Moshe Phillip

Nocturnal Glucose Control with an Artificial Pancreas at a Diabetes Camp

BACKGROUND Recent studies have shown that an artificial-pancreas system can improve glucose control and reduce nocturnal hypoglycemia. However, it is not known whether such results can be replicated in settings outside the hospital. METHODS In this multicenter, multinational, randomized, crossover trial, we assessed the short-term safety and efficacy of an artificial pancreas system for control of nocturnal glucose levels in patients (10 to 18 years of age) with type 1 diabetes at a diabetes camp. In two consecutive overnight sessions, we randomly assigned 56 patients to receive treatment with an artificial pancreas on the first night and a sensor-augmented insulin pump (control) on the second night or to the reverse order of therapies on the first and second nights. Thus, all the patients received each treatment in a randomly assigned order. The primary end points were the number of hypoglycemic events (defined as a sensor glucose value of <63 mg per deciliter [3.5 mmol per liter] for at least 10 consecutive minutes), the time spent with glucose levels below 60 mg per deciliter (3.3 mmol per liter), and the mean overnight glucose level for individual patients. RESULTS On nights when the artificial pancreas was used, versus nights when the sensor-augmented insulin pump was used, there were significantly fewer episodes of nighttime glucose levels below 63 mg per deciliter (7 vs. 22) and significantly shorter periods when glucose levels were below 60 mg per deciliter (P=0.003 and P=0.02, respectively, after adjustment for multiplicity). Median values for the individual mean overnight glucose levels were 126.4 mg per deciliter (interquartile range, 115.7 to 139.1 [7.0 mmol per liter; interquartile range, 6.4 to 7.7]) with the artificial pancreas and 140.4 mg per deciliter (interquartile range, 105.7 to 167.4 [7.8 mmol per liter; interquartile range, 5.9 to 9.3]) with the sensor-augmented pump. No serious adverse events were reported. CONCLUSIONS Patients at a diabetes camp who were treated with an artificial-pancreas system had less nocturnal hypoglycemia and tighter glucose control than when they were treated with a sensor-augmented insulin pump. (Funded by Sanofi and others; ClinicalTrials.gov number, NCT01238406.).

Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes

OBJECTIVE To assess the impact of continuous glucose monitoring on hypoglycemia in people with type 1 diabetes. RESEARCH DESIGN AND METHODS In this randomized, controlled, multicenter study, 120 children and adults on intensive therapy for type 1 diabetes and a screening level of glycated hemoglobin A1c (HbA1c) <7.5% were randomly assigned to a control group performing conventional home monitoring with a blood glucose meter and wearing a masked continuous glucose monitor every second week for five days or to a group with real-time continuous glucose monitoring. The primary outcome was the time spent in hypoglycemia (interstitial glucose concentration <63 mg/dL) over a period of 26 weeks. Analysis was by intention to treat for all randomized patients. RESULTS The time per day spent in hypoglycemia was significantly shorter in the continuous monitoring group than in the control group (mean ± SD 0.48 ± 0.57 and 0.97 ± 1.55 h/day, respectively; ratio of means 0.49; 95% CI 0.26–0.76; P = 0.03). HbA1c at 26 weeks was lower in the continuous monitoring group than in the control group (difference −0.27%; 95% CI −0.47 to −0.07; P = 0.008). Time spent in 70 to 180 mg/dL normoglycemia was significantly longer in the continuous glucose monitoring group compared with the control group (mean hours per day, 17.6 vs. 16.0, P = 0.009). CONCLUSIONS Continuous glucose monitoring was associated with reduced time spent in hypoglycemia and a concomitant decrease in HbA1c in children and adults with type 1 diabetes.

Endocrine Regulation of the Growth Plate

Longitudinal bone growth occurs at the growth plate by endochondral ossification. Within the growth plate, chondrocyte proliferation, hypertrophy, and cartilage matrix secretion result in chondrogenesis. The newly formed cartilage is invaded by blood vessels and bone cells that remodel the newly formed cartilage into bone tissue. This process of longitudinal bone growth is governed by a complex network of endocrine signals, including growth hormone, insulin-like growth factor I, glucocorticoid, thyroid hormone, estrogen, androgen, vitamin D, and leptin. Many of these signals regulate growth plate function, both by acting locally on growth plate chondrocytes and also indirectly by modulating other endocrine signals in the network. Some of the local effects of hormones are mediated by changes in paracrine factors that control chondrocyte proliferation and differentiation. Many human skeletal growth disorders are caused by abnormalities in the endocrine regulation of the growth plate. This review provides an overview of the endocrine signals that regulate longitudinal bone growth, their interactions, and the mechanisms by which they affect growth plate chondrogenesis.

Use of insulin pump therapy in the pediatric age-group: consensus statement from the European Society for Paediatric Endocrinology, the Lawson Wilkins Pediatric Endocrine Society, and the International Society for Pediatric and Adolescent Diabetes, endorsed by the American Diabetes Association and the European Association for the Study of Diabetes

Young patients with diabetes, their families, and their diabetes care providers continue to be faced with the challenge of striving to maintain blood glucose levels in the near-normal range. High blood glucose levels with elevated A1C levels are associated with long-term microvascular and macrovascular complications. Recurrent episodes of hypoglycemia, especially at young ages, may cause short- and long-term adverse effects on cognitive function and lead to hypoglycemia unawareness and may be associated with significant emotional morbidity for the child and parents. Fear of hypoglycemia, especially during the night, may compromise quality of life (QOL) for the family and jeopardize efforts to achieve optimal metabolic control. Over the past decade, continuous subcutaneous insulin infusion (CSII) has gained increasing popularity among patients with diabetes. CSII is the most physiologic method of insulin delivery currently available. It is able to closely simulate the normal pattern of insulin secretion, namely continuous 24-h adjustable “basal” delivery of insulin upon which are superimposed prandial “boluses.” In addition, CSII offers the possibility of more flexibility and more precise insulin delivery than multiple daily injection (MDI). However, there is still debate among diabetes care practitioners around the world as to whether CSII has advantages over MDI in terms of reduction in A1C levels, occurrence of severe hypoglycemic events, episodes of diabetic ketoacidosis (DKA), and frequency of hospitalizations in young patients. Furthermore, no clear criteria have been established to help the physician choose the “appropriate” patient for CSII therapy. To address these issues, the European Society for Pediatric Endocrinology (ESPE), the Lawson Wilkins Pediatric Endocrine Society (LWPES), and the International Society for Pediatric and Adolescent Diabetes (ISPAD) convened a panel of expert physicians for a consensus conference endorsed by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). For each major topic area, …

The effect of adenotonsillectomy on serum insulin-like growth factor-I and growth in children with obstructive sleep apnea syndrome

OBJECTIVE Obstructive sleep apnea syndrome (OSAS) in children is frequently associated with growth interruption. The objective of this study was to evaluate the effect of OSAS and adenotonsillectomy on the insulin-like growth factor-I (IGF-I) axis in children. STUDY DESIGN Thirteen prepubertal children (mean age, 6.0 +/- 2.8 years) were studied before and after adenotonsillectomy (T&A). Weight, height, overnight polysomnography, and IGF-I and IGF-binding protein-3 levels were evaluated before and 3 to 12 months after T&A. The childrens weights and heights were monitored for 18 months. RESULTS The respiratory disturbance index improved from 7.8 +/- 9.1 events/h to 1.0 +/- 2.1 events/h after T&A (P <.02). Slow-wave sleep increased from 29.1% +/- 7.2% to 34.6% +/- 9.8% after T&A (P <.02). The weight standard deviation score increased from 0.86 +/- 1 to 1. 24 +/- 0.9, 18 months after T&A (P <.01). Serum IGF-I levels increased from 146.3 +/- 76.2 ng/mL before T&A to 210.3 +/- 112.5 ng/mL after surgery (P <.01), but IGF-binding protein-3 levels did not change significantly. CONCLUSION The respiratory improvement after T&A in children with OSAS is associated with a significant increase in serum IGF-I levels and weight. We conclude that the IGF-I axis is affected in children with OSAS.

Leptin Acts as a Growth Factor on the Chondrocytes of Skeletal Growth Centers

Childhood obesity frequently is associated with an increase in height velocity and acceleration of epiphyseal growth plate maturation despite low levels of serum growth hormone (GH). In addition, obesity is associated with higher circulating levels of leptin, a 16‐kDa protein that is secreted from the adipocytes. In this study, we evaluated the direct effect of leptin on the chondrocyte population of the skeletal growth centers in the mouse mandibular condyle, a model of endochondral ossification. We found that chondrocytes in the growth centers contain specific binding sites for leptin. Leptin, at a concentration of 0.5‐1.0 μg/ml, stimulated in a dose‐dependent manner the width of the chondroprogenitor zone (up to 64%), whereas higher concentrations had an inhibitory effect. Leptin induction of both proliferation and differentiation activities in the mandibular condyle was confirmed by our findings of an increase in bromodeoxyuridine (BrdU) incorporation into DNA and in (acidic) Alcian blue (AB) staining of the cartilaginous matrix. Leptin also increased the abundance of the insulin‐like growth factor (IGF) I receptor and IGF‐I receptor messenger RNA (mRNA) within the chondrocytes and the progenitor cell population. Our results indicate that leptin acts as a skeletal growth factor with a direct peripheral effect on skeletal growth centers. Some of its effects on the growing bone may be mediated by the IGF system via regulation of IGF‐I receptor expression. We speculate that the high circulating levels of leptin in obese children might contribute to their growth.

Continuing Stability of Center Differences in Pediatric Diabetes Care: do advances in diabetes treatment improve outcome? The Hvidoere Study Group on Childhood Diabetes

OBJECTIVE—To reevaluate the persistence and stability of previously observed differences between pediatric diabetes centers and to investigate the influence of demography, language communication problems, and changes in insulin regimens on metabolic outcome, hypoglycemia, and ketoacidosis. RESEARCH DESIGN AND METHODS—This was an observational cross-sectional international study in 21 centers, with clinical data obtained from all participants and A1C levels assayed in one central laboratory. All individuals with diabetes aged 11–18 years (49.4% female), with duration of diabetes of at least 1 year, were invited to participate. Fourteen of the centers participated in previous Hvidoere Studies, allowing direct comparison of glycemic control across centers between 1998 and 2005. RESULTS—Mean A1C was 8.2 ± 1.4%, with substantial variation between centers (mean A1C range 7.4–9.2%; P < 0.001). There were no significant differences between centers in rates of severe hypoglycemia or diabetic ketoacidosis. Language difficulties had a significant negative impact on metabolic outcome (A1C 8.5 ± 2.0% vs. 8.2 ± 1.4% for those with language difficulties vs. those without, respectively; P < 0.05). After adjustement for significant confounders of age, sex, duration of diabetes, insulin regimen, insulin dose, BMI, and language difficulties, the center differences persisted, and the effect size for center was not reduced. Relative center ranking since 1998 has remained stable, with no significant change in A1C. CONCLUSIONS—Despite many changes in diabetes management, major differences in metabolic outcome between 21 international pediatric diabetes centers persist. Different application between centers in the implementation of insulin treatment appears to be of more importance and needs further exploration.

MD-Logic Artificial Pancreas System: A pilot study in adults with type 1 diabetes

OBJECTIVE Current state-of-the-art artificial pancreas systems are either based on traditional linear control theory or rely on mathematical models of glucose-insulin dynamics. Blood glucose control using these methods is limited due to the complexity of the biological system. The aim of this study was to describe the principles and clinical performance of the novel MD-Logic Artificial Pancreas (MDLAP) System. RESEARCH DESIGN AND METHODS The MDLAP applies fuzzy logic theory to imitate lines of reasoning of diabetes caregivers. It uses a combination of control-to-range and control-to-target strategies to automatically regulate individual glucose levels. Feasibility clinical studies were conducted in seven adults with type 1 diabetes (aged 19–30 years, mean diabetes duration 10 ± 4 years, mean A1C 6.6 ± 0.7%). All underwent 14 full, closed-loop control sessions of 8 h (fasting and meal challenge conditions) and 24 h. RESULTS The mean peak postprandial (overall sessions) glucose level was 224 ± 22 mg/dl. Postprandial glucose levels returned to <180 mg/dl within 2.6 ± 0.6 h and remained stable in the normal range for at least 1 h. During 24-h closed-loop control, 73% of the sensor values ranged between 70 and 180 mg/dl, 27% were >180 mg/dl, and none were <70 mg/dl. There were no events of symptomatic hypoglycemia during any of the trials. CONCLUSIONS The MDLAP system is a promising tool for individualized glucose control in patients with type 1 diabetes. It is designed to minimize high glucose peaks while preventing hypoglycemia. Further studies are planned in the broad population under daily-life conditions.

MD-Logic Artificial Pancreas System: A Pilot Study in Adults with Type 1 Diabetes Mellitus

OBJECTIVE Current state-of-the-art artificial pancreas systems are either based on traditional linear control theory or rely on mathematical models of glucose-insulin dynamics. Blood glucose control using these methods is limited due to the complexity of the biological system. The aim of this study was to describe the principles and clinical performance of the novel MD-Logic Artificial Pancreas (MDLAP) System. RESEARCH DESIGN AND METHODS The MDLAP applies fuzzy logic theory to imitate lines of reasoning of diabetes caregivers. It uses a combination of control-to-range and control-to-target strategies to automatically regulate individual glucose levels. Feasibility clinical studies were conducted in seven adults with type 1 diabetes (aged 19–30 years, mean diabetes duration 10 ± 4 years, mean A1C 6.6 ± 0.7%). All underwent 14 full, closed-loop control sessions of 8 h (fasting and meal challenge conditions) and 24 h. RESULTS The mean peak postprandial (overall sessions) glucose level was 224 ± 22 mg/dl. Postprandial glucose levels returned to <180 mg/dl within 2.6 ± 0.6 h and remained stable in the normal range for at least 1 h. During 24-h closed-loop control, 73% of the sensor values ranged between 70 and 180 mg/dl, 27% were >180 mg/dl, and none were <70 mg/dl. There were no events of symptomatic hypoglycemia during any of the trials. CONCLUSIONS The MDLAP system is a promising tool for individualized glucose control in patients with type 1 diabetes. It is designed to minimize high glucose peaks while preventing hypoglycemia. Further studies are planned in the broad population under daily-life conditions.

Ambulatory care of febrile infants younger than 2 months of age classified as being at low risk for having serious bacterial infections.

We prospectively examined whether febrile infants younger than 2 months of age who were defined as being at low risk for having bacterial infection could be observed as outpatients without the usual complete evaluation for sepsis and without antibiotic treatment. A total of 237 previously healthy febrile infants were seen at the Pediatric Emergency Room over 17 1/2 months. One hundred forty-eight infants (63%) fulfilled the criteria for being at low risk: no physical findings consisting of soft tissue or skeletal infections, no purulent otitis media, normal urinalysis, less than 25 white blood cells per high-power field on microsopic stool examination, peripheral leukocyte count 5000 to 15,000/mm3 with less than 1500 band cells/mm3. One infant appeared too ill to be included, and had sepsis and meningitis. None of the 148 infants at low risk had bacterial infections, versus 21 of 88 (24%) of those at high risk (P less than 0.0001); eight of 88 (9%) had bacteremia. Of the 148 infants classified as being at low risk for having bacterial infection, 62 (42%) were discharged to home, and 72 (49%) were initially observed for less than or equal to 24 hours and then discharged. Seventeen infants (11%) were hospitalized: in six, low risk became high risk; six had indications other than fever; and five because the study physicians could not be found. The 137 nontreated infants were closely observed as outpatients. The duration of fever was less than 48 hours in 42%, and less than 96 hours in 91%. All infants were observed for at least 10 days after the last examination. The fever resolved spontaneously in all infants but two, with otitis media, who were treated as outpatients. Our data suggest that management of fever in selected young infants as outpatients is feasible if meticulous follow-up is provided.