Daniel J. DeSalvo

Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial

BACKGROUND The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free-living, home-use setting. We aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity. METHODS We did a random-order crossover study in volunteers at least 18 years old who had type 1 diabetes and lived within a 30 min drive of four sites in the USA. Participants were randomly assigned (1:1) in blocks of two using sequentially numbered sealed envelopes to glycaemic regulation with a bihormonal bionic pancreas or usual care (conventional or sensor-augmented insulin pump therapy) first, followed by the opposite intervention. Both study periods were 11 days in length, during which time participants continued all normal activities, including athletics and driving. The bionic pancreas was initialised with only the participants body mass. Autonomously adaptive dosing algorithms used data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. The coprimary outcomes were the mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration less than 3·3 mmol/L, analysed over days 2-11 in participants who completed both periods of the study. This trial is registered with ClinicalTrials.gov, number NCT02092220. FINDINGS We randomly assigned 43 participants between May 6, 2014, and July 3, 2015, 39 of whom completed the study: 20 who were assigned to bionic pancreas first and 19 who were assigned to the comparator first. The mean CGM glucose concentration was 7·8 mmol/L (SD 0·6) in the bionic pancreas period versus 9·0 mmol/L (1·6) in the comparator period (difference 1·1 mmol/L, 95% CI 0·7-1·6; p<0·0001), and the mean time with CGM glucose concentration less than 3·3 mmol/L was 0·6% (0·6) in the bionic pancreas period versus 1·9% (1·7) in the comparator period (difference 1·3%, 95% CI 0·8-1·8; p<0·0001). The mean nausea score on the Visual Analogue Scale (score 0-10) was greater during the bionic pancreas period (0·52 [SD 0·83]) than in the comparator period (0·05 [0·17]; difference 0·47, 95% CI 0·21-0·73; p=0·0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study. INTERPRETATION Relative to conventional and sensor-augmented insulin pump therapy, the bihormonal bionic pancreas, initialised only with participant weight, was able to achieve superior glycaemic regulation without the need for carbohydrate counting. Larger and longer studies are needed to establish the long-term benefits and risks of automated glycaemic management with a bihormonal bionic pancreas. FUNDING National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and National Center for Advancing Translational Sciences.

Continuous Glucose Monitoring: Current Use and Future Directions

Continuous glucose monitoring (CGM) is an emerging technology that provides a continuous measure of interstitial glucose levels. In addition to providing a more complete pattern of glucose excursions, CGMs utilize real-time alarms for thresholds and predictions of hypo- and hyperglycemia, as well as rate of change alarms for rapid glycemic excursions. CGM users have been able to improve glycemic control without increasing their risk of hypoglycemia. Sensor accuracy, reliability, and wearability are important challenges to CGM success and are critical to the development of an artificial pancreas (or closed-loop system).

Effect of Acetaminophen on CGM Glucose in an Outpatient Setting

Acetaminophen (paracetamol) interferes with continuous glucose monitor (CGM) sensing, resulting in falsely elevated CGM glucose values in both sensors currently approved by the U.S. Food and Drug Administration (FDA). In amperometric glucose biosensors, particularly those measuring hydrogen peroxide, acetaminophen’s phenolic moiety is oxidized at the sensing electrode, producing an electrochemical signal not related to glucose (1). Limited published data exist documenting the magnitude of the effect of acetaminophen on CGM glucose (2), especially in the outpatient setting with contemporary sensor technology. Currently, the FDA recommends that insulin dosing decisions are based on blood glucose (BG) meter values, not CGM glucose values. Given the common use of acetaminophen, its interference with CGM sensing has significant clinical implications for patients who use CGM. To better understand this effect, we performed an acetaminophen challenge as part of an outpatient study designed to investigate the potential challenges to closed-loop systems, which use CGM sensor …

Day-and-night closed-loop control using the unified safety system in adolescents with type 1 diabetes at camp

Adolescence marks a challenging time in diabetes care (1). Automated insulin delivery has the potential to overcome some of the barriers, such as missed meal boluses and nocturnal hypoglycemia. The University of Virginia Unified Safety System (USS) is one of the most tested control-to-range approaches and operates on an Android-based system that uses a Dexcom G4 PLATINUM Share glucose sensor and Roche Accu-Chek pump (2). The objective of this study was to test the efficacy of USS in day-and-night closed-loop control (CLC) in adolescents with type 1 diabetes at camp, where large meals and physical activity challenge glucose control. In this study, eligible subjects with type 1 diabetes on pump therapy were randomized to either CLC ( n = 17) or sensor-augmented pump (SAP) ( n = 16) for 5 days. There was no A1C restriction. Clinical characteristics of the 33 subjects include mean ± SD (min–max) age of 17.9 ± 5.5 years (10.1–35.0), weight 68 ± 17 kg (37.3–104.3), A1C …

In children with premature adrenarche, bone age advancement by 2 or more years is common and generally benign

Abstract Background: Premature adrenarche (PA) is often associated with bone age (BA) advanced by ≥2 years, which increases the concern for underlying pathology, but the frequency and clinical significance of this is unknown. Our objective was to identify the proportion of PA patients with very advanced BA and normal BA and compare the clinical characteristics of the two groups. Methods: Charts of 427 patients aged 5–9 years, referred for early puberty over a 2-year period, were reviewed for clinical diagnosis, growth, parental heights, hormone levels and BA. We divided the PA patients into three separate groups based on degree of BA advancement. Predicted adult heights (PAH) were calculated and compared to mid-parental target height (TH). Results: Of 427 patients, 266 (62%) had PA (82% female). Of the 121 with BA, 30.6% had very advanced BA (≥2 years) and this group was taller (Ht SD+1.72 vs. +0.72, p<0.00001) and had higher BMI (SD+1.70 vs. +0.99, p<0.001) than patients with BA advanced by <1 year, but hormone levels were quite similar. Mean PAH was slightly less than TH for patients with very advanced BA, but there were no girls with PAH <60 inches 152.4 cm or boys with PAH <65 inches 165.1 cm in height. Conclusions: Very advanced BA is common in PA, and patients were significantly taller and more overweight than their peers. The impact of advanced BA on PAH appears to be minor. We question the need for ordering a BA in patients with PA, and suggest that extensive testing is unnecessary simply because of advanced BA.

Nighttime is the worst time: Parental fear of hypoglycemia in young children with type 1 diabetes

Fear of hypoglycemia is common in parents of young children with type 1 diabetes (T1D), but little is known about the specific fears that parents most often experience. Hypoglycemia fear has been associated with poorer glycemic control in older children, though not yet studied in a large cohort of very young children.

Early Detection of Infusion Set Failure During Insulin Pump Therapy in Type 1 Diabetes

Background: Insulin infusion set failure resulting in prolonged hyperglycemia or diabetic ketoacidosis can occur with pump therapy in type 1 diabetes. Set failures are frequently characterized by variable and unpredictable patterns of increasing glucose values despite increased insulin infusion. Early detection may minimize the risk of prolonged hyperglycemia, an important consideration for automated insulin delivery and closed-loop applications. Methods: A novel algorithm designed to alert the patient to the onset of infusion set failure was developed based upon continuous glucose sensor values and insulin delivered from an insulin pump. The method was calibrated on 12 weeks of infusion set wear without failures recorded by 4 patients in ambulatory conditions and prospectively validated on 18 weeks of infusion set wear with and without failures belonging to 9 other subjects in ambulatory conditions. Results: The algorithm, evaluated retrospectively, identified a failure 2.52 ± 1.91 days ahead of the actual event as recorded by the clinical team, corresponding to 50% sensitivity, 66% specificity and 55% accuracy. If set failure alarms had been activated in real time, the average time >180 mg/dl would be reduced from 82.7 ± 40.9 hours/week/subject (without alarm) to 58.8 ± 31.1 hours/week/subject (with alarm), corresponding to a potential 29% reduction in time spent >180mg/dl. Conclusion: The proposed method for early detection of infusion set failure based on glucose sensor and insulin data demonstrated favorable results on retrospective data and may be implemented as an additional safeguard in a future fully automated closed-loop system.

Accuracy Evaluation of Blood Glucose Monitoring Systems in Children on Overnight Closed-Loop Control:

Objective: This pilot study evaluated the difference in accuracy between the Bayer Contour® Next (CN) and HemoCue® (HC) glucose monitoring systems in children with type 1 diabetes participating in overnight closed-loop studies. Research Design and Methods: Subjects aged 10-18 years old were admitted to a clinical research center and glucose values were obtained every 30 minutes overnight. Glucose values were measured using whole blood samples for CN and HC readings and results were compared to Yellow Springs Instrument (YSI) reference values obtained with plasma from the same sample. System accuracy was compared using mean absolute relative difference (MARD) and International Organization for Standardization (ISO) accuracy standards. Results: A total of 28 subjects were enrolled in the study. Glucose measurements were evaluated at 457 time points. CN performed better than HC with an average MARD of 3.13% compared to 10.73% for HC (P < .001). With a limited sample size, CN met ISO criteria (2003 and 2013) at all glucose ranges while HC did not. Conclusions: CN performed very well, and would make an excellent meter for future closed-loop studies outside of a research center.

Cholestasis Secondary to Panhypopituitarism in an Infant

Cholestasis occurring in infancy should be evaluated completely to exclude hepatic as well as endocrine or metabolic causes. A rapid diagnosis should be made to ensure that hepatic and neurologic complications are prevented. We describe a rare case of infant cholestasis due to panhypopituitarism resulting in hypoglycemia and liver biopsy findings consistent with bile duct paucity. Existing bile ducts were noted to be small, and electron microscopy demonstrated diminutive and atrophied biliary cells with a diminished bile duct lumen size. Hypoglycemia and cholestasis resolved with treatment of the underlying panhypopituitarism. Panhypopituitarism should be considered in any infant who presents with cholestasis, hypoglycemia, and other manifestations of pituitary malfunction. Growth hormone deficiency may affect bile duct formation as demonstrated in this patient.

International comparison of smoking and metabolic control in patients with type 1 diabetes

Smoking may influence metabolic control and increase the risk of vascular complications in type 1 diabetes (T1D) (1,2). Antismoking public health policy may influence smoking habits in the population with diabetes; therefore, different behaviors between Europe and the U.S. may be expected (3,4). The T1D Exchange Registry (T1DX) in the U.S. and the Prospective Diabetes Follow-up Registry (DPV) in Germany and Austria are two large consortia of diabetes centers, which used their data sets to describe the prevalence of smoking habits in adults with T1D and analyzed the relationship between smoking status and metabolic outcomes. Our analyses include 20,405 patients with T1D aged ≥18 years and with T1D duration ≥1 year (10,579 participants from 65 T1DX centers and 9,826 participants from 297 DPV centers). Smoking status was defined by smoking at least one cigarette per day, former smokers reported smoking in the past, and nonsmokers never smoked. Smoking data were self-reported in …