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We have used homologous recombination to disrupt the mouse gene coding for the NaK2Cl cotransporter (NKCC2) expressed in kidney epithelial cells of the thick ascending limb and macula densa. This gene is one of several that when mutated causes Bartter's syndrome in humans, a syndrome characterized by severe polyuria and electrolyte imbalance. Homozygous NKCC2؊͞؊ pups were born in expected numbers and appeared normal. However, by day 1 they showed signs of extracellular volume depletion (hematocrit 51%; wild type 37%). They subsequently failed to thrive. By day 7, they were small and markedly dehydrated and exhibited renal insufficiency, high plasma potassium, metabolic acidosis, hydronephrosis of varying severity, and high plasma renin concentrations. None survived to weaning. Treatment of ؊͞؊ pups with indomethacin from day 1 prevented growth retardation and 10% treated for 3 weeks survived, although as adults they exhibited severe polyuria (10 ml͞day), extreme hydronephrosis, low plasma potassium, high blood pH, hypercalciuria, and proteinuria. Wild-type mice treated with furosemide, an inhibitor of NaK2Cl cotransporters, have a phenotype similar to the indomethacinrescued ؊͞؊ adults except that hydronephrosis was mild. The polyuria, hypercalciuria, and proteinuria of the ؊͞؊ adults and furosemide-treated wild-type mice were unresponsive to inhibitors of the renin angiotensin system, vasopressin, and further indomethacin. Thus absence of NKCC2 in the mouse causes polyuria that is not compensated elsewhere in the nephron. The NKCC2 mutant animals should be valuable for uncovering new pathophysiologic and therapeutic aspects of genetic disturbances in water and electrolyte recovery by the kidney.gene targeting ͉ NaK2Cl cotransporter ͉ nonsteroidal anti-inflammatory drug ͉ hydronephrosis

OBJECTIVEIntense exercise is a major challenge to the management of type 1 diabetes (T1D). Closed-loop control (CLC) systems (artificial pancreas) improve glycemic control during limited intensity and short duration of physical activity (PA). However, CLC has not been tested during extended vigorous outdoor exercise common among adolescents.RESEARCH DESIGN AND METHODSSkiing presents unique metabolic challenges: intense prolonged PA, cold, altitude, and stress/fear/excitement. In a randomized controlled trial, 32 adolescents with T1D (ages 10–16 years) participated in a 5-day ski camp (∼5 h skiing/day) at two sites: Wintergreen, VA, and Breckenridge, CO. Participants were randomized to the University of Virginia CLC system or remotely monitored sensor-augmented pump (RM-SAP). The CLC and RM-SAP groups were coarsely paired by age and hemoglobin A1c (HbA1c). All subjects were remotely monitored 24 h per day by the study physicians and clinical team.RESULTSCompared with physician-monitored open loop, percent time in range (70–180 mg/dL) improved using CLC: 71.3 vs. 64.7% (+6.6% [95% CI 1–12]; P = 0.005), with maximum effect late at night. Hypoglycemia exposure and carbohydrate treatments were improved overall (P = 0.001 and P = 0.007) and during the daytime with strong ski level effects (P = 0.0001 and P = 0.006); ski/snowboard proficiency was balanced between groups but with a very strong site effect: naive in Virginia and experienced in Colorado. There was no adverse event associated with CLC; the participants’ feedback was overwhelmingly positive.CONCLUSIONSCLC in adolescents with T1D improved glycemic control and reduced exposure to hypoglycemia during prolonged intensive winter sport activities, despite the added challenges of cold and altitude.

OBJECTIVETo evaluate the feasibility of a wearable artificial pancreas system, the Diabetes Assistant (DiAs), which uses a smart phone as a closed-loop control platform.RESEARCH DESIGN AND METHODSTwenty 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.RESULTSThe 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.CONCLUSIONSThis 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.

OBJECTIVEWe 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.RESEARCH DESIGN AND METHODSTwenty 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.RESULTSThe 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.CONCLUSIONSCLC 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.

We conclude that CLC technology has matured and is safe for prolonged use in patients' natural environment. Based on these promising results, a large randomized trial is warranted to assess long-term CLC efficacy and safety.

OBJECTIVETo determine the safety and efficacy of an automated unified safety system (USS) in providing overnight closed-loop (OCL) control in children and adolescents with type 1 diabetes attending diabetes summer camps.RESEARCH DESIGN AND METHODSThe Diabetes Assistant (DIAS) USS used the Dexcom G4 Platinum glucose sensor (Dexcom) and t:slim insulin pump (Tandem Diabetes Care). An initial inpatient study was completed for 12 participants to evaluate safety. For the main camp study, 20 participants with type 1 diabetes were randomized to either OCL or sensor-augmented therapy (control conditions) per night over the course of a 5- to 6-day diabetes camp.RESULTSSubjects completed 54 OCL nights and 52 control nights. On an intention-to-treat basis, with glucose data analyzed regardless of system status, the median percent time in range, from 70–150 mg/dL, was 62% (29, 87) for OCL nights versus 55% (25, 80) for sensor-augmented pump therapy (P = 0.233). A per-protocol analysis allowed for assessment of algorithm performance. The median percent time in range, from 70–150 mg/dL, was 73% (50, 89) for OCL nights (n = 41) versus 52% (24, 83) for control conditions (n = 39) (P = 0.037). There was less time spent in the hypoglycemic range <50, <60, and <70 mg/dL during OCL compared with the control period (P = 0.019, P = 0.009, and P = 0.023, respectively).CONCLUSIONSThe DIAS USS algorithm is effective in improving time spent in range as well as reducing nocturnal hypoglycemia during the overnight period in children and adolescents with type 1 diabetes in a diabetes camp setting.

OBJECTIVEThe Pediatric Artificial Pancreas (PedArPan) project tested a children-specific version of the modular model predictive control (MMPC) algorithm in 5-to 9-yearold children during a camp. RESEARCH DESIGN AND METHODSA total of 30 children, 5-to 9-years old, with type 1 diabetes completed an outpatient, open-label, randomized, crossover trial. Three days with an artificial pancreas (AP) were compared with three days of parent-managed sensoraugmented pump (SAP). RESULTSOvernight time-in-hypoglycemia was reduced with the AP versus SAP, median (25 th -75 th percentiles): 0.0% (0.0-2.2) vs. 2.2% (0.0-12.3) (P 5 0.002), without a significant change of time-in-target, mean: 56.0% (SD 22.5) vs. 59.7% (21.2) (P 5 0.430), but with increased mean glucose 173 mg/dL (36) vs. 150 mg/dL (39) (P 5 0.002). Overall, the AP granted a threefold reduction of time-in-hypoglycemia (P < 0.001) at the cost of decreased time-in-target, 56.8% (13.5) vs. 63.1% (11.0) (P 5 0.022) and increased mean glucose 169 mg/dL (23) vs. 147 mg/dL (23) (P < 0.001). CONCLUSIONSThis trial, the first outpatient single-hormone AP trial in a population of this age, shows feasibility and safety of MMPC in young children. Algorithm retuning will be performed to improve efficacy.Only three artificial pancreas (AP) trials have focused on the prepubertal population so far: two single-hormone AP studies, performed inpatient for less than 1 day (1,2) and a recent dual-hormone AP study, performed in a camp for 5 days (3). Here we report the first outpatient single-hormone AP trial focusing on 5-to 9-year-old children.Data were collected in the Pediatric Artificial Pancreas (PedArPan) camp, where sensor-augmented pump (SAP) therapy was compared with the modular model predictive control algorithm (MMPC) (4,5), running on the wearable platform Diabetes Assistant (DiAs) (6).