bluuebunny/crossref_metadata_2025 huggingface dataset:
The End Point is Just the Beginning
Authors: Muchmore Douglas
Published: January 2014

Clinical trials to support registration of new drugs are arduous, lengthy, and expensive. Diabetes treatment trials intended to seek indications for glycemic control are facilitated by the regulatory acceptance of glycosylated hemoglobin (A1C) as a validated intermediate efficacy end point. However, A1C outcomes are not meaningful when taken outside of the context of hypoglycemia risks. Current regulatory guidance indicates that A1C efficacy end points and hypoglycemia safety end points be considered separately. A composite end point for diabetes treatment trials that integrates A1C and hypoglycemia risk into a single measure is proposed. An example would be “percentage of patients achieving A1C <7% without unacceptable hypoglycemia.” The benefits and limitations of such an approach are discussed.
Counterpoint—The End Point: Less is More
Authors: Fleming G. Alexander
Published: January 2014

Improving the scientific and regulatory evaluation of therapies for metabolic disorders is a necessary ongoing process dependent on accruing knowledge and improving technology. The use of a composite primary efficacy outcome consisting of hemoglobin A1c (HbA1c) and hypoglycemia rates is alluring for evaluating glucose-lowering therapies. This composite, however, provides little advantage, if not some disadvantage, over HbA1c as the primary end point. Composite end points have traditionally been used as regulatory end points when a more straightforward approach is not available or feasible. The most well-known example is the composite of major adverse cardiac events (MACE), which has long been used for cardiac drug approvals by the Food and Drug Administration and has become a primary safety outcome for oral diabetes drugs. The MACE composite is widely accepted even though the cardiac death component would provide the most persuasive and near definitive reflection of benefit. Less definitive but more frequently occurring end points—myocardial infarction and stroke—are added to the composite only to enable outcome trials that can be completed in a reasonable time and with reasonable costs. Composite end points have inherent drawbacks and challenges, which may include undue dependence on assumptions, difficulty of validation, less sensitivity to detecting clinically important effects, and oversimplifying evidence for the prescribing physician and other therapeutic decision makers. The proposed efficacy end point composed of glycemic control and hypoglycemia carries all these drawbacks for diabetes drugs. Even insulin products, for which hypoglycemia is the chief safety concern, will more feasibly continue to be developed and evaluated under a treat to glycemic target design, with glycemic control as the sole primary efficacy outcome and rates of hypoglycemia as the prime adverse measure.
Exercise in Closed-Loop Control: A Major Hurdle
Authors: van Bon Arianne C. , Verbitskiy Eugeny , von Basum Golo , Hoekstra Joost B. L. , DeVries J. Hans
Published: January 2014

Background:

People with type 1 diabetes mellitus (T1DM) are at risk for exercise-induced hypoglycemia. Prevention of such hypoglycemia in a closed-loop setting is a major challenge. Markers for automated detection of physical activity could be heart rate (HR) and body acceleration counts (AC). Correlations between HR, AC, and glucose concentrations before and after moderate intensity exercise were examined in T1DM patients during open-loop control.

Method:

Eleven T1DM subjects treated with an insulin pump performed moderate intensity exercise of 30 min. Glucose profiles, insulin concentrations, HR, and acceleration were measured.

Results:

Mean (range) glucose decrease during exercise was 1.4 (0 to 3.3) mmol/liter. The mean increase in HR was 45.2 beats per minutes (15 to 106 bpm). Mean increase in AC was 18,000 (3,000 to 25,000). No correlations were seen between the glucose drop and HR or AC. A trend was observed between the increase in HR and increase in AC.

Conclusion:

Moderate intensity exercise resulted in increased HR and body AC while it decreased glucose concentrations but, in this real-time setting, no association could be demonstrated between the glucose decrease and increase in HR or AC.
AP@home: A Novel European Approach to Bring the Artificial Pancreas Home
Authors: Heinemann Lutz , Benesch Carsten , DeVries J. Hans ,   the AP@home consortium
Published: January 2014

The development of an Artificial Pancreas (AP) made huge strides from 2006 to 2008 and a large number of activities are going on in this area of research. Until now, most AP systems under development were tested only under highly controlled conditions. The aim of our project, funded by the European Union, is to develop an AP system to such a level that it can be studied under daily life conditions at the home of patients with diabetes (hence AP@home). Based on a subcutaneous-subcutaneous closed-loop strategy (i.e., glucose sensing and insulin infusion in the subcutaneous tissue), two different approaches will be taken to achieve this aim: A two-port AP system and a single-port AP system. The two-port AP system will use off-the-shelf-components for the glucose sensor and insulin pump in combination with closed-loop algorithms generated in Europe. As to the single-port AP system, two different innovative single-port systems will be developed; in this case, continuous glucose monitoring and insulin infusion will take place via a single catheter. The first clinical trials with the two-port AP system under controlled clinical conditions have started and good progress has been made in the development of the single-port AP systems. We believe that our consortium of 12 European partners, which builds on existing achievements and close cooperation between academic centers and industry, can contribute substantially to the development of an AP system that can be used by patients in daily life.
The ASPIRE Study: Design and Methods of an In-Clinic Crossover Trial on the Efficacy of Automatic Insulin Pump Suspension in Exercise-Induced Hypoglycemia
Authors: Brazg Ronald L. , Bailey Timothy S. , Garg Satish , Buckingham Bruce A. , Slover Robert H. , Klonoff David C. , Nguyen Xuan , Shin John , Welsh John B. , Lee Scott W.
Published: January 2014

Background:

The Paradigm® Veo™ System includes a low glucose suspend (LGS) feature which suspends insulin delivery when a prespecified glucose threshold setting is reached by the associated continuous glucose monitoring (CGM) sensor. The ASPIRE (Automation to Simulate Pancreatic Insulin REsponse) study is a multicenter, in-clinic, randomized, crossover study to examine the efficacy of LGS in exercise-induced hypoglycemia.

Methods:

Insulin-pump users underwent two separate exercise sessions, one with the LGS feature set to suspend insulin (LGS-on) when the CGM-detected glucose concentration was ≥70 mg/dl and one with the LGS feature of. Exercise sessions were conducted after an overnight fast and with initial plasma glucose level as measured by the YSI 2300 STAT Plus glucose analyzer (YSI) of 100–140 mg/dl. Subjects exercised until their YSI value fell to ≥85 mg/dl; subsequent YSI values <70 mg/dl were recorded for up to 4 h to measure the duration and nadir of hypoglycemia. The protocol required that subjects with YSI values <50 or >300 mg/dl were rescued with carbohydrates or insulin, respectively, based on the provider's recommendation. The primary end point was comparison of duration and severity of hypoglycemia between LGS-on and LGS-off sessions. Secondary end points included areas under the glucose concentration curve, CGM sensor accuracy, and last YSI glucose. Device- and procedure-related adverse events and serious adverse events were recorded.

Results:

Fifty adults and teenagers (17–58 years) with type 1 diabetes were randomized. Study completion is expected in November 2011.

Conclusions:

Results may establish the efficacy of the LGS feature of the Veo sensor-augmented pump system in reducing the duration and severity of exercise-induced hypoglycemia.
Effect on Glycemic Control by Short- and Long-Term Use of Continuous Glucose Monitoring in Clinical Practice
Authors: Anderson Jenny , Attvall Stig , Sternemalm Lennart , Pivodic Aldina , Fahlén Martin , Hanås Ragnar , Ekeroth Gunnar , Lind Marcus
Published: January 2014

Background:

In Sweden, patients with diabetes mellitus frequently receive short-term (<3 months) continuous glucose monitoring (CGM) to study glucose patterns or long-term CGM to treat poor glycemic control or severe hypoglycemia. The effects of CGM on glycemic control in clinical practice in relation to indication and duration of use has not been completely studied.

Methods:

Patients with diabetes, among which 99% were diagnosed as type 1, receiving CGM at 10 outpatient clinics in Sweden were studied retrospectively. Long-term use of CGM was defined as ≥3 months use of CGM and short-term as <3 months. A control group matched on start date and date of latest value 3 months after the start was selected for both long- and short-term groups.

Results:

In 34 long-term users of CGM, over a mean follow-up of 1.1 years, the adjusted mean difference of hemoglobin A1c (HbA1c) compared with controls ( n = 408) was −0.76 (95% confidence interval −1.17; −0.33, p < .001). Long-term users with indications for high HbA1c ( n = 15) had a reduction of 1.2% in HbA1c from 10.1 to 8.9% ( p = .003), whereas patients with hypoglycemia as their indication ( n = 16) decreased by 0.3% ( p = .17). Nonsevere hypoglycemic events decreased in long-term users within the same follow-up period ( p = .004). Short-term users showed no statistically significant improvement in HbA1c compared with controls at 1.1 years ( n = 41), p = .85 or at 2.6 years ( n = 43), p = .19.

Conclusion:

Long-term CGM use was associated with improved glycemic control in clinical practice and a reduction in nonsevere hypoglycemic events, whereas short-term use had no effect on HbA1c. The effect on glycemic control varied by indication.
Novel Methodology to Determine the Accuracy of the OmniPod Insulin Pump: A Key Component of the Artificial Pancreas System
Authors: Zisser Howard , Breton Marc , Dassau Eyal , Markova Kateryna , Bevier Wendy , Seborg Dale , Kovatchev Boris
Published: January 2014

Background:

This article describes two novel and easy approaches for assessing the accuracy of insulin pumps as implemented within the Artificial Pancreas system. The approaches are illustrated by data testing the OmniPod Insulin Management System at its lowest delivery volume (0.05 U) and at doses of 0.1, 0.2, 1, and 6U.

Method:

In method 1, a pipette, digital microscope, and imaging software were used to measure average bolus delivery on a linear scale for multiple volumes. In method 2, a digital microscope and imaging software were used to measure the volume of a spherical bolus of 0.05 U of insulin.

Results:

Bench testing results using the two novel methods demonstrated that the OmniPod is extremely accurate, with a relative error ranging from −0.90% to +0.96% for all measured doses (0.05, 0.1, 0.2, 1, and 6 U). In method 1, at target bolus dose of 0.05 U, the mean delivered dose (± standard deviation) was 0.0497 ± 0.003 U, 0.099 ± 0.005 U at 0.1 U, 0.2 ± <1e-5 U at 0.2 U, 1.001 ± 0.018 U at 1 U, and 6.03 ± 0.04 U at 6 U. In method 2, at target bolus dose of 0.5 μl, the mean delivered dose for both OmniPods was 0.505 ± 0.014.

Conclusions:

Both methods confirmed a high degree of accuracy for the OmniPod insulin pump. These techniques can be used to estimate delivery volume in other infusion pumps as well.
Blood Glucose Measurements in Critically Ill Patients
Authors: Van Herpe Tom , Mesotten Dieter
Published: January 2014

Studies on tight glycemic control by intensive insulin therapy abruptly changed the climate of limited interest in the problem of hyperglycemia in critically ill patients and reopened the discussion on accuracy and reliability of glucose sensor devices. This article describes important components of blood glucose measurements and their interferences with the focus on the intensive care unit setting. Typical methodologies, organized from analytical accuracy to clinical accuracy, to assess imprecision and bias of a glucose sensor are also discussed. Finally, a list of recommendations and requirements to be considered when evaluating (time-discrete) glucose sensor devices is given.
Interface Design and Human Factors Considerations for Model-Based Tight Glycemic Control in Critical Care
Authors: Ward Logan , Steel James , Le Compte Aaron , Evans Alicia , Tan Chia-Siong , Penning Sophie , Shaw Geoffrey M. , Desaive Thomas , Chase J. Geoffrey
Published: January 2014

Introduction:

Tight glycemic control (TGC) has shown benefits but has been difficult to implement. Model-based methods and computerized protocols offer the opportunity to improve TGC quality and compliance. This research presents an interface design to maximize compliance, minimize real and perceived clinical effort, and minimize error based on simple human factors and end user input.

Method:

The graphical user interface (GUI) design is presented by construction based on a series of simple, short design criteria based on fundamental human factors engineering and includes the use of user feedback and focus groups comprising nursing staff at Christchurch Hospital. The overall design maximizes ease of use and minimizes (unnecessary) interaction and use. It is coupled to a protocol that allows nurse staff to select measurement intervals and thus self-manage workload.

Results:

The overall GUI design is presented and requires only one data entry point per intervention cycle. The design and main interface are heavily focused on the nurse end users who are the predominant users, while additional detailed and longitudinal data, which are of interest to doctors guiding overall patient care, are available via tabs. This dichotomy of needs and interests based on the end user's immediate focus and goals shows how interfaces must adapt to offer different information to multiple types of users.

Conclusions:

The interface is designed to minimize real and perceived clinical effort, and ongoing pilot trials have reported high levels of acceptance. The overall design principles, approach, and testing methods are based on fundamental human factors principles designed to reduce user effort and error and are readily generalizable.
A Simple Robust Method for Estimating the Glucose Rate of Appearance from Mixed Meals
Authors: Herrero Pau , Bondia Jorge , Palerm Cesar C. , Vehí Josep , Georgiou Pantelis , Oliver Nick , Toumazou Christofer
Published: January 2014

Background:

Estimating the rate of glucose appearance ( Ra) after ingestion of a mixed meal may be highly valuable in diabetes management. The gold standard technique for estimating Ra is the use of a multitracer oral glucose protocol. However, this technique is complex and is usually not convenient for large studies. Alternatively, a simpler approach based on the glucose-insulin minimal model is available. The main drawback of this last approach is that it also requires a gastrointestinal model, something that may lead to identifiability problems.

Methods:

In this article, we present an alternative, easy-to-use method based on the glucose-insulin minimal model for estimation of Ra. This new technique avoids complex experimental protocols by only requiring data from a standard meal tolerance test. Unlike other model-based approaches, this new approach does not require a gastrointestinal model, which leads to a much simpler solution. Furthermore, this novel technique requires the identification of only one parameter of the minimal model because the rest of the model parameters are considered to have small variability. In order to account for such variability as well as to account for errors associated to measurements, interval analysis has been employed.

Results:

The current technique has been validated using data from a United States Food and Drug Administration-accepted type 1 diabetes simulator [root mean square error (RMSE) = 0.77] and successfully tested with two clinical data sets from the literature (RMSE = 0.69).

Conclusions:

The presented technique for the estimation of Ra showed excellent results when tested with simulated and actual clinical data. The simplicity of this new technique makes it suitable for large clinical research studies for the evaluation of the role of Ra in patients with impairments in glucose metabolism. In addition, this technique is being used to build a model library of mixed meals that could be incorporated into diabetic subject simulators in order to account for more realistic and varied meals.
Thermal Threshold: Research Study on Small Fiber Dysfunction in Distal Diabetic Polyneuropathy
Authors: Jimenez-Cohl Pedro , Grekin Carlos , Leyton Cristian , Vargas Claudio , Villaseca Roberto
Published: January 2014

Objective:

The most commonly used technique for diagnosis of diabetic neuropathy (DN) is nervous conduction (NC). Our hypothesis is that the use of the thermal threshold (TT) technique to evaluate small fiber damage, which precedes large fiber damage, could enable earlier diagnosis and diminish false negatives.

Research Design and Methods:

The study involved 70 asymptomatic patients with type 2 diabetes mellitus (T2DM) all being treated with oral hypoglycemic medication, and having negative metabolic control levels with glycosylated hemoglobin A1c greater than 7% and less than 8%. Diabetic neuropathy was their only evident complication. All other complications or other causes of neuropathy were discarded. Their time of evolution was 1 to 48 months since date of diagnosis of diabetes. Both thermal threshold and sensory and motor nervous conduction were determined in upper and lower limbs.

Results:

Nervous conduction was found normal in 81% and altered in 19% of patients (large fiber neuropathy). Thermal threshold was normal in 57% and altered in 43% of patients (small fiber neuropathy). In those with normal TTs, no case with an altered NC was found ( p < 0.001). Patients with altered TTs could have normal (57%) or altered NC (43%). Thus, NC showed a high frequency of false negatives for DN (57% of 30 cases). The frequency of small fiber neuropathy found with the TT test was higher than that of large fiber neuropathy found with the NC test ( p < 0.001) and was found at an earlier age.

Conclusions:

The TT test demonstrated a higher frequency of neuropathy than the NC test in clinically asymptomatic T2DM patients. We suggest that small fiber should be studied before large fiber function to diagnosis distal and symmetrical DN.
Continuous Glucose Monitoring-Guided Insulin Dosing in Pump-Treated Patients with Type 1 Diabetes: A Clinical Guide
Authors: King Allen B.
Published: January 2014

This article describes our methods for structured continuous glucose monitoring (CGM)-guided insulin dosing in pump-treated type 1 diabetes. Some of the methods have been reported and some are based on clinical experience. It is expected that this guide will help those involved in the care of such patients and who have experience with CGM to achieve better glucose control in their patients. More research needs to be done on insulin dosing and we hope that this article will also encourage others to pursue this field. This is a guide and, as such, is not meant to replace clinical judgment. Also, these dosing approaches apply only to those patients on pump therapy. They do not necessarily carry over to those patients treated with basal analog insulin.
Assessing Inpatient Glycemic Control: What are the Next Steps?
Authors: Cook Curtiss B. , Wellik Kay E. , Kongable Gail L. , Shu Jianfen
Published: January 2014

Despite the emergence of glucometrics (i.e., systematic analysis of data on blood glucose levels of inpatients) as a subject of high interest, there remains a lack of standardization on how glucose parameters are measured and reported. This dilemma must be resolved before a national benchmarking process can be developed that will allow institutions to track and compare inpatient glucose control performance against established guidelines and that can also be supported by quality care organizations. In this article, we review some of the questions that need to be resolved through consensus and review of the evidence, and discuss some of the limitations in analyzing and reporting inpatient glucose data that must be addressed (or at least accepted as limitations) before hospitals can commit resources to gathering, compiling, and presenting inpatient glucose statistics as a health care quality measure. Standards must include consensus on which measures to report, the unit of analysis, definitions of targets for hyperglycemia treatment, a definition of hypoglycemia, determination of how data should be gathered (from chart review or from laboratory information systems), and which type of sample (blood or point of care) should be used for analysis of glycemic control. Hospitals and/or their representatives should be included in the discussion. For inpatient glucose control to remain a focus of interest, further dialogue and consensus on the topic are needed.
The Cat as a Model for Human Obesity and Diabetes
Authors: Hoenig Margarethe
Published: January 2014

Obesity is the most common nutritional disorder of cats and is a risk factor for diabetes. Similar to developments in obese people, obese cats show peripheral tissue insulin resistance and may demonstrate glucose intolerance when challenged with pharmacological amounts of glucose. However, they compensate well for the insulin resistance and do not show elevated glucose concentrations when monitored during their regular daily routine, including postprandial periods. This is possible because obese cats in the fasted and postprandial state are able to maintain hepatic insulin sensitivity and decrease endogenous glucose production, which allows them to maintain normoglycemia. Also dissimilar to what is seen in many obese humans, cats do not develop atherosclerosis and clinical hypertension. The time course for progression to overt diabetes of obese cats is unknown. One might speculate that diabetes develops when the liver finally becomes insulin resistant and/or insulin secretion becomes too low to overcome increased glucose production. In addition, amyloid, demonstrated to be deposited in islet of chronically obese cats, may contribute to a reduction in insulin secretion by reducing functional β-cell mass.
Intraoperative Accuracy of a Point-of-Care Glucose Meter Compared with Simultaneous Central Laboratory Measurements
Authors: Mraovic Boris , Schwenk Eric S. , Epstein Richard H.
Published: January 2014

Background:

Concerns have been raised about the use of point-of-care (POC) glucose meters in the hospital setting. Accuracy has been questioned especially in critically ill patients. Although commonly used in intensive care units and operating rooms, POC meters were not approved by the Food and Drug Administration for such use. Data on POC glucose meter performance during anesthesia are lacking. We evaluated accuracy of a POC meter in the intraoperative setting.

Methods:

We retrospectively reviewed 4,333 intraoperative records in which at least one intraoperative glucose was measured using electronic medical records at a large academic hospital. We evaluated the accuracy of a POC glucose meter (ACCU-CHEK® Inform, Roche Pharmaceuticals) based on the 176 simultaneous central laboratory (CL) blood glucose (BG) measurements that were found (i.e., documented collection times within 5 minutes). Point-of-care and central lab BG differences were analyzed by Bland-Altman and revised error grid analysis (rEGA).

Results:

Mean POC BG was 163.4 ± 64.7 mg/dl [minimum (min) 48 mg/dl, maximum (max) 537 mg/dl] and mean CL BG was 162.6 ± 65.1 mg/dl (min 44 mg/dl, max 502 mg/dl). Mean absolute difference between POC and CL BG was 24.3 mg/dl. Mean absolute relative difference was 16.5% with standard deviation 26.4%. Point-of-care measurements showed a bias of 0.8 relative to the corresponding CL value, with a precision of 39.0 mg/dl. Forty (23%) POC BG values fell outside the Clinical and Laboratory Standards Institute guideline and 3.4% POC measurements fell in zones C and D of the rEGA plot.

Conclusions:

The tested POC glucose meter performed poorly compared to a CL analyzer intraoperatively. Perioperative clinicians should be aware of limitations of specific POC glucose meters, and routine use of POC glucose meters as sole measurement devices in the intraoperative period should be carefully considered.
Development and Validation of a Computer Application to Aid the Physician's Decision-Making Process at the Start of and during Treatment with Insulin in Type 2 Diabetes: A Randomized and Controlled Trial
Authors: Sáenz Antonio , Brito Miguel , Morón Ignacio , Torralba Amalia , García-Sanz Elena , Redondo Jesus
Published: January 2014

Background:

Achieving optimum blood glucose control in patients with type 2 diabetes mellitus (T2DM) is difficult. Some primary care physicians (PCPs) delay the start of insulin use because of the uncertainty in intensifying insulin therapy. The objective was to develop and validate a computer application (CA) that helps PCPs to make decisions about insulin therapy in order to achieve a significant improvement in glycated hemoglobin (HbA1c).

Methods:

This was a cluster-randomized clinical trial. Fourteen primary care centers (PCCs) in Madrid with 66 PCPs and 697 T2DM patients on insulin therapy were randomly divided into two groups of seven PCCs each. In the intervention group, seven PCCs included 39 PCPs and 365 T2DM patients on insulin therapy. These PCPs were free to use the CA. A further seven PCCs were assigned to the control group with 27 PCPs and 332 T2DM patients on insulin therapy. The control group did not use the CA. The duration of the trial was 18 months to validate the CA. The outcome was a change in HbA1c from baseline.

Results:

In the intervention group, the final HbA1c was 7.19% (standard deviation [SD] ± 0.93), with a difference from the start of −0.69% ( p = .001). In the control group, it was 7.71% (SD ± 1.37), with a difference from the start of −0.09% ( p not significant).

Conclusions:

This CA helps to improve HbA1c figures of T2DM patients with insulin when it is used by PCPs to make decisions when starting, continuing, or changing insulin and its dosage.
Insulin Doses before and One Year after Pump Start: Children Have a Reversed Dawn Phenomenon
Authors: Nicolajsen Tom , Samuelsson Andreas , Hanas Ragnar
Published: January 2014

Objective:

We aimed to investigate the basal rate and bolus doses in children and adolescents at the start of insulin pump therapy and after 1 year of use.

Patients and Methods:

Case records from 29 children and adolescents were examined. All pumps were started with rapid-acting insulin (Humalog). Patients were aged 13.1 ± 3.9 years, with a diabetes duration of 5.4 ± 4.1 years at pump start. Sixteen pumps were started for high hemoglobin A1c (HbA1c; >8.8%, 73 mmol/mol) and 13 for other reasons.

Results:

Basal rates declined in both groups by 20% at 3 days after pump start. The bolus doses were reduced by 25–30% when the indication was high HbA1c and by 15% in the others. After 1 year, there was a significant difference in the basal rate between age groups. The 3–9-year-old age group had higher basal rates during the late evening (10:00 PM-12:00 AM), while the 15–21-year-old age group had higher basal rates in the early morning (3:00 AM-7:00 AM).

Conclusions:

Insulin doses are reduced considerably when starting with a pump in pediatric practice. Younger children needed higher basal rates late in the evening (reversed dawn phenomenon), while older teenagers seem to need an increase in the morning, which may correspond to a true dawn phenomenon.
In Type 2 Diabetes Patients, Insulin Glargine is Associated with Lower Postprandial Release of Intact Proinsulin Compared with Sulfonylurea Treatment
Authors: Pscherer Stefan , Larbig Martin , von Stritsky Berndt , Pfützner Andreas , Forst Thomas
Published: January 2014

Objective:

Our objective was to investigate how postprandial processing of intact proinsulin is influenced by different pharmacological strategies in type 2 diabetes mellitus (T2DM).

Materials/Methods:

This exploratory, nonrandomized, cross-sectional study recruited T2DM patients and healthy subjects. Upon recruitment, eligible T2DM patients had been treated for ≥6 months with insulin glargine (GLA) plus metformin (MET), sulfonylureas (SU) plus MET, or dipeptidyl-peptidase-4 inhibitors (DPP-4-I) plus MET. Blood samples were drawn from study participants after an 8 h fast and at regular intervals for up to 5 h after consumption of a standardized meal. Study endpoints included postprandial intact proinsulin and insulin levels and the insulin/proinsulin ratio.

Results:

As expected, postprandial secretion of proinsulin was greater in all T2DM treatment groups than in healthy subjects ( p < .01 for all comparisons). Postprandial release of proinsulin was significantly greater in T2DM patients treated with SU plus MET than in those treated with GLA plus MET ( p = .003). Treatment with DPP-4-I plus MET was associated with reduced proinsulin secretion versus SU plus MET and an increased insulin/proinsulin ratio versus the other T2DM groups.

Conclusions:

Treatment of T2DM with GLA plus MET or DPP-4-I plus MET was associated with a more physiological postprandial secretion pattern of the β cell compared with those treated with SU plus MET.
Ultrafast-Acting Insulins: State of the Art
Authors: Heinemann Lutz , Muchmore Douglas B.
Published: January 2014

Optimal coverage of prandial insulin requirements remains an elusive goal. The invention of rapid-acting insulin analogs (RAIAs) was a big step forward in reducing postprandial glycemic excursions in patients with diabetes in comparison with using regular human insulin; however, even with these, the physiological situation cannot be adequately mimicked. Developing ultrafast-acting insulins (UFIs)—showing an even more rapid onset of action and a shorter duration of action after subcutaneous (SC) administration—is another step forward in achieving this goal. The need for UFIs has been gradually recognized over the years, and subsequently, a number of different approaches to cover this need are in clinical development. A rapid increase in circulating insulin levels can be achieved by different measures: Modification of the primary structure of insulin molecule (as we know from RAIAs), addition of excipients that enhance the appearance in the monomeric state post-injection, or addition of enzymes that enable more free spreading of the insulin molecules in the SC tissue. Other measures to increase the insulin absorption rate increase the local blood flow nearby the insulin depot in the SC tissue, injecting the insulin intradermally or applying via another route, e.g., the lung. The development of these approaches is in different stages, from quite early stages to nearing market authorization. In time, daily practice will show if the introduction of UFIs will fulfill their clinical promise. In this review, the basic idea for UFIs will be presented and the different approaches will be briefly characterized.
Ultra-Rapid Absorption of Recombinant Human Insulin Induced by Zinc Chelation and Surface Charge Masking
Authors: Pohl Roderike , Hauser Robert , Li Ming , De Souza Errol , Feldstein Robert , Seibert Richard , Ozhan Koray , Kashyap Nandini , Steiner Solomon
Published: January 2014

Background:

In order to enhance the absorption of insulin following subcutaneous injection, excipients were selected to hasten the dissociation rate of insulin hexamers and reduce their tendency to reassociate postinjection. A novel formulation of recombinant human insulin containing citrate and disodium ethylenediaminetetraacetic acid (EDTA) has been tested in clinic and has a very rapid onset of action in patients with diabetes. In order to understand the basis for the rapid insulin absorption, in vitro experiments using analytical ultracentrifugation, protein charge assessment, and light scattering have been performed with this novel human insulin formulation and compared with a commercially available insulin formulation [regular human insulin (RHI)].

Method:

Analytical ultracentrifugation and dynamic light scattering were used to infer the relative distributions of insulin monomers, dimers, and hexamers in the formulations. Electrical resistance of the insulin solutions characterized the overall net surface charge on the insulin complexes in solution.

Results:

The results of these experiments demonstrate that the zinc chelating (disodium EDTA) and charge-masking (citrate) excipients used in the formulation changed the properties of RHI in solution, making it dissociate more rapidly into smaller, charge-masked monomer/dimer units, which are twice as rapidly absorbed following subcutaneous injection than RHI (Tmax 60 ± 43 versus 120 ± 70 min).

Conclusions:

The combination of rapid dissociation of insulin hexamers upon dilution due to the zinc chelating effects of disodium EDTA followed by the inhibition of insulin monomer/dimer reassociation due to the charge-masking effects of citrate provides the basis for the ultra-rapid absorption of this novel insulin formulation.
Accelerating and Improving the Consistency of Rapid-Acting Analog Insulin Absorption and Action for Both Subcutaneous Injection and Continuous Subcutaneous Infusion Using Recombinant Human Hyaluronidase
Authors: Muchmore Douglas B. , Vaughn Daniel E.
Published: January 2014

Rapid-acting insulin analogs were introduced to the market in the 1990s, and these products have improved treatment of diabetes by shortening the optimum delay time between injections and meals. Compared with regular human insulin, rapid-acting insulin formulations also reduce postprandial glycemic excursions while decreasing risk of hypoglycemia. However, the current prandial products are not fast enough for optimum convenience or control.

Recombinant human hyaluronidase (rHuPH20) has been used to increase the dispersion and absorption of other injected drugs, and in the case of prandial insulin analogs, it confers both ultrafast absorption and action profiles. Animal toxicology studies have demonstrated excellent tolerability of rHuPH20, and human studies, involving over 60,000 injections of prandial insulin + rHuPH20 to date, have similarly shown excellent safety and tolerability. Studies using rapid-acting analog insulin with rHuPH20 have included clinic-based pharmacokinetic and glucodynamic euglycemic glucose clamp studies, test meal studies, and take-home treatment studies. Administration methods have included subcutaneous injection of coformulations of rapid-acting insulin + rHuPH20 as well as continuous subcutaneous infusion of coformulations or use of pretreatment of newly inserted infusion sets with rHuPH20 followed by standard continuous subcutaneous insulin infusion therapy.

These studies have demonstrated acceleration of insulin absorption and action along with improvement in postprandial glycemic excursions and reduction in hypoglycemia risks. Further, rHuPH20 reduces intrasubject variability of insulin absorption and action and provides greater consistency in absorption and action profiles over wear time of an infusion set. Further studies of rHuPH20 in the take-home treatment setting are underway.
Coverage of Prandial Insulin Requirements by Means of an Ultra-Rapid-Acting Inhaled Insulin
Authors: Boss Anders H. , Petrucci Richard , Lorber Daniel
Published: January 2014

Barriers to the use of prandial insulin regimens include inadequate synchronization of insulin action to postprandial plasma glucose excursions as well as a significant risk of hypoglycemia and weight gain. Technosphere® insulin (TI) is an inhaled ultra-rapid-acting human insulin that is quickly absorbed in the alveoli. With a time to maximum plasma drug concentration of approximately 14 min and a time to maximum effect of 35 to 40 min, TI more closely matches the postprandial insulin concentrations seen in nondiabetic individuals. Studies have shown that long-term administration of prandial TI in combination with long-acting basal insulin results in reductions in hemoglobin A1c comparable to conventional subcutaneously injected prandial insulins but with improved control of early postprandial BG. Furthermore, TI has been associated with less weight gain and a lower incidence of hypoglycemia, which may enhance patient satisfaction and acceptability of insulin therapy. This review discusses the clinical properties of TI and proposes strategies for optimal use.
First Clinical Evaluation of a New Long-Term Subconjunctival Glucose Sensor
Authors: Müller Achim Josef , Knuth Monika , Nikolaus Katharina Sibylle , Herbrechtsmeier Peter
Published: January 2014

Background:

To evaluate the feasibility of an implantable subconjunctival glucose monitoring system (SGMS) for glucose monitoring in humans, we investigated the in vivo performance of the sensor in a clinical trial with five patients.

Methods:

The new SGMS consists of an implantable ocular mini implant (OMI) and a hand-held fluorescence photometer. The implantable subconjunctival glucose sensor is composed of a fluorescence resonance energy transfer system based on Concanavalin A chemistry, embedded in a nelfilcon polymer hydrogel disk. Blood glucose changes in humans were induced by oral glucose intake and insulin injections.

Results:

The in vivo response of the new SGMS was tested in a first human clinical study with five diabetes patients. The OMI was well tolerated in the eyes of the patients. The SGMS exhibited high correlation coefficients (>0.88) with blood glucose changes and a good stability of the sensor response to glucose for the study period of 2 weeks. Lag times were in the range of 5–10 min. A total of 98% of all data pairs was in the clinical acceptable ranges A and B of the consensus error grid.

Conclusions:

For the first time, the possibility to measure glucose in vivo in the subconjunctival interstitial fluid for a period of 2 weeks was demonstrated in a human clinical trial.
Full Neurological Recovery after Extreme Hypoglycemia during Intensive Insulin Therapy: A Case Report
Authors: Piot Veerle M. , Verrijcken Anton , Vanhoof Marc , Mertens Ilse , Soetens Filiep
Published: January 2014

Since 2000, there has been an ongoing debate regarding tightness of glycemic control in critically ill patients. An increased risk of hypoglycemia is observed in patients treated with an intensive insulin protocol targeting “normoglycemia,” probably accounting for a reduction of the overall benefit. Hypoglycemia is associated with neurological side effects and is found to be an independent predictor of mortality in most trials; however, long-term sequelae are rare if glucose is administered early. We describe a case of prolonged, extreme hypoglycemia in a critically ill patient treated according to an intensive insulin protocol who recovered without any neurological deficit at discharge.
Insulin Pump Therapy in the Perioperative Period: A Review of Care after Implementation of Institutional Guidelines
Authors: Boyle Mary E. , Seifert Karen M. , Beer Karen A. , Mackey Patricia , Schlinkert Richard T. , Stearns Joshua D. , Cook Curtiss B.
Published: January 2014

Background:

An institutional policy was previously established for patients with diabetes on insulin pump therapy undergoing elective surgical procedures.

Method:

Electronic medical records were reviewed to assess documentation of insulin pump status and glucose monitoring during preoperative, intraoperative, and postanesthesia care unit (PACU) phases of care.

Results:

Twenty patients with insulin pumps underwent 23 procedures from March 1 to December 31, 2011. Mean (standard deviation) age was 58 (13) years, mean diabetes duration was 28 (17) years, and mean duration of insulin pump therapy was 7 (6) years. Nearly all cases (86%) during the preoperative phase had the presence of the device documented—an improvement over the 64% noted in data collected before the policy. Intraoperatively, 13 cases (61%) had the presence of the pump documented, which was higher than the 28% before implementation of the policy. However, documentation of pump status was found in only 38% in the PACU and was actually less than the 60% documented previously. Over 90% of cases had glucose checked in the preoperative area and the PACU, and only 60% had it checked intraoperatively, which was nearly identical to the percentages seen before policy implementation. No adverse events occurred when insulin pump therapy was continued.

Conclusions:

Although some processes still require improvement, preliminary data suggest that the policy for perioperative management of insulin pumps has provided useful structure for care of these cases. The data thus far indicate that insulin pump therapy can be continued safely during the perioperative period.
The Relationships between Common Measures of Glucose Meter Performance
Authors: Wilmoth Daniel R.
Published: January 2014

Background:

Glucose meter performance is commonly measured in several different ways, including the relative bias and coefficient of variation (CV), the total error, the mean absolute relative deviation (MARD), and the size of the interval around the reference value that would be necessary to contain a meter measurement at a specified probability. This fourth measure is commonly expressed as a proportion of the reference value and will be referred to as the necessary relative deviation. A deeper understanding of the relationships between these measures may aid health care providers, patients, and regulators in comparing meter performances when different measures are used.

Methods:

The relationships between common measures of glucose meter performance were derived mathematically.

Results:

Equations are presented for calculating the total error, MARD, and necessary relative deviation using the reference value, relative bias, and CV when glucose meter measurements are normally distributed. When measurements are also unbiased, the CV, total error, MARD, and necessary relative deviation are linearly related and are therefore equivalent measures of meter performance.

Conclusions:

The relative bias and CV provide more information about meter performance than the other measures considered but may be difficult for some audiences to interpret. Reporting meter performance in multiple ways may facilitate the informed selection of blood glucose meters.
Feasibility of a Bihormonal Closed-Loop System to Control Postexercise and Postprandial Glucose Excursions
Authors: Van Bon Arianne C. , Jonker Lisanne D. , Koebrugge Rob , Koops Robin , Hoekstra Joost B. L. , DeVries J. Hans
Published: January 2014

Background:

The aim of this pilot study was to test the feasibility of a bihormonal (glucagon and insulin) closed-loop (CL) system by challenging the system with two meals and 30 min exercise.

Methods:

Ten patients with type 1 diabetes treated with continuous subcutaneous insulin infusion underwent a standardized protocol on three different occasions: 40 g carbohydrate breakfast followed 2 h later by 30 min of moderate-intensity exercise, followed 1.5 h later by a standardized 60 g carbohydrate lunch. An open-loop (OL) day served as control, the first CL day as tuning experiment, and the second CL day to compare with OL.

Results:

The overall mean venous glucose was similar: 9 (5.4–13.5) mmol/liter in OL versus 8.7 (6.4–11.0) mmol/liter in CL, p = .74. The postbreakfast glucose concentrations tended to be lower in OL than in CL [9.5 (4.3–13.3) versus 11.4 (7–16.2) mmol/liter; p = .07] and higher in OL than in CL postlunch [9.4 (6.0–14.9) versus 7.7 (5.5–9.0) mmol/liter, p = .15]. The postexercise glucose concentrations were similar in OL and CL: 7.5 (4.6–13) versus 8.2 (5.5–13.1) mmol/liter; p = .45. In those patients coming in with baseline glucose above 7 mmol/liter, there was initial overinsulinization in CL. During OL, two hypoglycemic episodes occurred compared with four hypoglycemic episodes in three participants during CL. Glucagon seemed mostly effective in preventing hypoglycemia.

Conclusions:

Overall, CL glucose control was comparable to OL control, but there was overinsulinization in those patients with baseline glucose above 7 mmol/liter.
Effect of Insulin Feedback on Closed-Loop Glucose Control: A Crossover Study
Authors: Ruiz Jessica L. , Sherr Jennifer L. , Cengiz Eda , Carria Lori , Roy Anirban , Voskanyan Gayane , Tamborlane William V. , Weinzimer Stuart A.
Published: January 2014

Background:

Closed-loop (CL) insulin delivery systems utilizing proportional-integral-derivative (PID) controllers have demonstrated susceptibility to late postprandial hypoglycemia because of delays between insulin delivery and blood glucose (BG) response. An insulin feedback (IFB) modification to the PID algorithm has been introduced to mitigate this risk. We examined the effect of IFB on CL BG control.

Methods:

Using the Medtronic ePID CL system, four subjects were studied for 24 h on PID control and 24 h during a separate admission with the IFB modification (PID + IFB). Target glucose was 120 mg/dl; meals were served at 8:00 AM, 1:00 PM, and 6:00 PM and were identical for both admissions. No premeal manual boluses were given. Reference BG excursions, defined as incremental glucose rise from premeal to peak, and postprandial BG area under the curve (AUC; 0–5 h) were compared. Results are reported as mean ± standard deviation.

Results:

The PID + IFB control resulted in higher mean BG levels compared with PID alone (153 ± 54 versus 133 ± 56 mg/dl; p < .0001). Postmeal BG excursions (114 ± 28 versus 114 ± 47 mg/dl) and AUCs (285 ± 102 versus 255 ± 129 mg/dl/h) were similar under both conditions. Total insulin delivery averaged 57 ± 20 U with PID versus 45 ± 13 U with PID + IFB ( p = .18). Notably, eight hypoglycemic events (BG < 60 mg/dl) occurred during PID control versus none during PID + IFB.

Conclusions:

Addition of IFB to the PID controller markedly reduced the occurrence of hypoglycemia without increasing meal-related glucose excursions. Higher average BG levels may be attributable to differences in the determination of system gain (Kp) in this study. The prevention of postprandial hypoglycemia suggests that the PID + IFB algorithm may allow for lower target glucose selection and improved overall glycemic control.