Meal Bolus Research Articles

Feasibility of Adjacent Insulin Infusion and Continuous Glucose Monitoring via the Medtronic Combo-Set

Subcutaneously infused insulin may interfere with the function of nearby glucose-sensing electrodes and vice versa. The prototype of the Combo-Set device (Medtronic) incorporates a subcutaneous insulin delivery catheter and continuous glucose monitoring (CGM) sensor assembled on the same platform and separated by 11 mm. We aim to evaluate Combo-Set's insulin delivery and glucose-sensing functions. Ten subjects with type 1 diabetes wore a Combo-Set and a Sof-Sensor inserted subcutaneously in contralateral abdominal areas connected to iPro recorders (Medtronic) for 53.25 ± 0.75 h (mean ± standard deviation). The Combo-Set delivered insulin diluent except during meal tests on days 1 and 3 when insulin lispro was delivered as a meal bolus and postmeal basal. Venous plasma samples were collected at the following time points from meal start: 0, 30, 60, 120, and 180 min for insulin measurements. The accuracy of the Combo-Set sensors was evaluated and compared with that of the Sof-Sensor, with each referenced against capillary glucose values (Contour Link Meter, Bayer). Accuracy of the Combo-Set sensor was comparable to that of the Sof-Sensor. Clarke error grid analysis showed that 97% of Combo-Set and 93% of Sof-Sensor values were in the A+B regions (p = .20, not significant). The Combo-Set showed the expected postbolus peak insulin time (67 ± 9 min, mean ± standard error). One "no delivery" alarm occurred during the 21 patient days of use. A device providing for simultaneous adjacent placement of an insulin infusion catheter and a CGM sensor is feasible and functions within acceptable limits. The low "no delivery" alarm rate was similar to that of other infusion sets.

Should the Amounts of Fat and Protein Be Taken into Consideration to Calculate the Lunch Prandial Insulin Bolus? Results from a Randomized Crossover Trial

Concerning continuous subcutaneous insulin infusion (CSII), there are controversial results related to changes in glycemic response according to the meal composition and bolus design. Our aim is to determine whether the presence of protein and fat in a meal could involve a different postprandial glycemic response than that obtained with only carbohydrates (CHs). This was a crossover, randomized clinical trial. Seventeen type 1 diabetes (T1D) patients on CSII wore a blinded continuous glucose monitoring system sensor for 3 days. They ingested two meals (meal 1 vs. meal 2) with the same CH content (50 g) but different fat (8.9 g vs. 37.4 g) and protein (3.3 g vs. 28.9 g) contents. A single-wave insulin bolus was used, and the interstitial glucose values were measured every 30 min for 3 h. We evaluated the different postprandial glycemic response between meal 1 and meal 2 by using mixed-effects models. The postmeal glucose increase was 22 mg/dL for meal 1 and 31 mg/dL for meal 2. In univariate analysis, at different times not statistically significant differences in glucose levels between meals occurred. In mixed-model analysis, a time×meal interaction was found, indicating a different response between treatments along the time. However, most of the patients remained in the normoglycemic range (70-180 mg/dL) during the 3-h postmeal period (84.4% for meal 1 and 93.1% for meal 2). The presence of balanced amounts of protein and fat determined a different glycemic response from that obtained with only CH up to 3 h after eating. The clinical relevance of this finding remains to be elucidated.

Simultaneous Use of Two External Subcutaneous Pumps Delivering Insulin and SYMLIN: Use of a Double-Pump System

The combination of insulin and an amylin mimetic is an option for diabetes treatment.1,2 The effectiveness of this modality has been established, but there is a limited amount of literature regarding the use of this combined treatment via continuous subcutaneous infusion by external pumps. A short 16-week trial of 10 patients studied the pharmacokinetics of pramlintide (SYMLIN®, Amylin Pharmaceuticals, LLC, San Diego, CA) in continuous subcutaneous infusion and found this modality to be safe and well tolerated.3 Treatment was initiated in a small study of 10 subjects (7 females and 3 males) with age range 24-69 years. There were 5 patients with type 1 diabetes and 5 with type 2 diabetes (duration of diabetes: 15-38 years). Patients were switched from conventional multiple-dose insulin injection therapy or oral hypoglycemic agents to the combination of insulin and SYMLIN via continuous subcutaneous infusion using two external pumps simultaneously. Treatment was continued over a period of 1-5 years. Hemoglobin A1c (HbA1c), total daily insulin, total daily SYMLIN, weight, and blood glucose levels were measured, with follow-up ranging from 1-5 years. Patients using the double-pump system showed an average reduction in HbA1c from 8.3% to 6.9%. Total daily insulin was reduced from an average of 147 to 96 units per day. SYMLIN dosages increased from an average of 35 units per day to 50 units per day (Figure 1). Weight reduction was noted, with an initial average of 132 to 500 lb, decreasing to 110 to 360 lb. Figure 1 Insulin dosage vs SYMLIN dosage over duration of study. Amylin conversion of units to micrograms: 1 unit = 6 μg. Patients were treated with basal SYMLIN 0.5-2.5 unit/h (3-15 μg). Meal bolus was 2.5-10 units (15-60 μg). All patients completed a satisfaction survey and expressed satisfaction with the treatment regimen but indicated their preference for a dual or multichamber device. They also noted that they would not return to conventional SYMLIN injections if given the choice. We conclude that continuous infusion of insulin and SYMLIN via a pump system is a viable and effective therapeutic option. In this small observational study, all patients showed improvement in metabolic and weight control over a period of 1-5 years. Further studies with a larger population and a control group are needed to empower these results.

An Analysis of “No Effect of Insulin Pen with Memory Function on Glycemic Control in a Patient Cohort with Poorly Controlled Type 1 Diabetes: A Randomized Open-Label Study”

Missing meal bolus and nonadherence is an important barrier to achieving glycemic goals in type 1 diabetes (T1DM). In this issue of Journal of Diabetes Science and Technology, Danne and coauthors reported the results of a 24-week randomized-controlled study designed to evaluate if using an insulin pen with memory function, the HumaPen® Memoir™, might improve injection compliance and, therefore, overall glycemic control in T1DM. Patients treated with the pen device with memory function improved, albeit nonsignificantly, their mean HbA1c by 0.43%. Among the reasons to justify why this study was not positive, the most important is the high proportion of adult patients included in the study (87.9%)-children and adolescents being under-represented. I am convinced that pen devices with memory function might be helpful for forgetful patients (children, adolescents), as suggested in another recent study.

Pilot Studies of Wearable Outpatient Artificial Pancreas in Type 1 Diabetes

The artificial pancreas (AP) has been tested extensively in the hospital setting (1–5). Here we describe a next logical step in AP development—the first outpatient trials of a wearable AP based on a smartphone computational platform. Following Ethical Committee approvals and ClinicalTrials.gov registration (NCT01447992 and NCT01447979), two simultaneous studies were conducted in Padova, Italy, and Montpellier, France, in October 2011, enrolling a 38-year-old female and a 52-year-old male, respectively; both were Caucasian, type 1 diabetic insulin pump users. Day 1—At 17:00, the patients arrived at hotels located within 1 km from the emergency room. Subjects’ pumps were replaced by Omnipod Insulin Management Systems. The APs were activated in open-loop mode implementing the patients’ regular routines and remote monitoring was initiated. At 20:00, the patients had dinner at a local restaurant, without dietary restrictions and then spent the night in the hotel. Day 2—At 7:00, the patients were admitted to the clinic and the APs were switched to automated closed-loop control and challenged by breakfast at 8:00 and lunch at 12:00. At 18:00, the patients moved back to the hotel; dinner was at 20:00 in a local restaurant, without dietary restrictions. Meal bolus was recommended by the APs and approved by the patients; …

The Identifiable Virtual Patient Model: Comparison of Simulation and Clinical Closed-Loop Study Results

Optimizing a closed-loop insulin delivery algorithm for individuals with type 1 diabetes can be potentially facilitated by a mathematical model of the patient. However, model simulation studies that evaluate changes to the control algorithm need to produce conclusions similar to those that would be obtained from a clinical study evaluating the same modification. We evaluated the ability of a low-order identifiable virtual patient (IVP) model to achieve this goal. Ten adult subjects (42.5 ± 11.5 years of age; 18.0 ± 13.5 years diabetes; 6.9 ± 0.8% hemoglobin A1c) previously characterized with the IVP model were studied following the procedures independently reported in a pediatric study assessing proportional-integral-derivative control with and without a 50% meal insulin bolus. Peak postprandial glucose levels with and without the meal bolus and use of supplemental carbohydrate to treat hypoglycemia were compared using two-way analysis of variance and chi-square tests, respectively. The meal bolus decreased the peak postprandial glucose levels in both the adult-simulation and pediatricclinical study (231 ± 38 standard deviation to 205 ± 33 mg/dl and 226 ± 51 to 194 ± 47 mg/dl, respectively; p = .0472). No differences were observed between the peak postprandial levels obtained in the two studies (clinical and simulation study not different, p = .57; interaction p = .83) or in the use of supplemental carbohydrate (3 occurrences in 17 patient days of closed-loop control in the clinical-pediatric study; 7 occurrences over 20 patient days in the adult-simulation study, p = .29). Closed-loop simulations using an IVP model can predict clinical study outcomes in patients studied independently from those used to develop the model.

Closing the loop

Closing the loop

Journal of Diabetes NEWS

Journal of Diabetes NEWS

Timing of Meal Insulin Boluses to Achieve Optimal Postprandial Glycemic Control in Patients with Type 1 Diabetes

This study determined the optimal timing of insulin bolus administration in relation to meal consumption in adolescents and adults with type 1 diabetes. Twenty-three subjects participated in this crossover study consisting of three treatment arms: delivering an insulin glulisine bolus by insulin pump 20 min prior to a meal ("PRE"), immediately before the meal ("START"), and 20 min after meal initiation ("POST"). Blood glucose levels were measured every 30 min for a total of 240 min post-meal initiation. Mean blood glucose levels at 1 and 2 h after meal initiation, blood glucose area under the curve (AUC), and maximum blood glucose levels were analyzed. At both 60 and 120 min after meal initiation, the PRE arm showed significantly lower glycemic excursions than the START arm (P = 0.0029 and 0.0294, respectively) and the POST arm (P = 0.001 and 0.0408, respectively). Glycemic AUC was significantly less in the PRE arm versus both the START and POST arms (159.5 +/- 58.9 mg/dL vs. 187.0 +/- 43.1 mg/dL [P = 0.0297] and 184.5 +/- 33.2 mg/dL [P = 0.0463], respectively). Peak blood glucose levels were significantly lower in the PRE arm compared to the START arm (P = 0.0039) and the POST arm (P = 0.0027). A bolus of rapid-acting insulin 20 min prior to a meal results in significantly better postprandial glucose control than when the meal insulin bolus is given just prior to the meal or 20 min after meal initiation.

A Closed-Loop Artificial Pancreas Using Model Predictive Control and a Sliding Meal Size Estimator

The objective of this article is to present a comprehensive strategy for a closed-loop artificial pancreas. A meal detection and meal size estimation algorithm is developed for situations in which the subject forgets to provide a meal insulin bolus. A pharmacodynamic model of insulin action is used to provide insulin-on-board constraints to explicitly include the future effect of past and currently delivered insulin boluses. In addition, a supervisory pump shut-off feature is presented to avoid hypoglycemia. All of these components are used in conjunction with a feedback control algorithm using model predictive control (MPC). A model for MPC is developed based on a study of 20 subjects and is tested in a hypothetical clinical trial of 100 adolescent and 100 adult subjects using a Food and Drug Administration-approved diabetic subject simulator. In addition, a performance comparison of previously and newly proposed meal size estimation algorithms using 200 in silico subjects is presented. Using the new meal size estimation algorithm, the integrated artificial pancreas system yielded a daily mean glucose of 138 and 132 mg/dl for adolescents and adults, respectively, which is a substantial improvement over the MPC-only case, which yielded 159 and 145 mg/dl.

Insulin treatment in children and adolescents with diabetes

Department of Pediatrics, Uddevalla Hospital, Uddevalla,SwedenCorresponding author:Hans-Jacob Bangstad, MDDepartment of PaediatricsOslo University HospitalUlleval˚Kirkeveien 166Oslo N-0407Norway.Tel: 0047-22118765;fax: 0047-22118663;e-mail: haba@uus.noConflicts of interest: RH has received lecture honoraria fromNovo Nordisk, Lilly, Sanofi-Aventis, Medtronic and Roche. PJ-Chas received lecture fees from Eli Lilly, Novo-Nordisk, Sanofi-Aventis, Abbott, Bayer, Medtronic and Roche.The remainingauthors have declared no potential conflicts.Editors of the ISPAD Clinical Practice Consensus Guide-lines 2009 Compendium: Ragnar Hanas, Kim Donaghue,Georgeanna Klingensmith, and Peter Swift.This article is a chapter in the

Peritrophic matrix of Phlebotomus duboscqi and its kinetics during Leishmania major development

Light microscopy of native preparations, histology, and electron microscopy have revealed that Phlebotomus duboscqi belongs to a class of sand fly species with prompt development of the peritrophic matrix (PM). Secretion of electron-lucent fibrils, presumably chitin, starts immediately after the ingestion of a blood meal and, about 6 h later, is followed by secretion of amorphous electron-dense components, presumably proteins and glycoproteins. The PM matures in less than 12 h and consists of a thin laminar outer layer and a thick amorphous inner layer. No differences have been found in the timing of the disintegration of the PM in females infected with Leishmania major. In both groups of females (infected and uninfected), the disintegration of the PM is initiated at the posterior end. Although parasites are present at high densities in the anterior part of the blood meal bolus, they escape from the PM at the posterior end only. These results suggest that L. major chitinase does not have an important role in parasite escape from the PM. Promastigotes remain in the intraperitrophic space until the PM is broken down by sand-fly-derived chitinases and only then migrate anteriorly. Disintegration of the PM occurs simultaneously with the morphological transformation of parasites from procyclic forms to long nectomonads. A novel role is ascribed to the anterior plug, a component of the PM secreted by the thoracic midgut; this plug functions as a temporary barrier to stop the forward migration of nectomonads to the thoracic midgut.

Minimal Reduction in Insulin Dosage with Pramlintide Therapy When Pretreatment Near-Normal Glycemia is Established and Square-Wave Meal Bolus is Used

To evaluate the effect of near-normal glucose control before initiation of pramlintide therapy and square-wave meal bolus on self-reported hypoglycemia and the percentage change in dosing parameters after attaining the maximum pramlintide dosage. In this prospective study, insulin pump-treated patients with type 1 diabetes had insulin dosages optimally titrated on the basis of daily continuous glucose monitoring (CGM). Pramlintide therapy was initiated, and the dosage was increased 15 mcg/meal per week. Insulin dosage was adjusted during 30-minute visits after review of self-monitored blood glucose records, adverse effects, and hypoglycemia diary. Within 2 weeks of achieving a pramlintide dosage of 60 mcg/meal, the second CGM-guided insulin dosage adjustment was done. The primary end point was the percentage change in total basal insulin dosage (TBD) from baseline. The secondary end points were the percentage change in the insulin to carbohydrate ratio (ICR) and the assessment of symptoms of nausea and hypoglycemia during the pramlintide dosing escalation. Nine patients were enrolled. The difference between before and during CGM-guided insulin dosing was a mean (+/- standard deviation) TBD change of -11.2 +/- 13.2% (P = 0.023) and mean ICR change of 7.8 +/- 13.4% (P = 0.053). Pramlintide was well tolerated and resulted in decrease in weight and hemoglobin A1c values. Hypoglycemia occurred in 6 patients during the study; the assistance of another person was not required in any of these cases. No hypoglycemia was reported in the first week of starting pramlintide. Mild to moderate nausea was reported in 6 patients during the titration phase. Patients with near-normal glucose control who use a square-wave bolus may not need initial bolus dosage reduction. With weight loss, small adjustments in both TBD and ICR may be required. Greater incidence of hypoglycemia seen in previous studies may in part be due to mismatched insulin dosing.

Application of novel dual wave meal bolus and its impact on glycated hemoglobin A1c level in children with type 1 diabetes

An insulin pump is an advanced technology offering new options of bolus - normal (N), dual wave (D-W) or square wave (S-W) bolus to deliver mealtime insulin. To assess the impact of D-W/S-W boluses on metabolic control (glycated haemoglobin A1c, HbA1c) and to estimate the paediatric patients compliance with implementation of this system in daily practice. The cross-sectional study included 499 records of patients aged 0-18 yr. Data from the insulin pump memory provided information on the number of D-W/S-W boluses during a 2-wk period, the insulin requirement (U/kg/d) and the percentage of basal insulin. The HbA1c value (%) and the patient's weight were determined during medical examinations. Mealtime dose of insulin in D-W/S-W bolus was calculated based on the amount of carbohydrate and fat/protein products. The number of applied D-W/S-W boluses was 16.6 +/- 0.77/14 d (ranged 0-95), while 18.8% of patients did not program D-W/S-W boluses. The lowest HbA1c value was found in the group using two and/or more D-W/S-W boluses per day (p = 0.001) compared with the group administrating less than one D-W/S-W bolus/d. Patients with HbA1c level <7.5% had a statistically higher relevant number of D-W/S-W boluses, 19.55 (95% CI: 17.44-21.65) vs. 12.42 (95% CI: 10.22-14.61) (p < 0.001), while there was no correlation between the number of boluses and HbA1c in patients in the remission phase (<0.5 IU/kg/d) (r = 0.012, p = 0.930). Patients using at least one D-W/S-W bolus per day achieved a recommended level of HbA1c. Paediatric patients with type 1 diabetes mellitus were found to be able to apply D-W/S-W boluses in daily self-treatment process based on food counting.

Benefits of a bolus calculator in pre‐ and postprandial glycaemic control and meal flexibility of paediatric patients using continuous subcutaneous insulin infusion (CSII)

To assess the efficacy in pre- and postprandial glycaemic control and the impact on treatment satisfaction of a bolus calculator (Bolus Wizard) incorporated into the insulin pump in Type 1 diabetic (T1D) paediatric patients using continuous subcutaneous insulin infusion (CSII) treatment at various stages of pubertal development. Thirty-six T1D patients on CSII treatment (19 males; mean age 13.9 +/- 3.5 years; range 4.9-17.8 years), were prospectively enrolled into this two-period crossover study. Eighteen patients were randomized to begin phase A using the Bolus Wizard, followed by phase B, using their current conventional insulin dosing method to determine pre-meal boluses. The remaining subjects were randomized to begin with phase B followed by phase A. Each study period lasted 2 weeks. A questionnaire assessing treatment satisfaction with the Bolus Wizard was compiled. There was a significant reduction in blood glucose levels before and 2 h after meals and in the number of correction boluses during phase A with respect to phase B of the study. The lower frequency of hypoglycaemic events during phase A did not reach statistical significance. There were no differences between the two phases: insulin requirement, daily bolus rate (%) and meal bolus quantity. When paediatric patients used CSII, the bolus insulin dose calculated using the Bolus Wizard was more effective in improving pre- and postprandial glycaemic control with fewer correction boluses, without differences in the prandial insulin requirements and without restriction in the carbohydrate content of meals. The use of the Bolus Wizard was easy and was associated with a high level of satisfaction in these patients.

An Improved PID Switching Control Strategy for Type 1 Diabetes

In order for an "artificial pancreas" to become a reality for ambulatory use, a practical closed-loop control strategy must be developed and validated. In this paper, an improved PID control strategy for blood glucose control is proposed and critically evaluated in silico using a physiologic model of Hovorka et al. [1]. The key features of the proposed control strategy are: 1) a switching strategy for initiating PID control after a meal and insulin bolus; 2) a novel time-varying setpoint trajectory; 3) noise and derivative filters to reduce sensitivity to sensor noise; and 4) a practical controller tuning strategy. Simulation results demonstrate that proposed control strategy compares favorably to alternatives for realistic conditions that include meal challenges, incorrect carbohydrate meal estimates, changes in insulin sensitivity, and measurement noise.

An extension to the compartmental model of type 1 diabetic patients to reproduce exercise periods with glycogen depletion and replenishment

The purpose of this work is to present the main interactions promoted by exercise and synthesize them into mathematical equations. It is intended to extend the ability of the compartmental glucose–insulin model introduced by Sorensen [1985. A physiologic model of glucose metabolism in man and its use to design and assess improved insulin therapies for diabetes. Ph.D. Dissertation, Chemical Engineering Department, MIT, Cambridge] to reproduce variations in the blood glucose concentration induced by exercise in diabetic patients and to complement the previous work by Lenart and Parker [2002. Modeling exercise effects in type I diabetic patients. In: Proceedings of the 15th Triennial World Congress, Barcelona, Spain] and Lenart, DiMascio and Parker [2002. Modeling glycogen–exercise interactions in type I diabetic patients. In: Proceedings of the A.I.Ch.E. Annual Meeting, Indianapolis, IN]. The immediate consequences of exercise are incorporated in this research: redistribution of blood flows, increments in peripheral glucose and insulin uptakes, and increment in hepatic glucose production. The extended model was verified with experimental data for light and moderate intensity exercise. In addition, data extrapolation was introduced to simulate heavy intensity exercise. The hepatic glycogen reservoir limits the peripheral glucose uptake for prolonged exercise. Therefore, the depletion and replenishment of hepatic glycogen were modeled, looking to reproduce the blood glucose levels for a type 1 diabetic patient during a normal day, with meal intakes, insulin infusions and/or boluses, and a predefined exercise regime. From the extensive simulation evaluation, it is found that the new exercise model provides a good approximation to the available experimental data from literature.

A feedforward–feedback glucose control strategy for type 1 diabetes mellitus

As the “artificial pancreas” becomes closer to reality, automated insulin delivery based on real-time glucose measurements becomes feasible for people with diabetes. This paper is concerned with the development of novel feedforward–feedback control strategies for real-time glucose control and type 1 diabetes. Improved post-meal responses can be achieved by a pre-prandial snack or bolus, or by reducing the glucose setpoint prior to the meal. Several feedforward–feedback control strategies provide attractive alternatives to the standard meal insulin bolus and are evaluated in simulations using a physiological model.

Plasmodium vivax: Impaired escape of Vk210 phenotype ookinetes from the midgut blood bolus of Anopheles pseudopunctipennis

The site in the midguts of Anopheles pseudopunctipennis where the development of Plasmodium vivax circumsporozoite protein Vk210 phenotype is blocked was investigated, and compared to its development in An. albimanus. Ookinete development was similar in time and numbers within the blood meal bolus of both mosquito species. But, compared to An. pseudopunctipennis, a higher proportion of An. albimanus were infected ( P = 0.0001) with higher ookinete ( P = 0.0001) and oocyst numbers ( P = 0.0001) on their internal and external midgut surfaces, respectively. Ookinetes were located in the peritrophic matrix (PM), but neither inside epithelial cells nor on the haemocoelic midgut surface by transmission electron microscopy in 24 h p.i.– An. pseudopunctipennis mosquito samples. In contrast, no parasites were detected in the PM of An. albimanus at this time point. These results suggest that P. vivax Vk210 ookinetes cannot escape from and are destroyed within the midgut lumen of An. pseudopunctipennis.

The Use of Insulin Pumps With Meal Bolus Alarms in Children With Type 1 Diabetes to Improve Glycemic Control

OBJECTIVE—The aim of this study was to determine whether the use of meal bolus alarms would result in fewer missed meal boluses per week in youth with type 1 diabetes using continuous subcutaneous insulin infusion (CSII) therapy. RESEARCH DESIGN AND METHODS—This was a randomized trial of 48 youth using CSII, who were in suboptimal glycemic control with HbA1c (A1C) values ≥8.0%. Twenty-four subjects were randomized to use a Deltec Cozmo insulin pump with meal bolus alarms (experimental group), while the other 24 subjects continued use of their current insulin pumps (control group) without meal bolus alarms. RESULTS—After 3 months of study, the number of missed meal boluses per week was significantly lower in the experimental group (from 4.9 ± 3.7 to 2.5 ± 2.5; P = 0.0005) but not significantly lower in the control group (from 4.3 ± 2.7 to 4.2 ± 3.9; P = 0.7610). Also after 3 months, the mean A1C value of the experimental group declined significantly (from 9.32 ± 1.12 to 8.86 ± 1.10; P = 0.0430). No significant decline in A1C was present for the control group (from 8.93 ± 1.04 to 8.67 ± 1.17; P = 0.1940). After 6 months of study, the significant decline in A1C from baseline in the experimental group was no longer present. Pooling of all available data from the control and experimental groups showed that at baseline and 3 and 6 months, the number of missed meal boluses per week was significantly correlated with A1C values. CONCLUSIONS—While meal bolus alarms may have the potential to improve suboptimal glycemic control in youth using CSII, our results demonstrated that these alarms had only a transient, modest effect in doing so.