Gregory P. Forlenza

The epidemic of type 1 diabetes: what is it telling us?

Purpose of review Type 1 diabetes (T1D) is an autoimmune disorder which affects millions around the world. The incidence of T1D in children is increasing worldwide at a rate that cannot be explained by genetics alone. This review explores the recent research regarding possible causes of this epidemic. Recent findings Investigation into T1D epidemiology has recently focused on several hypotheses. These theories include the role of infections, early childhood diet, vitamin D exposure, environmental pollutants, increased height velocity, obesity, and insulin resistance in the risk for T1D. Over the past year, the evidence has strengthened for early childhood infections, dietary proteins, and insulin resistance as risk factors for T1D, but not for vitamin D exposure or environmental pollutants. Summary Investigation into the source of the current epidemic of T1D has shed light on several possible causes, but has not provided definitive answers, yet.

Ankyloglossia, Exclusive Breastfeeding, and Failure to Thrive

A 6-month-old term boy was hospitalized to evaluate the cause of his failure to thrive, mandated as part of an investigation by the Department of Children and Families after an allegation of medical neglect was made. On admission the patient was below birth weight, and a medical workup for failure to thrive was pursued; however, he was noted to have severe ankyloglossia and was an exclusively breastfed infant. The only interventions during his hospitalization were frenotomy and assistance to the mother to increase her milk supply. The infant immediately experienced weight gain and has continued to show slow, but steady, weight gain as an outpatient. We illustrate here many of the controversies concerning ankyloglossia.

Closed Loop Control During Intense Prolonged Outdoor Exercise in Adolescents With Type 1 Diabetes: The Artificial Pancreas Ski Study

OBJECTIVE Intense 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 METHODS Skiing 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. RESULTS Compared 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. CONCLUSIONS CLC 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.

Application of Zone Model Predictive Control Artificial Pancreas During Extended Use of Infusion Set and Sensor: A Randomized Crossover-Controlled Home-Use Trial

OBJECTIVE As artificial pancreas (AP) becomes standard of care, consideration of extended use of insulin infusion sets (IIS) and continuous glucose monitors (CGMs) becomes vital. We conducted an outpatient randomized crossover study to test the safety and efficacy of a zone model predictive control (zone-MPC)–based AP system versus sensor augmented pump (SAP) therapy in which IIS and CGM failures were provoked via extended wear to 7 and 21 days, respectively. RESEARCH DESIGN AND METHODS A smartphone-based AP system was used by 19 adults (median age 23 years [IQR 10], mean 8.0 ± 1.7% HbA1c) over 2 weeks and compared with SAP therapy for 2 weeks in a crossover, unblinded outpatient study with remote monitoring in both study arms. RESULTS AP improved percent time 70–140 mg/dL (48.1 vs. 39.2%; P = 0.016) and time 70–180 mg/dL (71.6 vs. 65.2%; P = 0.008) and decreased median glucose (141 vs. 153 mg/dL; P = 0.036) and glycemic variability (SD 52 vs. 55 mg/dL; P = 0.044) while decreasing percent time <70 mg/dL (1.3 vs. 2.7%; P = 0.001). AP also improved overnight control, as measured by mean glucose at 0600 h (140 vs. 158 mg/dL; P = 0.02). IIS failures (1.26 ± 1.44 vs. 0.78 ± 0.78 events; P = 0.13) and sensor failures (0.84 ± 0.6 vs. 1.1 ± 0.73 events; P = 0.25) were similar between AP and SAP arms. Higher percent time in closed loop was associated with better glycemic outcomes. CONCLUSIONS Zone-MPC significantly and safely improved glycemic control in a home-use environment despite prolonged CGM and IIS wear. This project represents the first home-use AP study attempting to provoke and detect component failure while successfully maintaining safety and effective glucose control.

Total pancreatectomy with islet autotransplantation resolves pain in young children with severe chronic pancreatitis

Objectives: Fear of diabetes and major surgery may prohibit referral of young children severely affected by pancreatitis for total pancreatectomy with islet autotransplant (TPIAT). We evaluated outcomes in our youngest TPIAT recipients, 3 to 8 years of age at surgery. Methods: Medical records were reviewed for 17 children (9 girls) ages 8 years or younger undergoing TPIAT from 2000 to 2014. Most (14/17) had genetic risk factors for pancreatitis. Since 2006, TPIAT recipients were followed prospectively with health questionnaires including assessments of pain and narcotic use, and scheduled hemoglobin A1c (HbA1c) and mixed-meal tolerance tests (6 mL/kg Boost HP) before surgery, and at regular intervals after. Patients are 1 to 11 years post-TPIAT (median 2.2 years). Data are reported as median (25th, 75th percentile). Results: All had relief of pain, with all 17 patients off narcotics at most recent follow-up. Hospitalization rates decreased from 5.0 hospitalization episodes per person-year of follow-up before TPIAT, to 0.35 episodes per person-year of follow-up after TPIAT. Fourteen (82%) discontinued insulin, higher than the observed insulin independence rate of 41% in 399 patients older than 8 years of age undergoing TPIAT over the same interval (P = 0.004). Median post-TPIAT HbA1c was 5.9% (5.6%, 6.3%), and within patient post-TPIAT mean HbA1c was ⩽6.5% for all but 2 patients. Conclusions: Young children with severe refractory chronic pancreatitis may be good candidates for TPIAT, with high rates of pain relief and insulin independence, and excellent glycemic control in the majority.

Predictive Hyperglycemia and Hypoglycemia Minimization: In-Home Evaluation of Safety, Feasibility, and Efficacy in Overnight Glucose Control in Type 1 Diabetes

OBJECTIVE The objective of this study was to determine the safety, feasibility, and efficacy of a predictive hyperglycemia and hypoglycemia minimization (PHHM) system compared with predictive low-glucose insulin suspension (PLGS) alone in overnight glucose control. RESEARCH DESIGN AND METHODS A 42-night trial was conducted in 30 individuals with type 1 diabetes in the age range 15–45 years. Participants were randomly assigned each night to either PHHM or PLGS and were blinded to the assignment. The system suspended the insulin pump on both the PHHM and PLGS nights for predicted hypoglycemia but delivered correction boluses for predicted hyperglycemia on PHHM nights only. The primary outcome was the percentage of time spent in a sensor glucose range of 70–180 mg/dL during the overnight period. RESULTS The addition of automated insulin delivery with PHHM increased the time spent in the target range (70–180 mg/dL) from 71 ± 10% during PLGS nights to 78 ± 10% during PHHM nights (P < 0.001). The average morning blood glucose concentration improved from 163 ± 23 mg/dL after PLGS nights to 142 ± 18 mg/dL after PHHM nights (P < 0.001). Various sensor-measured hypoglycemic outcomes were similar on PLGS and PHHM nights. All participants completed 42 nights with no episodes of severe hypoglycemia, diabetic ketoacidosis, or other study- or device-related adverse events. CONCLUSIONS The addition of a predictive hyperglycemia minimization component to our existing PLGS system was shown to be safe, feasible, and effective in overnight glucose control.

Growth hormone treatment of patients with Fanconi Anemia after hematopoietic cell transplantation

Short stature is common in patients with Fanconi anemia (FA) and may be due to growth hormone deficiency (GHD) [1–4], especially after hematopoietic cell transplantation (HCT) [5]. Yet, there are no published data on the effectiveness of recombinant human GH treatment in these patients. Therefore, we conducted a retrospective case review study that included 4 patients with FA treated with GH for ≥2 years who reached near adult height. All patients received allogeneic HCT at the University of Minnesota between 2002 and 2008. We hypothesized that height would increase by at least 0.5 SDS in response to therapy. Patients who met two of the three criteria: height ≤−1.5 SDS, growth velocity ≤−2.0 SDS, or height SDS >2 SD below the mid-parental height, underwent GH stimulation testing with clonidine and arginine. GHD was defined as a stimulated GH level <10 μg/L [6]. Evaluation included physical examination, bone age radiograph, magnetic resonance imaging (MRI) or computed tomography scan of the brain, thyroid tests, and growth factor levels. This study was approved by the University of Minnesota Institutional Review Board. The mean age at FA diagnosis was 7.0±1.9 years and was 8.7±2.2 years at HCT. All patients had GHD. Patient 1 had an ectopic pituitary gland with pituitary stalk anomaly and Patient 3 had a pituitary microadenoma on MRI. Patients 2 and 4 had normal brain scans. Patient 2 was diagnosed with premature ovarian failure at 12 years and was treated with estrogen replacement throughout the course of GH therapy. Patients 1 and 4 had a transient subclinical hypothyroidism, which resolved without treatment within a year. Patient 2 had normal thyroid function. Patient 3 had primary hypothyroidism prior to starting GH therapy and was euthyroid on levothyroxine during GH treatment. Table I shows GH treatment data. The average age at GH start was 10.7±1.8 years. GH dose was 0.28±0.03 mg/kg/week. The initial bone age was delayed (2 SD below the mean) for Patients 1 and 2. The average growth rate was 4.0±1.1 cm/yr (−2.2±1.8 SD) at baseline, 6.6±3.9 cm/yr (1.7±4.9 SD) in year 1, 9.2±3.1 cm/yr (4.0±1.0 SD) in year 2, 5.6±2.0 cm/yr (1.1±3.7 SD) in year 3, and 5.7±1.1 cm/yr (1.2±2.1 SD) in year 4. The mean increase in height was 0.9±0.6 SDS (p=0.05). The smallest response to GH therapy was seen in Patient 4 who was the oldest and showed no improvement in insulin-like growth factor-1 (IGF-1) SDS, suggesting that optimization of GH dose based on IGF-1 levels may have improved outcome. There were no adverse events from GH. Table I Growth hormone treatment data In conclusion, GH treatment was well tolerated and had a positive effect on growth, resulting in an increase in height of at least 0.5 SDS in three out of four patients. It should be noted, however, that the long-term risk of GH treatment in these patients is unknown. Although HCT reduces the risk of leukemia, all patients with FA are at increased risk of solid tumors, including head and neck cancers, and gynecological cancers [7–9]. Therefore, continued surveillance is needed.

Next generation sequencing in endocrine practice

With the completion of the Human Genome Project and advances in genomic sequencing technologies, the use of clinical molecular diagnostics has grown tremendously over the last decade. Next-generation sequencing (NGS) has overcome many of the practical roadblocks that had slowed the adoption of molecular testing for routine clinical diagnosis. In endocrinology, targeted NGS now complements biochemical testing and imaging studies. The goal of this review is to provide clinicians with a guide to the application of NGS to genetic testing for endocrine conditions, by compiling a list of established gene mutations detectable by NGS, and highlighting key phenotypic features of these disorders. As we outline in this review, the clinical utility of NGS-based molecular testing for endocrine disorders is very high. Identifying an exact genetic etiology improves understanding of the disease, provides clear explanation to families about the cause, and guides decisions about screening, prevention and/or treatment. To illustrate this approach, a case of hypophosphatasia with a pathogenic mutation in the ALPL gene detected by NGS is presented.

Ambulatory glucose profile analysis of the juvenile diabetes research foundation continuous glucose monitoring dataset-Applications to the pediatric diabetes population.

Increased continuous glucose monitor (CGM) use presents both the benefit and burden of increased data for clinicians to rapidly analyze. The ambulatory glucose profile (AGP) is an evolving a universal software report for CGM data analysis.

Successful Application of Closed-Loop Artificial Pancreas Therapy after Islet Autotransplantation

Total pancreatectomy with islet autotransplantation (TPIAT) may relieve the pain of chronic pancreatitis while avoiding postsurgical diabetes. Minimizing hyperglycemia after TPIAT limits beta cell apoptosis during islet engraftment. Closed‐loop (CL) therapy combining an insulin pump with a continuous glucose monitor (CGM) has not been investigated previously in islet transplant recipients. Our objective was to determine the feasibility and efficacy of CL therapy to maintain glucose profiles close to normoglycemia following TPIAT. Fourteen adult subjects (36% male; aged 35.9 ± 11.4 years) were randomized to subcutaneous insulin via CL pump (n = 7) or multiple daily injections with blinded CGM (n = 7) for 72 h at transition from intravenous to subcutaneous insulin. Mean serum glucose values were significantly lower in the CL pump group than in the control group (111 ± 4 vs. 130 ± 13 mg/dL; p = 0.003) without increased risk of hypoglycemia (percentage of time <70 mg/dL: CL pump 1.9%, control 4.8%; p = 0.46). Results from this pilot study suggest that CL therapy is superior to conventional therapy in maintaining euglycemia without increased hypoglycemia. This technology shows significant promise to safely maintain euglycemic targets during the period of islet engraftment following islet transplantation.