Mary B. Abraham

Effectiveness of a Predictive Algorithm in the Prevention of Exercise-Induced Hypoglycemia in Type 1 Diabetes

BACKGROUND Sensor-augmented pump therapy (SAPT) with a predictive algorithm to suspend insulin delivery has the potential to reduce hypoglycemia, a known obstacle in improving physical activity in patients with type 1 diabetes. The predictive low glucose management (PLGM) system employs a predictive algorithm that suspends basal insulin when hypoglycemia is predicted. The aim of this study was to determine the efficacy of this algorithm in the prevention of exercise-induced hypoglycemia under in-clinic conditions. METHODS This was a randomized, controlled cross-over study in which 25 participants performed 2 consecutive sessions of 30 min of moderate-intensity exercise while on basal continuous subcutaneous insulin infusion on 2 study days: a control day with SAPT alone and an intervention day with SAPT and PLGM. The predictive algorithm suspended basal insulin when sensor glucose was predicted to be below the preset hypoglycemic threshold in 30 min. We tested preset hypoglycemic thresholds of 70 and 80 mg/dL. The primary outcome was the requirement for hypoglycemia treatment (symptomatic hypoglycemia with plasma glucose <63 mg/dL or plasma glucose <50 mg/dL) and was compared in both control and intervention arms. RESULTS Results were analyzed in 19 participants. In the intervention arm with both thresholds, only 6 participants (32%) required treatment for hypoglycemia compared with 17 participants (89%) in the control arm (P = 0.003). In participants with a 2-h pump suspension on intervention days, the plasma glucose was 84 ± 12 and 99 ± 24 mg/dL at thresholds of 70 and 80 mg/dL, respectively. CONCLUSIONS SAPT with PLGM reduced the need for hypoglycemia treatment after moderate-intensity exercise in an in-clinic setting.

Reduction in Hypoglycemia With the Predictive Low-Glucose Management System: A Long-Term Randomized Controlled Trial in Adolescents With Type 1 Diabetes

OBJECTIVE Short-term studies with automated systems that suspend basal insulin when hypoglycemia is predicted have shown a reduction in hypoglycemia; however, efficacy and safety have not been established in long-term trials. RESEARCH DESIGN AND METHODS We conducted a 6-month, multicenter, randomized controlled trial in children and adolescents with type 1 diabetes using the Medtronic MiniMed 640G pump with Suspend before low (predictive low-glucose management [PLGM]) compared with sensor-augmented pump therapy (SAPT) alone. The primary outcome was percentage time in hypoglycemia with sensor glucose (SG) <3.5 mmol/L (63 mg/dL). RESULTS In an intent-to-treat analysis of 154 subjects, 74 subjects were randomized to SAPT and 80 subjects to PLGM. At baseline, the time with SG <3.5 mmol/L was 3.0% and 2.8% in the SAPT and PLGM groups, respectively. During the study, PLGM was associated with a reduction in hypoglycemia compared with SAPT (% time SG <3.5 mmol/L: SAPT vs. PLGM, 2.6 vs. 1.5, P < 0.0001). A similar effect was also noted in time with SG <3 mmol/L (P < 0.0001). This reduction was seen both during day and night (P < 0.0001). Hypoglycemic events (SG <3.5 mmol/L for >20 min) also declined with PLGM (SAPT vs. PLGM: events/patient-year 227 vs. 139, P < 0.001). There was no difference in glycated hemoglobin (HbA1c) at 6 months (SAPT 7.6 ± 1.0% vs. PLGM 7.8 ± 0.8%, P = 0.35). No change in quality of life measures was reported by participants/parents in either group. There were no PLGM-related serious adverse events. CONCLUSIONS In children and adolescents with type 1 diabetes, PLGM reduced hypoglycemia without deterioration in glycemic control.

Exercise training improves vascular function in adolescents with type 2 diabetes

The impact of exercise training on vascular health in adolescents with type 2 diabetes has not been previously studied. We hypothesized that exercise training would improve micro‐ and macrovascular health in adolescents with type 2 diabetes. Thirteen adolescents (13–21 years, 10F) with type 2 diabetes were recruited from Princess Margaret Hospital. Participants were randomized to receive either an exercise program along with standard clinical care (n = 8) or standard care alone (n = 5). Those in the intervention group received 12 weeks of gym‐based, personalized, and supervised exercise training. Those in the control group were instructed to maintain usual activity levels. Assessments were conducted at baseline and following week 12. The exercise group was also studied 12 weeks following the conclusion of their program. Assessments consisted of conduit artery endothelial function (flow‐mediated dilation, FMD) and microvascular function (cutaneous laser Doppler). Secondary outcomes included body composition (dual‐energy X‐ray absorptiometry, DXA), glycemic control (whole body insulin sensitivity, M) assessed using the euglycemic–hyperinsulinemic clamp protocol, cardiorespiratory fitness ( V˙O2peak ), and muscular strength (1RM). Exercise training increased FMD (P < 0.05), microvascular function (P < 0.05), total lean mass (P < 0.05), and muscle strength (P < 0.001). There were no changes in cardiorespiratory fitness, body weight, BMI, or M. In the control group, body weight (P < 0.01), BMI (P < 0.01), and total fat mass (P < 0.05) increased. At week 24, improvements in vascular function were reversed. This study indicates that exercise training can improve both conduit and microvascular endothelial function and health, independent of changes in insulin sensitivity in adolescents with type 2 diabetes.

Efficacy of Hydrochlorothiazide and low renal solute feed in Neonatal Central Diabetes Insipidus with transition to Oral Desmopressin in early infancy

BackgroundThe treatment of central diabetes insipidus (DI) with desmopressin in the neonatal period is challenging because of the significant risk of hyponatremia with this agent. The fixed anti-diuresis action of desmopressin and the obligate high fluid intake with milk feeds lead to considerable risk of water intoxication and hyponatremia. To reduce this risk, thiazide diuretics, part of the treatment of nephrogenic DI, were used in conjunction with low renal solute feed and were effective in a single case series of neonatal central DI.AimWe evaluated the efficacy of early treatment of neonatal central DI with hydrochlorothiazide with low solute feed and investigated the clinical indicators for transition to desmopressin during infancy.MethodsA retrospective chart review was conducted at Princess Margaret Hospital, Perth of neonates diagnosed with central DI and treated with hydrochlorothiazide, between 2007 and 2013. Four newborns were identified. Mean sNa and mean change in sNa with desmopressin and hydrochlorothiazide treatment were recorded along with episodes of hyponatremia and hypernatremia. Length and weight trajectories during the first 12 months were assessed.ResultsThe mean change in sNa per day with hydrochlorothiazide and low renal solute feed was 2.5 - 3 mmol/L; on desmopressin treatment, the mean change in sNa was 6.8-7.9 mmol/L. There was one episode of symptomatic hyponatremia with intranasal desmopressin with no episodes of hyponatremia or hypernatremia during treatment with hydrochlorothiazide or following transition to oral desmopressin. Transition to oral desmopressin between 3 to 12 months of age was associated with good control of DI. Following introduction of solids, sNa remained stable but weight gain was slow. This improved following transition to desmopressin in one infant.ConclusionsHydrochlorothiazide with low renal solute feed is a safe and effective treatment option in neonatal central DI. However, transition to desmopressin should be considered early in infancy following initiation of solids to facilitate growth.

Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia.

Abstract Hyperinsulinaemic hypoglycaemia (HH) is characterised by inappropriate insulin secretion and is the most common cause for persistent neonatal hypoglycaemia. The only treatment available for medically unresponsive hypoglycaemia is a near-total pancreatectomy. A neonate with severe HH, due to a homozygous ABCC8 mutation, was not responsive to treatment with maximal doses of diazoxide and subcutaneous daily octreotide, and underwent a near-total pancreatectomy; however, hypoglycaemia persisted. Introduction of sirolimus, an mTOR (mammalian target of rapamycin) inhibitor, obviated the requirement for glucose infusion. Euglycaemia was achieved with no significant adverse events from the drug. Sirolimus therapy was ceased at 13 months of age. No episodes of persistent hypoglycaemia were observed after cessation of sirolimus. This report demonstrates the successful use of sirolimus for persistent hypoglycaemia in the critically ill infant post pancreatectomy. Sirolimus could be considered in patients with severe HH not responsive to conventional medical and surgical therapy. However, the long-term efficacy and safety with this immunosuppressive drug in very young patients are not assured.

Report and review of described associations of Mayer-Rokitansky-Küster-Hauser syndrome and Silver-Russell syndrome

Silver–Russell syndrome (SRS) and Mayer‐Rokitansky‐Küster‐Hauser (MRKH) syndrome are described in isolation. However, their co‐occurrence has only been rarely reported. Here, we present a case report of an adolescent with SRS who was diagnosed with MRKH during the evaluation of primary amenorrhoea. Multiplex ligation‐dependent probe amplification analysis showed a normal methylation pattern and normal dosage at 11p15.5. A PubMed search for all peer‐reviewed publications (original articles and reviews) using the key words Silver–Russell syndrome, Mayer‐Rokitansky‐Küster‐Hauser syndrome, genetics, hypomethylation and reproductive anomalies identified three cases of SRS with MRKH, two of which were associated with significant hypomethylation of the H19 imprinting control region of the 11p15.5 locus. This report highlights the association between SRS and MRKH. The absence of hypomethylation and normal dosage at 11p15.5 suggests these two rare entities share alternative aetiopathogenic mechanisms.

Arginine extravasation leading to skin necrosis

Arginine hydrochloride is used in the evaluation of short stature and in the management of urea cycle disorders. In recent times, it has been used in the treatment of stroke‐like episodes of MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke‐like episodes). We want to highlight the need for good intravenous access and monitoring the drip site to prevent extravasation injuries that can be caused by arginine, which is a hyperosmolar solution.

Reduced prevalence of impaired awareness of hypoglycemia in a population‐based clinic sample of youth with type 1 diabetes

Impaired awareness of hypoglycemia (IAH) is associated with an increased risk for severe hypoglycemia (SH). However, reduced rates of SH raise the question as to whether there has been a reduction in IAH. The aim of this study was to determine the change in prevalence of IAH in a population‐based cohort of adolescents with Type 1 diabetes (T1D).

Transient pseudohypoaldosteronism in infancy secondary to urinary tract infection

Hyponatraemia with hyperkalaemia in infancy is a typical presentation of congenital adrenal hyperplasia. In the presence of pyelonephritis, the same biochemical picture can occur with transient type 1 pseudohypoaldosteronism (PHA‐1) also termed type 4 renal tubular acidosis. Recognition of PHA‐1 enables appropriate management thus avoiding unnecessary investigations and treatment. To improve awareness of this condition, we present a case series to highlight the clinical and biochemical features of PHA‐1.

Unexpected Management Behaviors in Adolescents With Type 1 Diabetes Using Sensor-Augmented Pump Therapy:

Background: Continuous glucose monitoring can improve glycemic outcomes in individuals with type 1 diabetes. However, the constant exposure to real-time glucose levels can sometimes lead the individual to make some risky choices to address the glycemic excursions. Hence, the purpose of this study was to explore the aberrant management behaviors of youth with type 1 diabetes on sensor-augmented pump therapy (SAPT). Methods: Participants in a clinical trial using SAPT on Medtronic MiniMed™ 640G pump who experienced deteriorating glycemic control or unexplained hypoglycemia were identified by the health care professional. The pump and/or sensor data uploaded to CareLink™ Therapy Management Software were reviewed in these participants. Results: Uncharacteristic management behaviors were identified in five adolescent males. Continuous exposure to high glucose levels resulted in obsessive behaviors displaying a perfectionistic attitude in two participants. Multiple boluses were delivered frequently as uneaten carbohydrates in participant 1 while participant 2 resorted to delivery of extra insulin by cannula fills. In contrast, participant 3 chose to remain hyperglycemic to avoid weight gain while participant 4 trusted the system and used sensor glucose readings for calibrations, with resultant deterioration in glycemic control in both participants. On the other hand, participant 5, due to mistrust in the pump suspend function, consumed carbohydrates with downward glucose trends with rebound hyperglycemia. Conclusions: Constant exposure to real-time data can lead to unsafe management responses in adolescents with the behavior influenced by trust or mistrust in the system. Adolescents should be empowered with problem-solving strategies for safe management.