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1.  Accuracy of a New Patch Pump Based on a Microelectromechanical System (MEMS) Compared to Other Commercially Available Insulin Pumps 
The JewelPUMP™ (JP) is a new patch pump based on a microelectromechanical system that operates without any plunger. The study aimed to evaluate the infusion accuracy of the JP in vitro and in vivo. For the in vitro studies, commercially available pumps meeting the ISO standard were compared to the JP: the MiniMed® Paradigm® 712 (MP), Accu-Chek® Combo (AC), OmniPod® (OP), Animas® Vibe™ (AN). Pump accuracy was measured over 24 hours using a continuous microweighing method, at 0.1 and 1 IU/h basal rates. The occlusion alarm threshold was measured after a catheter occlusion. The JP, filled with physiological serum, was then tested in 13 patients with type 1 diabetes simultaneously with their own pump for 2 days. The weight difference was used to calculate the infused insulin volume. The JP showed reduced absolute median error rate in vitro over a 15-minute observation window compared to other pumps (1 IU/h): ±1.02% (JP) vs ±1.60% (AN), ±1.66% (AC), ±2.22% (MP), and ±4.63% (OP), P < .0001. But there was no difference over 24 hours. At 0.5 IU/h, the JP was able to detect an occlusion earlier than other pumps: 21 (19; 25) minutes vs 90 (85; 95), 58 (42; 74), and 143 (132; 218) minutes (AN, AC, MP), P < .05 vs AN and MP. In patients, the 24-hour flow error was not significantly different between the JP and usual pumps (–2.2 ± 5.6% vs –0.37 ± 4.0%, P = .25). The JP was found to be easier to wear than conventional pumps. The JP is more precise over a short time period, more sensitive to catheter occlusion, well accepted by patients, and consequently, of potential interest for a closed-loop insulin delivery system.
PMCID: PMC4455475  PMID: 25079676
catheter occlusion; continuous subcutaneous insulin infusion (CSII); insulin delivery accuracy; insulin pump; insulin therapy; microelectromechanical system (MEMS); patch pump; type 1 diabetes
2.  Multicenter Closed-Loop/Hybrid Meal Bolus Insulin Delivery with Type 1 Diabetes 
Diabetes Technology & Therapeutics  2014;16(10):623-632.
Background: This study evaluated meal bolus insulin delivery strategies and associated postprandial glucose control while using an artificial pancreas (AP) system.
Subjects and Methods: This study was a multicenter trial in 53 patients, 12–65 years of age, with type 1 diabetes for at least 1 year and use of continuous subcutaneous insulin infusion for at least 6 months. Four different insulin bolus strategies were assessed: standard bolus delivered with meal (n=51), standard bolus delivered 15 min prior to meal (n=40), over-bolus of 30% delivered with meal (n=40), and bolus purposely omitted (n=46). Meal carbohydrate (CHO) intake was 1 g of CHO/kg of body weight up to a maximum of 100 g for the first three strategies or up to a maximum of 50 g for strategy 4.
Results: Only three of 177 meals (two with over-bolus and one with standard bolus 15 min prior to meal) had postprandial blood glucose values of <60 mg/dL. Postprandial hyperglycemia (blood glucose level >180 mg/dL) was prolonged for all four bolus strategies but was shorter for the over-bolus (41% of the 4-h period) than the two standard bolus strategies (73% for each). Mean postprandial blood glucose level was 15.9 mg/dL higher for the standard bolus with meal compared with the prebolus (baseline-adjusted, P=0.07 for treatment effect over the 4-h period).
Conclusions: The AP handled the four bolus situations safely, but at the expense of having elevated postprandial glucose levels in most subjects. This was most likely secondary to suboptimal performance of the algorithm.
PMCID: PMC4183919  PMID: 25188375
3.  Safety of Outpatient Closed-Loop Control: First Randomized Crossover Trials of a Wearable Artificial Pancreas 
Diabetes Care  2014;37(7):1789-1796.
We estimate the effect size of hypoglycemia risk reduction on closed-loop control (CLC) versus open-loop (OL) sensor-augmented insulin pump therapy in supervised outpatient setting.
Twenty patients with type 1 diabetes initiated the study at the Universities of Virginia, Padova, and Montpellier and Sansum Diabetes Research Institute; 18 completed the entire protocol. Each patient participated in two 40-h outpatient sessions, CLC versus OL, in randomized order. Sensor (Dexcom G4) and insulin pump (Tandem t:slim) were connected to Diabetes Assistant (DiAs)—a smartphone artificial pancreas platform. The patient operated the system through the DiAs user interface during both CLC and OL; study personnel supervised on site and monitored DiAs remotely. There were no dietary restrictions; 45-min walks in town and restaurant dinners were included in both CLC and OL; alcohol was permitted.
The primary outcome—reduction in risk for hypoglycemia as measured by the low blood glucose (BG) index (LGBI)—resulted in an effect size of 0.64, P = 0.003, with a twofold reduction of hypoglycemia requiring carbohydrate treatment: 1.2 vs. 2.4 episodes/session on CLC versus OL (P = 0.02). This was accompanied by a slight decrease in percentage of time in the target range of 3.9–10 mmol/L (66.1 vs. 70.7%) and increase in mean BG (8.9 vs. 8.4 mmol/L; P = 0.04) on CLC versus OL.
CLC running on a smartphone (DiAs) in outpatient conditions reduced hypoglycemia and hypoglycemia treatments when compared with sensor-augmented pump therapy. This was accompanied by marginal increase in average glycemia resulting from a possible overemphasis on hypoglycemia safety.
PMCID: PMC4067397  PMID: 24929429
4.  Assessment of Patient Perceptions About Web Telemonitoring Applied to Artificial Pancreas Use at Home 
Patients with chronic diseases as well as health care systems could benefit from telemedicine applications such as remote monitoring (RM). RM relies on a device that sends patients’ health data to a remote server accessible by care teams. Recent smartphone-based artificial pancreas (AP) systems collect comprehensive set of information and could therefore support the development of RM applied to diabetes. To better understand how RM could be integrated in future AP systems, we wanted to get patients’ opinion on this concept, as they are the final users of these systems. An online questionnaire with 11 items was sent to 20 experienced patients who tested AP and RM during our recent outpatient studies in France and Italy. We received 17 answers. All patients considered that during their participation in trials, RM was useful, reassuring, and essential. One-third wouldn’t have participated without it. When AP is commercialized, 88% of respondents think that AP should go with a RM tool, but it should be activated only at certain times, at first use or in case of difficulties (82%). Participants ask for technical support when a device fails (88%) and for medical help in case of prolonged hyperglycemia (65%) or severe or repeated hypoglycemia (53%), but not after each case of hypoglycemia (6%). More than 75% think that RM could help them to improve their blood glucose control. This preliminary work indicates that patients expect RM to be part of future AP development. Larger studies remain to be performed to investigate its usefulness and potential economic effectiveness.
PMCID: PMC4455392  PMID: 24876571
artificial pancreas; remote monitoring; telemedicine; type 1 diabetes; questionnaire
5.  Day and Night Closed-Loop Control in Adults With Type 1 Diabetes 
Diabetes Care  2013;36(12):3882-3887.
To compare two validated closed-loop (CL) algorithms versus patient self-control with CSII in terms of glycemic control.
This study was a multicenter, randomized, three-way crossover, open-label trial in 48 patients with type 1 diabetes mellitus for at least 6 months, treated with continuous subcutaneous insulin infusion. Blood glucose was controlled for 23 h by the algorithm of the Universities of Pavia and Padova with a Safety Supervision Module developed at the Universities of Virginia and California at Santa Barbara (international artificial pancreas [iAP]), by the algorithm of University of Cambridge (CAM), or by patients themselves in open loop (OL) during three hospital admissions including meals and exercise. The main analysis was on an intention-to-treat basis. Main outcome measures included time spent in target (glucose levels between 3.9 and 8.0 mmol/L or between 3.9 and 10.0 mmol/L after meals).
Time spent in the target range was similar in CL and OL: 62.6% for OL, 59.2% for iAP, and 58.3% for CAM. While mean glucose level was significantly lower in OL (7.19, 8.15, and 8.26 mmol/L, respectively) (overall P = 0.001), percentage of time spent in hypoglycemia (<3.9 mmol/L) was almost threefold reduced during CL (6.4%, 2.1%, and 2.0%) (overall P = 0.001) with less time ≤2.8 mmol/L (overall P = 0.038). There were no significant differences in outcomes between algorithms.
Both CAM and iAP algorithms provide safe glycemic control.
PMCID: PMC3836152  PMID: 24170747
6.  Artifcial Pancreas Goes Outpatient: A New Diabetes Ecosystem 
PMCID: PMC3876319  PMID: 24351167
artificial pancreas; closed-loop insulin delivery; continuous glucose monitoring; control algorithm; insulin pump
7.  DiAs Web Monitoring: A Real-Time Remote Monitoring System Designed for Artificial Pancreas Outpatient Trials 
Developments in an artificial pancreas (AP) for patients with type 1 diabetes have allowed a move toward performing outpatient clinical trials. “Home-like” environment implies specific protocol and system adaptations among which the introduction of remote monitoring is meaningful. We present a novel tool allowing multiple patients to monitor AP use in home-like settings.
We investigated existing systems, performed interviews of experienced clinical teams, listed required features, and drew several mockups of the user interface. The resulting application was tested on the bench before it was used in three outpatient studies representing 3480 h of remote monitoring.
Our tool, called DiAs Web Monitoring (DWM), is a web-based application that ensures reception, storage, and display of data sent by AP systems. Continuous glucose monitoring (CGM) and insulin delivery data are presented in a colored chart to facilitate reading and interpretation. Several subjects can be monitored simultaneously on the same screen, and alerts are triggered to help detect events such as hypoglycemia or CGM failures. In the third trial, DWM received approximately 460 data per subject per hour: 77% for log messages, 5% for CGM data. More than 97% of transmissions were achieved in less than 5 min.
Transition from a hospital setting to home-like conditions requires specific AP supervision to which remote monitoring systems can contribute valuably. DiAs Web Monitoring worked properly when tested in our outpatient studies. It could facilitate subject monitoring and even accelerate medical and technical assessment of the AP. It should now be adapted for long-term studies with an enhanced notification feature.
J Diabetes Sci Technol 2013;7(6):1427–1435
PMCID: PMC3876321  PMID: 24351169
artificial pancreas; remote monitoring; telemedicine; type 1 diabetes
8.  Accuracy and Reliability of Continuous Glucose Monitoring Systems: A Head-to-Head Comparison 
This study assessed the accuracy and reliability of three continuous glucose monitoring (CGM) systems.
Research Design and Methods
We studied the Animas® (West Chester, PA) Vibe™ with Dexcom® (San Diego, CA) G4™ version A sensor (G4A), the Abbott Diabetes Care (Alameda, CA) Freestyle® Navigator I (NAV), and the Medtronic (Northridge, CA) Paradigm® with Enlite™ sensor (ENL) in 20 patients with type 1 diabetes mellitus. All systems were investigated both in a clinical research center (CRC) and at home. In the CRC, patients received a meal with a delayed and increased insulin dose to induce a postprandial glucose peak and nadir. Hereafter, randomization determined which two of the three systems would be worn at home until the end of functioning, attempting use beyond manufacturer-specified lifetime. Patients performed at least five reference finger sticks per day. An analysis of variance was performed on all data points ≥15 min apart.
Overall average mean absolute relative difference (MARD) (SD) measured at the CRC was 16.5% (14.3%) for NAV and 16.4% (15.6%) for ENL, outperforming G4A at 20.5% (18.2%) (P<0.001). Overall MARD when assessed at home was 14.5% (16.7%) for NAV and 16.5 (18.8%) for G4A, outperforming ENL at 18.9% (23.6%) (P=0.006). Median time until end of functioning was similar: 10.0 (1.0) days for G4A, 8.0 (3.5) days for NAV, and 8.0 (1.5) days for ENL (P=0.119).
In the CRC, G4A was less accurate than NAV and ENL sensors, which seemed comparable. However, at home, ENL was less accurate than NAV and G4A. Moreover, CGM systems often show sufficient accuracy to be used beyond manufacturer-specified lifetime.
PMCID: PMC3746288  PMID: 23650900
9.  Feasibility of Outpatient Fully Integrated Closed-Loop Control 
Diabetes Care  2013;36(7):1851-1858.
To evaluate the feasibility of a wearable artificial pancreas system, the Diabetes Assistant (DiAs), which uses a smart phone as a closed-loop control platform.
Twenty patients with type 1 diabetes were enrolled at the Universities of Padova, Montpellier, and Virginia and at Sansum Diabetes Research Institute. Each trial continued for 42 h. The United States studies were conducted entirely in outpatient setting (e.g., hotel or guest house); studies in Italy and France were hybrid hospital–hotel admissions. A continuous glucose monitoring/pump system (Dexcom Seven Plus/Omnipod) was placed on the subject and was connected to DiAs. The patient operated the system via the DiAs user interface in open-loop mode (first 14 h of study), switching to closed-loop for the remaining 28 h. Study personnel monitored remotely via 3G or WiFi connection to DiAs and were available on site for assistance.
The total duration of proper system communication functioning was 807.5 h (274 h in open-loop and 533.5 h in closed-loop), which represented 97.7% of the total possible time from admission to discharge. This exceeded the predetermined primary end point of 80% system functionality.
This study demonstrated that a contemporary smart phone is capable of running outpatient closed-loop control and introduced a prototype system (DiAs) for further investigation. Following this proof of concept, future steps should include equipping insulin pumps and sensors with wireless capabilities, as well as studies focusing on control efficacy and patient-oriented clinical outcomes.
PMCID: PMC3687268  PMID: 23801798
10.  Patch Pump Versus Conventional Pump: Postprandial Glycemic Excursions and the Influence of Wear Time 
Background and Aims
The aim of this study was to compare blood glucose and plasma insulin profiles after bolus insulin infusion by a patch pump (PP) versus a conventional pump (CP), directly after placement and after Day 3 of use.
Patients and Methods
Twenty patients with type 1 diabetes came in for two blocks of visits: one block of two visits while wearing the OmniPod® (Insulet Corp., Bedford, MA) insulin pump (PP) and one block of two visits while wearing the Medtronic Diabetes (Northridge, CA) Paradigm® pump (CP). Patients administered an identical mealtime insulin bolus of at least 6 IU.
For PP, maximum glucose levels were 28.7% lower on Day 3 (P=0.020), when maximum insulin levels were 30.3% higher (P=0.002). For CP, maximum glucose levels were 26.5% lower on Day 3 (P=0.015), when maximum insulin levels were 46.4% higher (P=0.003). Glucose levels (mean [interquartile range]) were significantly lower on Day 3 for PP (168.2 [145.8] mg/dL vs. 139.4 [77.8] mg/dL; P=0.013), but not significantly so for CP (159.0 [66.1] mg/dL vs. 139.5 [57.9] mg/dL; P=0.084). Mean insulin levels were significantly higher on Day 3 for CP (195 [120] pmol/L vs. 230 [90] pmol/L; P=0.01), but not significantly so for PP (178 [106] pmol/L vs. 194 [120] pmol/L; P=0.099). There were no significant differences between the two catheter lengths.
Postprandial glycemic excursions were lower on Day 3 of catheter wear time, but there were no differences between PPs and CPs. These findings support the proposal that catheter wear time plays an important role in insulin absorption.
PMCID: PMC3709595  PMID: 23650901
12.  Fully Integrated Artificial Pancreas in Type 1 Diabetes 
Diabetes  2012;61(9):2230-2237.
Integrated closed-loop control (CLC), combining continuous glucose monitoring (CGM) with insulin pump (continuous subcutaneous insulin infusion [CSII]), known as artificial pancreas, can help optimize glycemic control in diabetes. We present a fundamental modular concept for CLC design, illustrated by clinical studies involving 11 adolescents and 27 adults at the Universities of Virginia, Padova, and Montpellier. We tested two modular CLC constructs: standard control to range (sCTR), designed to augment pump plus CGM by preventing extreme glucose excursions; and enhanced control to range (eCTR), designed to truly optimize control within near normoglycemia of 3.9–10 mmol/L. The CLC system was fully integrated using automated data transfer CGM→algorithm→CSII. All studies used randomized crossover design comparing CSII versus CLC during identical 22-h hospitalizations including meals, overnight rest, and 30-min exercise. sCTR increased significantly the time in near normoglycemia from 61 to 74%, simultaneously reducing hypoglycemia 2.7-fold. eCTR improved mean blood glucose from 7.73 to 6.68 mmol/L without increasing hypoglycemia, achieved 97% in near normoglycemia and 77% in tight glycemic control, and reduced variability overnight. In conclusion, sCTR and eCTR represent sequential steps toward automated CLC, preventing extremes (sCTR) and further optimizing control (eCTR). This approach inspires compelling new concepts: modular assembly, sequential deployment, testing, and clinical acceptance of custom-built CLC systems tailored to individual patient needs.
PMCID: PMC3425406  PMID: 22688340
13.  Assessment of Patient-Led or Physician-Driven Continuous Glucose Monitoring in Patients With Poorly Controlled Type 1 Diabetes Using Basal-Bolus Insulin Regimens 
Diabetes Care  2012;35(5):965-971.
The benefits of real-time continuous glucose monitoring (CGM) have been demonstrated in patients with type 1 diabetes. Our aim was to compare the effect of two modes of use of CGM, patient led or physician driven, for 1 year in subjects with poorly controlled type 1 diabetes.
Patients with type 1 diabetes aged 8–60 years with HbA1c ≥8% were randomly assigned to three groups (1:1:1). Outcomes for glucose control were assessed at 1 year for two modes of CGM (group 1: patient led; group 2: physician driven) versus conventional self-monitoring of blood glucose (group 3: control).
A total of 257 subjects with type 1 diabetes underwent screening. Of these, 197 were randomized, with 178 patients completing the study (age: 36 ± 14 years; HbA1c: 8.9 ± 0.9%). HbA1c improved similarly in both CGM groups and was reduced compared with the control group (group 1 vs. group 3: −0.52%, P = 0.0006; group 2 vs. group 3: −0.47%, P = 0.0008; groups 1 + 2 vs. group 3: −0.50%, P < 0.0001). The incidence of hypoglycemia was similar in the three groups. Patient SF-36 questionnaire physical health score improved in both experimental CGM groups (P = 0.004). Sensor consumption was 34% lower in group 2 than in group 1 (median [Q1–Q3] consumption: group 1: 3.42/month [2.20–3.91] vs. group 2: 2.25/month [1.27–2.99], P = 0.001).
Both patient-led and physician-driven CGM provide similar long-term improvement in glucose control in patients with poorly controlled type 1 diabetes, but the physician-driven CGM mode used fewer sensors.
PMCID: PMC3329830  PMID: 22456864
14.  Clinical Requirements for Closed-Loop Control Systems 
Closed-loop (CL) therapy systems should be safe, efficacious, and easily manageable for type 1 diabetes mellitus patient use. For the first two clinical requirements, noninferiority and superiority criteria must be determined based on current conventional and intensive therapy outcomes. Current frequencies of hypoglycemia and diabetic ketoacidosis are reviewed and safety expectations for CL therapy systems are proposed. Glycosylated hemoglobin levels lower than current American Diabetes Association recommendations for different age groups are proposed as superiority criteria. Measures of glycemic variability are described and the recording of blood glucose levels as percentages within, above, and below a target range are suggested as reasonable alternatives to sophisticated statistical analyses. It is also suggested that Diabetes Quality of Life and Fear of Hypoglycemia surveys should be used to track psychobehavioral outcomes.
Manageability requirements for safe and effective clinical management of CL systems are worth being underscored. The weakest part of the infusion system remains the catheter, which is exposed to variable and under-delivery incidents. Detection methods are needed to warn both the system and the patient about altered insulin delivery, including internal pressure and flow alarms. Glucose monitor sensor accuracy is another requirement; it includes the definition of conditions that lead to capillary glucose measurement, eventually followed by sensor recalibration or replacement. The crucial clinical requirement will be a thorough definition of the situations when the patient needs to move from CL to manual management of insulin delivery, or inversely can switch back to CL after a requested interruption. Instructions about these actions will constitute a major part of the education process of the patients before using CL systems and contribute to the manageability of these systems.
PMCID: PMC3380791  PMID: 22538159
closed-loop control; diabetic ketoacidosis; diabetes quality of life; efficacy; fear of hypoglycemia; glucose monitoring; glycemic variability; glycosylated hemoglobin; hypoglycemia; insulin delivery; management of insulin infusion; noninferiority; safety; superiority
15.  Artificial Pancreas: Past, Present, Future 
Diabetes  2011;60(11):2672-2682.
PMCID: PMC3198099  PMID: 22025773
16.  Multinational Study of Subcutaneous Model-Predictive Closed-Loop Control in Type 1 Diabetes Mellitus: Summary of the Results 
In 2008–2009, the first multinational study was completed comparing closed-loop control (artificial pancreas) to state-of-the-art open-loop therapy in adults with type 1 diabetes mellitus (T1DM).
The design of the control algorithm was done entirely in silico, i.e., using computer simulation experiments with N = 300 synthetic “subjects” with T1DM instead of traditional animal trials. The clinical experiments recruited 20 adults with T1DM at the Universities of Virginia (11); Padova, Italy (6); and Montpellier, France (3). Open-loop and closed-loop admission was scheduled 3–4 weeks apart, continued for 22 h (14.5 h of which were in closed loop), and used a continuous glucose monitor and an insulin pump. The only difference between the two sessions was that insulin dosing was performed by the patient under a physician’s supervision during open loop, whereas insulin dosing was performed by a control algorithm during closed loop.
In silico design resulted in rapid (less than 6 months compared to years of animal trials) and cost-effective system development, testing, and regulatory approvals in the United States, Italy, and France. In the clinic, compared to open-loop, closed-loop control reduced nocturnal hypoglycemia (blood glucose below 3.9 mmol/liter) from 23 to 5 episodes (p < .01) and increased the amount of time spent overnight within the target range (3.9 to 7.8 mmol/liter) from 64% to 78% (p = .03).
In silico experiments can be used as viable alternatives to animal trials for the preclinical testing of insulin treatment strategies. Compared to open-loop treatment under identical conditions, closed-loop control improves the overnight regulation of diabetes.
PMCID: PMC3005047  PMID: 21129332
closed-loop control; continuous glucose monitoring; type 1 diabetes mellitus
17.  Systems medicine and integrated care to combat chronic noncommunicable diseases 
Genome Medicine  2011;3(7):43.
We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
PMCID: PMC3221551  PMID: 21745417
18.  Closed-Loop Insulin Delivery Using a Subcutaneous Glucose Sensor and Intraperitoneal Insulin Delivery 
Diabetes Care  2009;33(1):121-127.
Attempts to build an artificial pancreas by using subcutaneous insulin delivery from a portable pump guided by an subcutaneous glucose sensor have encountered delays and variability of insulin absorption. We tested closed-loop intraperitoneal insulin infusion from an implanted pump driven by an subcutaneous glucose sensor via a proportional-integral-derivative (PID) algorithm.
Two-day closed-loop therapy (except for a 15-min premeal manual bolus) was compared with a 1-day control phase with intraperitoneal open-loop insulin delivery, according to randomized order, in a hospital setting in eight type 1 diabetic patients treated by implanted pumps. The percentage of time spent with blood glucose in the 4.4–6.6 mmol/l range was the primary end point.
During the closed-loop phases, the mean ± SEM percentage of time spent with blood glucose in the 4.4–6.6 mmol/l range was significantly higher (39.1 ± 4.5 vs. 27.7 ± 6.2%, P = 0.05), and overall dispersion of blood glucose values was reduced among patients. Better closed-loop glucose control came from the time periods excluding the two early postprandial hours with a higher percentage of time in the 4.4–6.6 mmol/l range (46.3 ± 5.3 vs. 28.6 ± 7.4, P = 0.025) and lower mean blood glucose levels (6.9 ± 0.3 vs. 7.9 ± 0.6 mmol/l, P = 0.036). Time spent with blood glucose <3.3 mmol/l was low and similar for both investigational phases.
Our results demonstrate the feasibility of intraperitoneal insulin delivery for an artificial β-cell and support the need for further study. Moreover, according to a semiautomated mode, the features of the premeal bolus in terms of timing and amount warrant further research.
PMCID: PMC2797956  PMID: 19846796
19.  Incremental Value of Continuous Glucose Monitoring When Starting Pump Therapy in Patients With Poorly Controlled Type 1 Diabetes 
Diabetes Care  2009;32(12):2245-2250.
To compare the improvements in glycemic control associated with transitioning to insulin pump therapy in patients using continuous glucose monitoring versus standard blood glucose self-monitoring.
The RealTrend study was a 6-month, randomized, parallel-group, two-arm, open-label study of 132 adults and children with uncontrolled type 1 diabetes (A1C ≥8%) being treated with multiple daily injections. One group was fitted with the Medtronic MiniMed Paradigm REAL-Time system (PRT group), an insulin pump with integrated continuous subcutaneous glucose monitoring (CGM) capability, with instructions to wear CGM sensors at least 70% of the time. Conventional insulin pump therapy was initiated in the other group (continuous subcutaneous insulin infusion [CSII] group). Outcome measures included A1C and glycemic variability.
A total of 115 patients completed the study. Between baseline and trial end, A1C improved significantly in both groups (PRT group −0.81 ± 1.09%, P < 0.001; CSII group −0.57 ± 0.94%, P < 0.001), with no significant difference between groups. When the 91 patients who were fully protocol-compliant (including CGM sensor wear ≥70% of the time) were considered, A1C improvement was significantly greater in the PRT group (P = 0.004) (PRT group −0.96 ± 0.93%, P < 0.001; CSII group −0.55 ± 0.93%, P < 0.001). Hyperglycemia parameters decreased in line with improvements in A1C with no impact on hypoglycemia.
CGM-enabled insulin pump therapy improves glycemia more than conventional pump therapy during the first 6 months of pump use in patients who wear CGM sensors at least 70% of the time.
PMCID: PMC2782985  PMID: 19767384
20.  Closed-Loop Artificial Pancreas Using Subcutaneous Glucose Sensing and Insulin Delivery and a Model Predictive Control Algorithm: Preliminary Studies in Padova and Montpellier 
New effort has been made to develop closed-loop glucose control, using subcutaneous (SC) glucose sensing and continuous subcutaneous insulin infusion (CSII) from a pump, and a control algorithm. An approach based on a model predictive control (MPC) algorithm has been utilized during closed-loop control in type 1 diabetes patients. Here we describe the preliminary clinical experience with this approach.
Six type 1 diabetes patients (three in each of two clinical investigation centers in Padova and Montpellier), using CSII, aged 36 ± 8 and 48 ± 6 years, duration of diabetes 12 ± 8 and 29 ± 4 years, hemoglobin A1c 7.4% ± 0.1% and 7.3% ± 0.3%, body mass index 23.2 ± 0.3 and 28.4 ± 2.2 kg/m2, respectively, were studied on two occasions during 22 h overnight hospital admissions 2–4 weeks apart. A Freestyle Navigator® continuous glucose monitor and an OmniPod® insulin pump were applied in each trial. Admission 1 used open-loop control, while admission 2 employed closed-loop control using our MPC algorithm.
In Padova, two out of three subjects showed better performance with the closed-loop system compared to open loop. Altogether, mean overnight plasma glucose (PG) levels were 134 versus 111 mg/dl during open loop versus closed loop, respectively. The percentage of time spent at PG > 140 mg/dl was 45% versus 12%, while postbreakfast mean PG was 165 versus 156 mg/dl during open loop versus closed loop, respectively. Also, in Montpellier, two patients out of three showed a better glucose control during closed-loop trials. Avoidance of nocturnal hypoglycemic excursions was a clear benefit during algorithm-guided insulin delivery in all cases.
This preliminary set of studies demonstrates that closed-loop control based entirely on SC glucose sensing and insulin delivery is feasible and can be applied to improve glucose control in patients with type 1 diabetes, although the algorithm needs to be further improved to achieve better glycemic control.
PMCID: PMC2769890  PMID: 20144414
continuous glucose monitoring; control algorithm; glucose sensor; insulin pump; modeling; simulation; type 1 diabetes
21.  CXCL5 is an adipose tissue derived factor that links obesity to insulin resistance 
Cell metabolism  2009;9(4):339-349.
We show here high levels of expression and secretion of the chemokine CXCL5 in the macrophage fraction of white adipose tissue (WAT). Moreover, we find that CXCL5 is dramatically increased in serum of human obese compared to lean subjects. Conversely, CXCL5 concentration is decreased in obese subjects after a weight reduction program, or in obese non-insulin resistant, compared to insulin resistant obese subjects. Most importantly we demonstrate that treatment with recombinant CXCL5 blocks insulin-stimulated glucose uptake in muscle in mice. CXCL5 blocks insulin signaling by activating the Jak2/STAT5/SOCS2 pathway. Finally, by treating obese, insulin resistant mice with either anti-CXCL5 neutralizing antibodies or antagonists of CXCR2, which is the CXCL5 receptor we demonstrate that CXCL5 mediates insulin resistance. Furthermore CXCR2−/− mice are protected against obesity-induced insulin resistance. Taken together, these results show that secretion of CXCL5 by WAT resident macrophages represents a link between obesity, inflammation, and insulin resistance.
PMCID: PMC2804846  PMID: 19356715
22.  Consensus Report of the Coalition for Clinical Research—Self-Monitoring of Blood Glucose 
The Coalition for Clinical Research—Self-Monitoring of Blood Glucose Scientific Board, a group of nine academic clinicians and scientists from the United States and Europe, convened in San Francisco, California, on June 11–12, 2008, to discuss the appropriate uses of self-monitoring of blood glucose (SMBG) and the measures necessary to accurately assess the potential benefit of this practice in noninsulin-treated type 2 diabetes mellitus (T2DM). Thirteen consultants from the United States, Europe, and Canada from academia, practice, and government also participated and contributed based on their fields of expertise. These experts represent a range of disciplines that include adult endocrinology, pediatric endocrinology, health education, mathematics, statistics, psychology, nutrition, exercise physiology, and nursing. This coalition was organized by Diabetes Technology Management, Inc. Among the participants, there was consensus that: protocols assessing the performance of SMBG in noninsulin treated T2DM must provide the SMBG intervention subjects with blood glucose (BG) goals and instructions on how to respond to BG data in randomized controlled trials (RCTs);intervention subjects in clinical trials of SMBG-driven interventions must aggressively titrate their therapeutic responses or lifestyle changes in response to hyperglycemia;control subjects in clinical trials of SMBG must be isolated from SMBG-driven interventions and not be contaminated by physician experience with study subjects receiving a SMBG intervention;the best endpoints to measure in a clinical trial of SMBG in T2DM include delta Hemoglobin A1c levels, hyperglycemic events, hypoglycemic events, time to titrate noninsulin therapy to a maximum necessary dosage, and quality of life indices;either individual randomization or cluster randomization may be appropriate methods for separating control subjects from SMBG intervention subjects, provided that precautions are taken to avoid bias and that the sample size is adequate;treatment algorithms for assessing SMBG in T2DM may include a dietary, exercise, and/or medication intervention, which are all titratable according to the SMBG values;the medical literature contains very little information about the performance of SMBG in T2DM from RCTs in which treatment algorithms were used for dysglycemic values; andresearch on the performance of SMBG in T2DM based on sound scientific principles and clinical practices is needed at this time.
PMCID: PMC2769823  PMID: 19885292
consensus; diabetes; glucose; self monitoring; trial; type 2 diabetes
23.  Insulin Delivery Route for the Artificial Pancreas: Subcutaneous, Intraperitoneal, or Intravenous? Pros and Cons 
Insulin delivery is a crucial component of a closed-loop system aiming at the development of an artificial pancreas. The intravenous route, which has been used in the bedside artificial pancreas model for 30 years, has clear advantages in terms of pharmacokinetics and pharmacodynamics, but cannot be used in any ambulatory system so far. Subcutaneous (SC) insulin infusion benefits from the broad expansion of insulin pump therapy that promoted the availability of constantly improving technology and fast-acting insulin analog use. However, persistent delays of insulin absorption and action, variability and shortterm stability of insulin infusion from SC-inserted catheters generate effectiveness and safety issues in view of an ambulatory, automated, glucose-controlled, artificial beta cell. Intraperitoneal insulin delivery, although still marginally used in diabetes care, may offer an interesting alternative because of its more-physiological plasma insulin profiles and sustained stability and reliability of insulin delivery.
PMCID: PMC2769765  PMID: 19885254
artificial pancreas; closed-loop control; insulin delivery
25.  Effects of oral monosodium (l)-glutamate on insulin secretion and glucose tolerance in healthy volunteers 
To investigate the effects of glutamate on insulin secretion and glucose tolerance in humans.
Monosodium (l)-glutamate (10 g) was given orally in a double-blind placebo-controlled cross-over study to 18 healthy volunteers, aged 19–28 years, with an oral (75 g) glucose load.
The 75 min insulin response (AUC(0,75 min)), up to tmax of glutamate kinetics, was significantly correlated with the AUC(0,75 min) of glutamate concentrations (r = 0.485, P = 0.049). Glucose tolerance was not affected.
Oral (l)-glutamate enhances glucose-induced insulin secretion in healthy volunteers in a concentration-dependent manner.
PMCID: PMC1874333  PMID: 12047489
clinical investigation; glucose tolerance; glutamate; insulin secretion; insulin sensitivity

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