OBJECTIVE -The most promising ␤-cell replacement therapy for children with type 1 diabetes is a closed-loop artificial pancreas incorporating continuous glucose sensors and insulin pumps. The Medtronic MiniMed external physiological insulin delivery (ePID) system combines an external pump and sensor with a variable insulin infusion rate algorithm designed to emulate the physiological characteristics of the ␤-cell. However, delays in insulin absorption associated with the subcutaneous route of delivery inevitably lead to large postprandial glucose excursions.RESEARCH DESIGN AND METHODS -We studied the feasibility of the Medtronic ePID system in youth with type 1 diabetes and hypothesized that small manual premeal "priming" boluses would reduce postprandial excursions during closed-loop control. Seventeen adolescents (aged 15.9 Ϯ 1.6 years; A1C 7.1 Ϯ 0.8%) underwent 34 h of closed-loop control; 8 with full closed-loop (FCL) control and 9 with hybrid closed-loop (HCL) control (premeal priming bolus).RESULTS -Mean glucose levels were 135 Ϯ 45 mg/dl in the HCL group versus 141 Ϯ 55 mg/dl in the FCL group (P ϭ 0.09); daytime glucose levels averaged 149 Ϯ 47 mg/dl in the HCL group versus 159 Ϯ 59 mg/dl in the FCL group (P ϭ 0.03). Peak postprandial glucose levels averaged 194 Ϯ 47 mg/dl in the HCL group versus 226 Ϯ 51 mg/dl in the FCL group (P ϭ 0.04). Nighttime control was similar in both groups (111 Ϯ 27 vs. 112 Ϯ 28 mg/dl).CONCLUSIONS -Closed-loop glucose control using an external sensor and insulin pump provides a means to achieve near-normal glucose concentrations in youth with type 1 diabetes during the overnight period. The addition of small manual priming bolus doses of insulin, given 15 min before meals, improves postprandial glycemic excursions. Diabetes Care 31:934-939, 2008

O ptimal treatment of type 1 diabetes should achieve normoglycemia at all times, without risk of hypoglycemia. Such a treatment should dramatically reduce or prevent diabetes complications and significantly improve patients' quality of life. This goal may be accomplished through pancreatic or islet cell transplantation, but availability of these tissues is limited, survival and function are unpredictable, and longterm immunosuppressive therapy is required (1). The potential for an automated closed-loop system, or artificial ␤-cell, to achieve round-the-clock glycemic control, has not been fully explored.An artificial ␤-cell requires a glucose sensor, an insulindelivery pump, and an algorithm for calculating insulin delivery. Technological and scientific advances have made sensors and pumps available, but linking the two as a "closed loop" has been challenging (2). Lingering questions remain regarding the suitability of different glucosesensing sites (subcutaneous versus intravascular), insulindelivery sites (subcutaneous versus intravascular versus intraperitoneal), and sensor reliability. In addition, no one algorithm has been universally accepted as optimal for insulin delivery (3).Herein, we describe the feasibility of achieving glycemic control in patients with type 1 diabetes using a system comprised of a subcutaneous glucose sensor, an external insulin pump, and an algorithm emulating the ␤-cell's multiphasic glucose-induced insulin release (4 -6). ). Subjects had been treated with continuous subcutaneous insulin infusion (CSII) using Lispro insulin (Lilly, Indianapolis, IN) for at least 6 months before study enrollment and were required to have an HbA 1c Ͻ9%. Data from a previously published study (7) characterizing insulin secretion over a 24-h period in nondiabetic subjects are included for comparison of the glucose profiles (n ϭ 17) obtained with a similar diet. The study was approved by the University of California, Los Angeles Institutional Review Board, and all patients gave written informed consent. RESEARCH DESIGN AND METHODSGlycemic control under CSII therapy was characterized over a 3-day outpatient period using a continuous glucose monitoring system (CGMS) (Medtronic MiniMed, Northridge, CA). The CGMS records sensor current every 5 min and glucose profiles are obtained retrospectively (8). Patients were instructed to keep their daily routine but to take a minimum of seven fingerstick blood glucose readings per day (preprandial and 2-h postprandial and at bedtime) with their home glucose meters. Patients were also instructed to record meal carbohydrate content, physical activity, and any hypoglycemic episodes or supplemental carbohydrate in a logbook.To evaluate the closed-loop insulin delivery system, patients were admitted to the general clinical research center at ϳ5:00 P.M., and their insulin pump was replaced with a Medtronic 511 Paradigm Pump capable of communicating telemetrically with a laptop computer. Two subcutaneous glucose sensors were inserted in the abdominal area and connected to...

BACKGROUNDContinuous glucose monitoring highlights the complexity of postprandial glucose patterns present in type 1 diabetes and points to the limitations of current approaches to mealtime insulin dosing based primarily on carbohydrate counting. METHODSA systematic review of all relevant biomedical databases, including MEDLINE, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials, was conducted to identify research on the effects of dietary fat, protein, and glycemic index (GI) on acute postprandial glucose control in type 1 diabetes and prandial insulin dosing strategies for these dietary factors. RESULTSAll studies examining the effect of fat (n = 7), protein (n = 7), and GI (n = 7) indicated that these dietary factors modify postprandial glycemia. Late postprandial hyperglycemia was the predominant effect of dietary fat; however, in some studies, glucose concentrations were reduced in the first 2-3 h, possibly due to delayed gastric emptying. Ten studies examining insulin bolus dose and delivery patterns required for high-fat and/or high-protein meals were identified. Because of methodological differences and limitations in experimental design, study findings were inconsistent regarding optimal bolus delivery pattern; however, the studies indicated that high-fat/protein meals require more insulin than lower-fat/protein meals with identical carbohydrate content. CONCLUSIONSThese studies have important implications for clinical practice and patient education and point to the need for research focused on the development of new insulin dosing algorithms based on meal composition rather than on carbohydrate content alone.

The present study investigated the relationship between blood and subcutaneous interstitial fluid (ISF) glucose by employing an amperometric glucose sensor specifically developed for 3-day continuous glucose monitoring. The apparent sensor sensitivity and ISF glucose equilibration delay were estimated on separate days during hyperglycemic clamps in four dogs in which insulin was either suppressed with somatostatin, allowed to change, or increased with an exogenous infusion. A 2-h sensor “settling-in” period was allowed before the clamps. During insulin deficiency, the sensor sensitivity and ISF glucose delay were 0.23 ± 0.03 nA per mg/dl and 4.4 ± 0.8 min. Sensitivity was not affected by increases in endogenous (0.30 ± 0.04 vs. 0.28 ± 0.04 nA per mg/dl) or exogenous insulin (0.18 ± 0.01 vs. 0.16 ± 0.01 nA per mg/dl) nor was the delay (3.3 ± 1.2 vs. 5.7 ± 1.1 and 9.2 ± 2.6 vs. 12.3 ± 1.7 min; P > 0.05 for all). Sensor glucose accurately predicted plasma glucose without correcting for delays <10 min ( r > 0.9 for all), whereas for longer delays a digital corrective filter was used ( r = 0.91 with filter). We conclude that the relationship between blood and ISF glucose is not affected by insulin and that delays in ISF glucose equilibration can be corrected with digital filters.

BACKGROUND In some studies, tight glycemic control with insulin improved outcomes in adults undergoing cardiac surgery, but these benefits are unproven in critically ill children at risk for hyperinsulinemic hypoglycemia. We tested the hypothesis that tight glycemic control reduces morbidity after pediatric cardiac surgery. METHODS In this two-center, prospective, randomized trial, we enrolled 980 children, 0 to 36 months of age, undergoing surgery with cardiopulmonary bypass. Patients were randomly assigned to either tight glycemic control (with the use of an insulin-dosing algorithm targeting a blood glucose level of 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) or standard care in the cardiac intensive care unit (ICU). Continuous glucose monitoring was used to guide the frequency of blood glucose measurement and to detect impending hypoglycemia. The primary outcome was the rate of health care–associated infections in the cardiac ICU. Secondary outcomes included mortality, length of stay, organ failure, and hypoglycemia. RESULTS A total of 444 of the 490 children assigned to tight glycemic control (91%) received insulin versus 9 of 490 children assigned to standard care (2%). Although normoglycemia was achieved earlier with tight glycemic control than with standard care (6 hours vs. 16 hours, P<0.001) and was maintained for a greater proportion of the critical illness period (50% vs. 33%, P<0.001), tight glycemic control was not associated with a significantly decreased rate of health care–associated infections (8.6 vs. 9.9 per 1000 patient-days, P = 0.67). Secondary outcomes did not differ significantly between groups, and tight glycemic control did not benefit high-risk subgroups. Only 3% of the patients assigned to tight glycemic control had severe hypoglycemia (blood glucose <40 mg per deciliter [2.2 mmol per liter]). CONCLUSIONS Tight glycemic control can be achieved with a low hypoglycemia rate after cardiac surgery in children, but it does not significantly change the infection rate, mortality, length of stay, or measures of organ failure, as compared with standard care. (Funded by the National Heart, Lung, and Blood Institute and others; SPECS ClinicalTrials.gov number, NCT00443599.)