent (AHA) therapy. This modeling approach was used to gain novel insight into the mechanisms by which oral AHA affects BW.

Methods:

Twenty-four hour glucose profiles were used to predict UGE before and after treatment with oral AHA. Model-predicted changes in BW due to reduced UGE were compared with reported changes in BW to quantify non-UGE-dependent effects (fluid retention, food intake, and energy expenditure).

Results:

In type 2 diabetes patients [hemoglobin A1c (HbA1c) >7.3%], the energy lost to UGE is predicted to decrease an average of 100 kcal/day for each 1% decrease in HbA1c. This effect, alone, is predicted to increase BW 1.4 kg after 6 months. Differences from this value reported for changes in BW with oral AHA therapy (+1.4 kg for pioglitazone and rosiglitazone; −0.4 kg for glyburide; −0.9 kg for sitagliptin and vildagliptin; −2.3 kg for metformin) are therefore predicted to be due to additional, non-UGE-dependent mechanisms.

Conclusions:

Weight gain following thiazolidinedione therapy is predicted to result from both reduced UGE and non-UGE-dependent mechanisms. Reduced UGE alone is predicted to account for most of the weight gain reported following sulfonylurea therapy. Weight loss observed in response to metformin and weight maintenance observed in response to dipeptidyl peptidase-4 inhibitors may result from an increase in satiety, energy expenditure, or both.
Coordinated Basal—Bolus Infusion for Tighter Postprandial Glucose Control in Insulin Pump Therapy
Authors: Bondia Jorge , Dassau Eyal , Zisser Howard , Calm Remei , Vehí Josep , Jovanovič Lois , Doyle Francis J.
Published: January 2014

Background:

Basal and bolus insulin determination in intensive insulin therapy for type 1 diabetes mellitus (T1DM) are currently considered independently of each other. A new strategy that coordinates basal and bolus insulin infusion to cope with postprandial glycemia in pump therapy is proposed. Superior performance of this new strategy is demonstrated through a formal analysis of attainable performances in an in silico study.

Methods:

The set inversion via interval analysis algorithm has been applied to obtain the feasible set of basal and bolus doses that, for a given meal, mathematically guarantee a postprandial response fulfilling the International Diabetes Federation (IDF) guidelines (i.e., no hypoglycemia and 2 h postprandial glucose below 140 mg/dl). Hypoglycemia has been defined as a glucose value below 70 mg/dl. A 5 h time horizon has been considered for a 70 kg in silico T1DM subject consuming meals in the range of 30 to 80 g of carbohydrates.

Results:

The computed feasible sets demonstrate that current separated basal/bolus strategy dramatically limits the attainable performance. For a nominal basal of 0.8 IU/h leading to a basal glucose of approximately 100 mg/dl, IDF guidelines cannot be fulfilled for meals greater than 50 g of carbohydrates, independent of the bolus insulin computed. However, coordinating the basal and bolus insulin delivery can achieve this. A decrement of basal insulin during the postprandial period is required together with an increase in bolus insulin, in appropriate percentages, which is meal dependent. After 3 h, basal insulin can be restored to its nominal value.

Conclusions:

The new strategy meets IDF guidelines in a typical day, contrary to the standard basal/bolus strategy, yielding a mean 2 h postprandial glucose reduction of 36.4 mg/dl without late hypoglycemia. The application of interval analysis for the computation of feasible sets is demonstrated to be a powerful tool for the analysis of attainable performance in glucose control.
Clinical Evaluation of a Transcutaneous Interrogated Fluorescence Lifetime-Based Microsensor for Continuous Glucose Reading
Authors: Nielsen Jannik K. , Christiansen Jens S. , Kristensen Jesper S. , Toft Hans O. , Hansen Lars Lundby , Aasmul Søren , Gregorius Klaus
Published: January 2014

Background:

Continuous glucose monitoring is presently used worldwide. Accuracy, precision, durability, invasiveness, and lack of drift of sensors and lag time are key parameters essential to these systems. This article describes a new online minimally invasive biodegradable microsensor for optical, transcutaneous interrogation, which has at least 14 days of functionality.

Method:

Studies were performed in vitro and in vivo on pigs, as well as on type 1 diabetic humans. Functionality has been ensured in laboratory settings, and precision and durability have been tested in vivo. During in vivo studies, venous blood samples were used as reference. Results were based on one single point calibration per experiment.

Results:

Excellent stability was found in 14-day in vitro trials as well as in vivo in up to 70-hour trials. The overall median relative absolute difference of type 1 diabetic patients was 11.4%. Error grid analysis showed 97.7% of all values in the A+B zone. Comparable results were found in animal studies. No sensor drift was observed in any trial.

Conclusion:

Results point toward the possibility of developing a stable and precise minimally invasive glucose reader for at least 2 weeks of continuous use.
An Automated Discontinuous Venous Blood Sampling System for Ex Vivo Glucose Determination in Humans
Authors: Schaller Roland , Feichtner Franz , Köhler Hans , Bodenlenz Manfred , Plank Johannes , Wutte Andrea , Mader Julia K. , Ellmerer Martin , Hainisch Reinhard , Pieber Thomas R. , Schaupp Lukas
Published: January 2014

Background:

Intensive insulin therapy reduces mortality and morbidity in critically ill patients but places great demands on medical staff who must take frequent blood samples for the determination of glucose levels. A cost-effective solution to this resourcing problem could be provided by an effective and reliable automated blood sampling (ABS) system suitable for ex vivo glucose determination.

Method:

The primary study aim was to compare the performance of a prototype ABS system with a manual reference system over a 30 h sampling period under controlled conditions in humans. Two venous cannulae were inserted to connect the ABS system and the reference system. Blood samples were taken with both systems at 15, 30, and 60 min intervals and analyzed using a Beckman glucose analyzer. During the study, blood glucose levels were altered through four meal ingestions.

Results:

The median Pearson coefficient of correlation between manually and automatically withdrawn blood samples was 0.976 (0.953–0.996). The system error was −3.327 ± 5.546% (−6.03–0.49). Through Clark error grid analysis, 420 data pairs were analyzed, showing that 98.6% of the data were in zone A and 1.4% were in zone B. Insulin titration error grid analysis revealed an acceptable treatment in 100% of cases. A 17.5-fold reduction in the occurrence of blood-withdrawal failures through occluded catheters was moreover achieved by the added implementation in the ABS system of a “keep vein open” saline infusion.

Conclusions:

Our study showed that the ABS system described provides a user-friendly, reliable automated means for reproducible and accurate blood sampling from a peripheral vein for blood glucose determination and thus represents a promising alternative to frequent manual blood sampling.
Smart Home-Based Health Platform for Behavioral Monitoring and Alteration of Diabetes Patients
Authors: Helal Abdelsalam , Cook Diane J. , Schmalz Mark
Published: January 2014

Background:

Researchers and medical practitioners have long sought the ability to continuously and automatically monitor patients beyond the confines of a doctor's office. We describe a smart home monitoring and analysis platform that facilitates the automatic gathering of rich databases of behavioral information in a manner that is transparent to the patient. Collected information will be automatically or manually analyzed and reported to the caregivers and may be interpreted for behavioral modification in the patient.

Method:

Our health platform consists of five technology layers. The architecture is designed to be flexible, extensible, and transparent, to support plug-and-play operation of new devices and components, and to provide remote monitoring and programming opportunities.

Results:

The smart home-based health platform technologies have been tested in two physical smart environments. Data that are collected in these implemented physical layers are processed and analyzed by our activity recognition and chewing classification algorithms. All of these components have yielded accurate analyses for subjects in the smart environment test beds.

Conclusions:

This work represents an important first step in the field of smart environment-based health monitoring and assistance. The architecture can be used to monitor the activity, diet, and exercise compliance of diabetes patients and evaluate the effects of alternative medicine and behavior regimens. We believe these technologies are essential for providing accessible, low-cost health assistance in an individual's own home and for providing the best possible quality of life for individuals with diabetes.
Pharmacists' Role in Improving Diabetes Medication Management
Authors: Smith Marie
Published: January 2014

Today there are significant gaps between reaching the goal of “optimal medication therapy” and the current state of medication use in the United States. Pharmacists are highly accessible and well-trained—yet often underutilized—key health care professionals who can move us closer toward achieving better medication therapy outcomes for patients. Diabetes medication management programs led by pharmacists are described. This is consistent with the “medical home” concept of care that promotes primary care providers working collaboratively to coordinate patient-centered care. Pharmacists utilize their clinical expertise in monitoring and managing diabetes medication plans to positively impact health outcomes and empower patients to actively manage their health. In addition, pharmacists can serve as a resource to other health care providers and payers to assure safe, appropriate, cost-effective diabetes medication use.
Recent Advances in Internet-Delivered, Evidence-Based Weight Control Programs for Adults
Authors: Krukowski Rebecca A. , West Delia Smith , Harvey-Berino Jean
Published: January 2014

With the explosion of Internet accessibility, online delivery offers potential for significantly greater reach of evidence-based obesity treatment programs for adults. Online behavioral weight control has been shown to produce significant weight loss, with more recent programs demonstrating larger losses and general consumer satisfaction. A growing literature indicates several program parameters that may offer greatest engagement in online obesity interventions and better weight loss outcomes, including interactive, dynamic Web site features and synchronous counselor contact, although this research is in the early stages, and a clear picture of the essential components for the most effective online obesity program remains to be determined. Further research is required to enhance weight loss outcomes, determine cost-effectiveness of Internet-delivered programs, and identify the individuals most likely to benefit from treatment in this format.
Near-Infrared Microspectroscopic Analysis of Rat Skin Tissue Heterogeneity in Relation to Noninvasive Glucose Sensing
Authors: Alexeeva Natalia V. , Arnold Mark A.
Published: January 2014

Background:

Noninvasive glucose measurements are possible by analysis of transmitted near-infrared light over the 4000- to 5000-cm−1 spectral range. Such measurements are highly sensitive to the exact position of the fiber-optic interface on the surface of the skin sample. A critical question is the degree of heterogeneity of the major chemical components of the skin matrix in relation to the size of the fiber-optic probed used to collect noninvasive spectra. Microscopic spectral mapping is used to map the chemical distribution for a set of excised sections of rat skin.

Method:

A Fourier transform near-infrared microspectrometer was used to collect transmission spectra from 16 tissue samples harvested from a set of four healthy Harlan-Sprague male rats. A reference point in the center of the tissue sample was probed regularly to track dehydration, changes in tissue composition, and changes in instrument performance. Amounts of the major skin constituents were determined by fitting microspectra to a set of six pure component absorbance spectra corresponding to water, type I collagen protein, keratin protein, fat, an offset term, and a slope term.

Results:

Microspectroscopy provides spectra with root mean square noise levels on 100% lines between 418 and 1475 microabsorbance units, which is sufficient for measuring the main chemical components of skin. The estimated spatial resolution of the microscope is 220 μm. The amounts of each tissue matrix component were determined for each 480 × 360-μm2 location of a 4.8 × 3.6-mm2 rectangular block of skin tissue. These spectra were used to generate two-dimensional distribution maps for each of the principal skin components.

Conclusions:

Distribution of the chemical components of rat skin is significant relative to the dimensions of noninvasive glucose sensing. Chemical distribution maps reveal that variations in the chemical composition of the skin samples are on the same length scale as the fiber-optic probe used to collect noninvasive near-infrared spectra. Analysis of variance between tissue slices collected for one animal and analysis of variations between animals indicate that animal-to-animal variation for all four chemical components is significantly higher than variations between samples for a given animal. These findings justify the collection and interpretation of near-infrared microspectroscopic maps of human skin to establish chemical heterogeneity and its impact on noninvasive glucose sensing for the management of diabetes.
Single Walled Carbon Nanotubes as Reporters for the Optical Detection of Glucose
Authors: Barone Paul W. , Strano Michael S.
Published: January 2014

This article reviews current efforts to make glucose sensors based on the inherent optical properties of single walled carbon nanotubes. The advantages of single walled carbon nanotubes over traditional organic and nanoparticle fluorophores for in vivo-sensing applications are discussed. Two recent glucose sensors made by our group are described, with the first being an enzyme-based glucose sensor that couples a reaction mediator, which quenches nanotube fluorescence, on the surface of the nanotube with the reaction of the enzyme. The second sensor is based on competitive equilibrium binding between dextran-coated nanotubes and concanavalin A. The biocompatibility of a model sensor is examined using the chicken embryo chorioallantoic membrane as a tissue model. The advantages of measuring glucose concentration directly, like most optical sensors, versus measuring the flux in glucose concentration, like most electrochemical sensors, is discussed.
Noninvasive Glucose Monitoring: A Novel Approach
Authors: Harman-Boehm Ilana , Gal Avner , Raykhman Alexander M. , Zahn Jeffrey D. , Naidis Eugene , Mayzel Yulia
Published: January 2014

Background:

The main concern in noninvasive (NI) glucose measurement is achieving high accuracy readings, although no blood (or other fluid) is involved in the process. Using methods based on different physical properties of a measured object can ensure the independence of each of the readings and therefore improve the validity of the end result. By using a combination of (three) independent technologies—ultrasonic, electromagnetic, and thermal—GlucoTrack™ presents a unique approach for a real-time, truly NI blood glucose spot measurement.

Methods:

Clinical trials were performed in two stages. Stage 1 was an initial method validation and performance verification of the device. In this stage, 50 type 1 and 2 diabetic patients, as well as healthy subjects, were evaluated with GlucoTrack against Ascensia Elite® (Bayer). In the second stage, 85 additional diabetic subjects were evaluated in half and full daytime sessions using a GlucoTrack comparison with HemoCue® (Glucose 201+).

Results:

A total of 135 subjects were tested during the trial period, producing 793 data pairs. Using Clarke error grid analysis, 92% of the readings fell in the clinically acceptable zones A and B, with 50% in the A zone. Mean and median relative absolute differences were 29.9 and 19.9%, respectively.

Conclusions:

Integrating several modalities for NI assessment of glucose level enables more accurate readings, while a possible aberration in one modality is bypassed by the others. The present generation of GlucoTrack gives promising results; however, further improvement of the accuracy of the device is needed.
Comparison of Intuitiveness, Ease of Use, and Preference in Two Insulin Pens
Authors: Asakura Toshinari , Jensen Klaus H.
Published: January 2014

Background:

The intuitiveness, instruction time, and handling of the Levemir® (insulin detemir) FlexPen® and the Lantus® OptiClik® pen (with insulin glargine) were investigated.

Methods:

This randomized open-label crossover study involved two groups of insulin-device-naive Japanese patients with type 2 diabetes [mean (SD) age 61.9 ± 12.3 years, 57% male]. Patients were evaluated on the ease-of-use of each insulin pen without instruction [intuitiveness group ( n = 32)], or with instruction [instruction time group ( n = 29)]. Patient preferences for the respective devices were assessed by questionnaire.

Results and Discussion:

FlexPen required significantly less instruction time ( p < .001) and was objectively more intuitive to use ( p < .001) than OptiClik. Nevertheless, few patients in the intuitiveness group felt confident injecting either pen prior to instruction (FlexPen, 31%; OptiClik, 16%). No patients in the instruction time group found FlexPen difficult to learn, whereas 45% of patients found OptiClik difficult or very difficult to learn. FlexPen was rated simpler to use (77% versus 12%; p < .001), easier to inject (67% versus 13%; p < .001), and more convenient (71% versus 12%; p < .001) compared with OptiClik. More patients would trust FlexPen to deliver insulin injections ( p < .01) and would prefer to use FlexPen compared with OptiClik (82% versus 13%; p < .001).

Conclusions:

FlexPen was faster to teach, simpler to use, and more trusted by patients compared with OptiClik. Mean injection time was significantly shorter for FlexPen than OptiClik, with or without instruction. This study highlights not only how easy it is for patients to learn to use FlexPen, but also how easily health care providers can teach patients to use it.
The Role of Immunomodulation Therapy in Autoimmune Diabetes
Authors: Ludvigsson Johnny
Published: January 2014

Type 1 diabetes (T1DM) is characterized by loss of virtually all endogenous insulin secretion. If residual insulin secretion is preserved, this will lead to improved metabolic balance, less acute and late complications, improved quality of life, and, in case of pronounced improvement of residual insulin secretion, complete remission and even cure of the disease.

Immune suppression or immune modulation have been demonstrated as a proof of principle to stop/decrease the destructive process and thereby preserve beta-cell function. Several methods to save residual beta-cell function have been tried for more than three decades with little or no evidence of efficacy. Positive effects have been seen mainly in adult patients but have been minimal or absent in children with diabetes. Furthermore, the safety of these immune interventions and/or their benefit to risk relationships have not been found to justify clinical use.

More specific immune modulation with anti-CD3 monoclonal antibodies has resulted in more encouraging postponement of C-peptide decline, but with frequent and serious adverse effects. Still more promising are the autoantigen therapies, of which glutamic acid decarboxylase (GAD) vaccination has shown significant preservation of residual insulin secretion in 10–18-year-old type 1 diabetes patients with recent onset. Efficacy was most impressive in the subgroup of patients with diabetes of short duration (<3 months). The treatment was simple, well tolerated, and showed no treatment-related adverse events. If these results can be confirmed, there is a realistic hope that GAD vaccination, perhaps in combination with vaccinations with other autoantigens and/or other therapies, will result in remission for some patients. The prospects of cure and prevention of T1DM will become less remote.
Evaluation of Current Literature to Determine the Potential Effects of Radio Frequency Identification on Technology Used in Diabetes Care
Authors: Christe Barbara
Published: January 2014

This article examines recently published studies exploring the impact of radio frequency identification (RFID) systems on the technology involved in patient care. The conclusions will be extrapolated to include insulin delivery devices. Background material will also be presented to support examination of the variables involved in electromagnetic fields and potential interference from these RFID systems.
Insulin-Like Growth Factor-I as a Candidate Metabolic Biomarker: Military Relevance and Future Directions for Measurement
Authors: Nindl Bradley C.
Published: January 2014

Insulin-like growth factor (IGF)-I is a ubiquitous peptide hormone involved in a host of critical physiological processes (e.g., protein synthesis and glucose homeostasis) and has been suggested to be a biomarker reflecting health and metabolic status. In most cases (muscle, bone, tendon, body composition, and cognitive function), elevated IGF-I concentrations are considered beneficial; however, cancer remains a notable exception. While the fact that both increased and decreased IGF-I can be considered reflective of favorable and beneficial health outcomes may appear as a paradox, it is important to emphasize that, in both cases, measured IGF-I concentrations do offer important insight into physiological processes. The effects of military operational field training on the circulating IGF-I system are discussed within the context of novel measurement technologies that (1) are field expedient and (2) provide more meaningful information. Prospective experimental approaches involving physical activity that sample and measure IGF-I in the body's various biocompartments will provide greater insight into the complex role that IGF-I possesses. Minimally invasive technologies that are field expedient, cost-effective, and allow for continuous and real-time feedback will have the greatest likelihood of being adapted and used in military environments.
A Review of Variant Hemoglobins Interfering with Hemoglobin A1c Measurement
Authors: Little Randie R. , Roberts William L.
Published: January 2014

Hemoglobin A1c (HbA1c) is used routinely to monitor long-term glycemic control in people with diabetes mellitus, as HbA1c is related directly to risks for diabetic complications. The accuracy of HbA1c methods can be affected adversely by the presence of hemoglobin (Hb) variants or elevated levels of fetal hemoglobin (HbF). The effect of each variant or elevated HbF must be examined with each specific method.

The most common Hb variants worldwide are HbS, HbE, HbC, and HbD. All of these Hb variants have single amino acid substitutions in the Hb β chain. HbF is the major hemoglobin during intrauterine life; by the end of the first year, HbF falls to values close to adult levels of approximately 1%. However, elevated HbF levels can occur in certain pathologic conditions or with hereditary persistence of fetal hemoglobin. In a series of publications over the past several years, the effects of these four most common Hb variants and elevated HbF have been described.

There are clinically significant interferences with some methods for each of these variants. A summary is given showing which methods are affected by the presence of the heterozygous variants S, E, C, and D and elevated HbF. Methods are divided by type (immunoassay, ion-exchange high-performance liquid chromatography, boronate affinity, other) with an indication of whether the result is artificially increased or decreased by the presence of a Hb variant. Laboratorians should be aware of the limitations of their method with respect to these interferences.
Beyond Health Information Technology: Critical Factors Necessary for Effective Diabetes Disease Management
Authors: Ciemins Elizabeth L. , Coon Patricia J. , Fowles Jinnet Briggs , Min Sung-Joon
Published: January 2014

Background:

Electronic health records (EHRs) have been implemented throughout the United States with varying degrees of success. Past EHR implementation experiences can inform health systems planning to initiate new or expand existing EHR systems. Key “critical success factors,” e.g., use of disease registries, workflow integration, and real-time clinical guideline support, have been identified but not fully tested in practice.

Methods:

A pre/postintervention cohort analysis was conducted on 495 adult patients selected randomly from a diabetes registry and followed for 6 years. Two intervention phases were evaluated: a “low-dose” period targeting primary care provider (PCP) and patient education followed by a “high-dose” EHR diabetes management implementation period, including a diabetes disease registry and office workflow changes, e.g., diabetes patient preidentification to facilitate real-time diabetes preventive care, disease management, and patient education.

Results:

Across baseline, “low-dose,” and “high-dose” postintervention periods, a significantly greater proportion of patients (a) achieved American Diabetes Association (ADA) guidelines for control of blood pressure (26.9 to 33.1 to 43.9%), glycosylated hemoglobin (48.5 to 57.5 to 66.8%), and low-density lipoprotein cholesterol (33.1 to 44.4 to 56.6%) and (b) received recommended preventive eye (26.2 to 36.4 to 58%), foot (23.4 to 40.3 to 66.9%), and renal (38.5 to 53.9 to 71%) examinations or screens.

Conclusions:

Implementation of a fully functional, specialized EHR combined with tailored office workflow process changes was associated with increased adherence to ADA guidelines, including risk factor control, by PCPs and their patients with diabetes. Incorporation of previously identified “critical success factors” potentially contributed to the success of the program, as did use of a two-phase approach.
The Clinical Research Tool: A High-Performance Microdialysis-Based System for Reliably Measuring Interstitial Fluid Glucose Concentration
Authors: Ocvirk Gregor , Hajnsek Martin , Gillen Ralph , Guenther Arnfried , Hochmuth Gernot , Kamecke Ulrike , Koelker Karl-Heinz , Kraemer Peter , Obermaier Karin , Reinheimer Cornelia , Jendrike Nina , Freckmann Guido
Published: January 2014

Background:

A novel microdialysis-based continuous glucose monitoring system, the so-called Clinical Research Tool (CRT), is presented. The CRT was designed exclusively for investigational use to offer high analytical accuracy and reliability. The CRT was built to avoid signal artifacts due to catheter clogging, flow obstruction by air bubbles, and flow variation caused by inconstant pumping. For differentiation between physiological events and system artifacts, the sensor current, counter electrode and polarization voltage, battery voltage, sensor temperature, and flow rate are recorded at a rate of 1 Hz.

Method:

In vitro characterization with buffered glucose solutions (cglucose = 0 − 26 × 10−3 mol liter−1) over 120 h yielded a mean absolute relative error (MARE) of 2.9 ± 0.9% and a recorded mean flow rate of 330 ± 48 nl/min with periodic flow rate variation amounting to 24 ± 7%. The first 120 h in vivo testing was conducted with five type 1 diabetes subjects wearing two systems each. A mean flow rate of 350 ± 59 nl/min and a periodic variation of 22 ± 6% were recorded.

Results:

Utilizing 3 blood glucose measurements per day and a physical lag time of 1980 s, retrospective calibration of the 10 in vivo experiments yielded a MARE value of 12.4 ± 5.7. Clarke error grid analysis resulted in 81.0%, 16.6%, 0.8%, 1.6%, and 0% in regions A, B, C, D, and E, respectively.

Conclusion:

The CRT demonstrates exceptional reliability of system operation and very good measurement performance. The ability to differentiate between artifacts and physiological effects suggests the use of the CRT as a reference tool in clinical investigations.
A Cell-Based Approach for Diabetes Treatment Using Engineered Non-β Cells
Authors: Bara Heather , Thulé Peter M. , Sambanis Athanassios
Published: January 2014

Background:

Implantation of insulin-secreting cells has the potential to provide tight glycemic regulation in diabetic subjects. Implantation of cadaveric human islets in immunosuppressed human patients is currently applied at a very small scale. To overcome the limitations of tissue availability and recipient immunosuppression, encapsulation of nonautologous cells and use of potentially autologous nonislet cells, the latter engineered for insulin secretion, are being pursued. This article reports on recent findings with the implantation of tissue constructs containing enteroendocrine cells stably expressing recombinant insulin in diabetic mice. The concept of a dual recombinant hepatic and enteroendocrine cell system, which may better approximate the secretory response of islets, is discussed.

Methods:

Mouse GLUTag-INS cells engineered to secrete human insulin were developed and incorporated in tissue constructs as reported previously. Constructs were implanted intraperitoneally in diabetic mice, and blood glucose levels, animal weights, and plasma insulin levels were measured at various time points.

Results:

GLUTag-INS-containing tissue constructs secreted insulin preimplantation and postexplantation, and human insulin was detected in the plasma of diabetic mice. However, normoglycemia was not restored.

Conclusions:

A variety of cell types and of encapsulation methods to enhance immune acceptance of insulin-secreting grafts are being pursued. Recombinant enteroendocrine cells show promise, but it is likely that they need to be combined with recombinant hepatic cells to achieve glycemic normalization.
The Clinical Use of Hemoglobin A1c
Authors: Saudek Christopher D. , Brick Jessica C.
Published: January 2014

Hemoglobin A1c (HbA1c) has been accepted as an index of glycemic control since the mid-1970s and is the best marker for diabetic microvascular complications. Clinically, it is now used to assess glycemic control in people with diabetes. Assays are most reliable when certified by the National Hemoglobin Standardization Program but are subject to confounders and effect modifiers, particularly in the setting of hematologic abnormalities. Other measures of chronic glycemic control—fructosamine and 1,5-anhydroglucitol—are far less widely used. The relationship of HbA1c to average blood glucose was intensively studied recently, and it has been proposed that this conversion can be used to report an “estimated average glucose, eAG” in milligrams/deciliter or millimolar units rather than as per cent glycated hemoglobin. Finally, HbA1c has been proposed as a useful method of screening for and diagnosing diabetes.
Influence of Variables on Hemoglobin A1c Values and Nonheterogeneity of Hemoglobin A1c Reference Ranges
Authors: Higgins Trefor , Cembrowski George , Tran David , Lim Erin , Chan Julie
Published: January 2014

Introduction:

Hemoglobin A1c (HbAlc) values are influenced by analytical interferences such as HbF and hemoglobin variants and clinical factors such as increased red cell turnover. Although less well-known, demographic factors such as race, age, and sex also influence HbA1c values. The HbA1c reference range should be homogenous in the United States based on the use of National Glycohemoglobin Standardization Program certified methods and the recommendations in the National Academy of Clinical Biochemistry guidelines.

Methods:

Data on age, race, sex, HbA1c, and glucose values were extracted from the National Health and Nutrition Examination study for a 3 year period. A search for reference range data for laboratories in the United States was performed using the Google search engine.

Results:

Extracted data agree with published data on the influence of age, sex, and smoking status on HbA1c values. There is substantial heterogeneity in HbA1c reference ranges in laboratories in the United States.

Conclusion:

Age, sex, and smoking status influence HbA1c values. Despite standardization of HbA1c methods and published recommendations, there is wide heterogeneity in HbA1c reference ranges in the United States.
Arguments for and against the Role of Glucose Variability in the Development of Diabetes Complications
Authors: Kilpatrick Eric S.
Published: January 2014

There is now unequivocal evidence that improving glycemic control in both type 1 and type 2 diabetes reduces the likelihood of developing the micro- and macrovascular complications of the disease. However, it is still unclear whether a patient with very variable glucose is at any different a risk of these problems than someone who has the same mean glucose but much more stable glycemia. This article reviews the evidence that exists to both support and refute the claim that increased glucose variability should be regarded as an independent risk factor for the development of diabetic vascular disease.
Increases in Whole Blood Glucose Measurements Using Optically Based Self-Monitoring of Blood Glucose Analyzers Due to Extreme Canadian Winters
Authors: Cembrowski George C. , Smith Barbara , O'Malley Ellen M.
Published: January 2014

Background:

Temperature and humidity have been reported to influence the results of whole blood glucose (WBG) measurements.

Methods:

To determine whether patient WBG values were affected by seasonal variation, we conducted a retrospective analysis of 3 years' worth of weekly averages of patient WBG in five Edmonton hospitals.

Results:

In all five hospitals, the winter WBG averages were consistently higher than the summer WBG averages, with the differences varying between 5% and 9%. Whole blood glucose averages were negatively correlated with the outside temperature. This seasonal variation was not observed in weekly patient averages of specimens run in a central hospital laboratory. Interpretation It is probable that the seasonal variation of WBG arises from the very low indoor humidities that are associated with external subzero temperatures. These increases in WBG in cold weather may be due to limitations in the WBG measuring systems when operated in decreased humidities and/or increased evaporation of the blood sample during the blood glucose measurement process. The implications of this seasonal variation are significant in that it (1) introduces increased variability in patient WBG, (2) may result in increased glucose-lowering therapy during periods of external cold and low indoor humidity, and (3) confounds evaluations of WBG meter technology in geographic regions of subzero temperature and low indoor humidity. To mitigate the risk of diagnosing and treating factitious hyperglycemia, the humidity of patient care areas must be strictly controlled.
Seasonal Variation in Hemoglobin A1c: Is It the Same in Both Hemispheres?
Authors: Higgins Trefor , Saw Sharon , Sikaris Ken , Wiley Carmen L , Cembrowski George C. , Lyon Andrew W. , Khajuria Annu , Tran David
Published: January 2014

Introduction:

There are several reports from locations in the northern hemisphere of seasonal variation in hemoglobin A1c (HbA1c) levels with higher values noted in the cooler months. The variation has been attributed to holiday seasons, temperature differences, and changes in diet. This article describes the seasonal variation in both hemispheres and in a country on the equator with minimal temperature variation.

Methods:

The mean and median HbA1c by month was calculated for a maximum of 2 years for HbA1c data from the different locations: Edmonton and Calgary, Canada; Singapore; Melbourne, Australia; and Marshfield, Wisconsin. The mean monthly temperature for each location was found from available meteorological information.

Results:

In both northern and southern hemispheres, the HbA1c was higher in cooler months and lower in the warmer months. In Singapore, where there is minimal temperature variation, there is also minimal variation in HbA1c values over the year. The difference in HbA1c over a year appears to be related to the difference in temperature.

Conclusion:

Hemoglobin A1c is higher in cooler months and lower in the warmer months in both hemispheres. In a country with minimal monthly temperature variation, there is only minimal variation in HbA1c values through the year. In all locations, the mean and median HbA1c declined over the study period, possibly due to better glycemic control of patients with diabetes or an increase in use of HbA1c as a screening test for diabetes or a combination of both.