Cerebral blood flow is lower in youth with type 2 diabetes compared to obese controls: A pilot study.

AIM: The cerebral vasculature may be susceptible to the adverse effects of type 2 diabetes. In this pilot study, we compared cerebral blood flow (CBF) in youth with type 2 diabetes to obese, euglycemic controls, and explored the association between CBF and a non-invasive measure of atherosclerosis, carotid intima-medial thickness (IMT). METHODS: Global and regional CBF were compared between youth with type 2 diabetes (mean age 16.7 ± 2.0 years, n = 20) and age, race, and sex similar obese youth without diabetes (17.4 ± 1.9 years, n = 19) using arterial spin labeling magnetic resonance imaging. Mean CBF values were compared between groups. Voxel-wise results were evaluated for statistical significance (p < 0.05) after adjustment for multiple comparisons. Carotid IMT in the type 2 diabetes group was correlated with CBF. RESULTS: Compared to obese controls, the type 2 diabetes group had significantly lower global CBF (49.7 ± 7.2 vs. 63.8 ± 11.5 ml/gm/min, p < 0.001). Significantly lower CBF was observed in multiple brain regions for the type 2 diabetes group, while no regions with higher CBF were identified. In the type 2 diabetes group, carotid IMT was inversely correlated with CBF, both globally (r = -0.70, p = 0.002) and in regional clusters. CONCLUSIONS: In this pilot study, lower CBF was seen in youth with type 2 diabetes compared to youth with obesity and IMT was inversely correlated with CBF. Cerebrovascular impairment may be present in youth with type 2 diabetes. These findings could represent a mechanistic link to explain previously reported brain volume and neurocognitive differences.

A Clinic-based Approach to Diagnosis and Management of Prediabetes in High-risk Children and Adolescents.

BACKGROUND: Type 2 diabetes (T2D) in youth is increasing in prevalence. Diabetes screening is recommended for at-risk youth but best-practice strategies for management of pediatric prediabetes are unknown. This study leverages a pediatric prediabetes clinic to assess identification of high-risk patients, the rate of clinic follow-up and progression to T2D in youth over time. METHODS: Retrospective chart review of children referred to a single center for evaluation of prediabetes over a 3-year period. Measurements included hemoglobin A1c (HbA1C) and oral glucose tolerance testing. Patients were classified as normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or T2D based on 2019 American Diabetes Association criteria. Patients classified as IGT/T2D were prescribed metformin. RESULTS: Of the 254 patients included; 25.6% had IGT and 6.7% had T2D. The IGT/T2D groups were older and more obese than the NGT group. There was a moderate correlation between HbA1C and fasting glucose (r = 0.59, P < 0.001); HbA1C and 2-hour glucose (r = 0.63, P < 0.001). Over the 3-year study, 52 of 82 patients with IGT/T2D (63%) returned for follow-up. Four patients regained NGT; 3 of those had isolated impaired fasting glucose (100 to 102 mg/dL). Three patients (4.6%) progressed from IGT to T2D over an average of 13 ±â€…6.2 months. In those patients, body mass index had increased 1.7 ±â€…2.3 kg/m2 from baseline. CONCLUSIONS: A pediatric prediabetes clinic may allow for identification of high-risk youth but lost to follow-up rates are high. Continued weight gain is a risk factor for progression to T2D and effective weight management programs are needed.

Central Diabetes Insipidus in a Patient With NFKB2 Mutation: Expanding the Endocrine Phenotype in DAVID Syndrome.

CONTEXT: Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome is a recently described, rare disorder characterized by anterior pituitary hormone deficiencies and common variable immunodeficiency associated with NFKB2 mutations. Posterior pituitary hormone deficiencies have not been reported in patients with DAVID syndrome. CASE DESCRIPTION: We report a pediatric patient who initially presented with hypogammaglobulinemia and alopecia totalis, who was identified to have a de novo NFKB2 mutation at one year of age. He developed central diabetes insipidus and central adrenal insufficiency at three and four years of age, respectively. At seven years of age, he had not developed GH or TSH deficiencies. Whole exome sequencing ruled out known genetic causes of central diabetes insipidus, adrenal insufficiency, and hypopituitarism. CONCLUSION: This is a report of central diabetes insipidus in a patient with DAVID syndrome caused by an NFKB2 mutation. This case report expands the evolving endocrine phenotype associated with NFKB2 mutations beyond anterior pituitary deficiencies.

Brain gray matter volume differences in obese youth with type 2 diabetes: a pilot study.

BACKGROUND: Adults with type 2 diabetes (T2D) have significantly lower gray matter volume (GMV) compared to healthy peers. Whether GMV differences exist in youth with T2D remains unclear. Thus, we compared global and regional GMV between obese youth with T2D with age, race and sex similar healthy controls. METHODS: In a cross-sectional study, 20 obese youth with T2D underwent T1-weighted brain magnetic resonance imaging (MRI). Comparisons were made to 20 age, race and sex similar controls. Differences in global and regional GMV between groups were identified using voxel-based morphometry (VBM). RESULTS: Youth with T2D had a significantly lower global GMV-to-intracranial volume ratio (0.51±0.02 in T2D vs. 0.53±0.02 in controls, p=0.02, Cohen's d=0.85). There were 14 regions where GMV was significantly lower in the T2D group, and nine of these were found in either the temporal or occipital lobes. There were six regions with increased GMV in T2D. All regional differences were significant at p<0.05 after adjusting for multiple comparisons. CONCLUSIONS: Results from this pilot study show obese youth with T2D have significantly lower global GMV and regional GMV differences, when compared to their age, race and sex similar peers. Future work is needed to determine whether these brain findings are a direct result of adolescent-onset T2D.

Obese adolescents with type 2 diabetes perform worse than controls on cognitive and behavioral assessments.

BACKGROUND: Children with type 1 diabetes demonstrate worse cognitive performance compared with their peers. Little is known regarding the cognitive and behavioral performance in obese adolescents with type 2 diabetes. METHODS: Cross sectional evaluation of 20 obese adolescents with type 2 diabetes and 20 healthy adolescents was performed in Cincinnati, Ohio. Cognitive tests that included measures of processing speed, working memory, verbal and semantic fluency and parent reports of executive function and problem behavior were compared. Academic achievement and the relationship between cognitive/behavioral scores and diabetes duration and diabetes control (hemoglobin A1c) were assessed in the type 2 diabetes group only. RESULTS: The type 2 diabetes group had mean duration of diabetes of 2.8 ± 2.2 yr and hemoglobin A1c of 7.9 ± 2.2%. Adolescents with type 2 diabetes scored lower than controls on tests of working and verbal memory and processing speed (all p < 0.05) and worse for Internalizing, Externalizing, and Total Problems behaviors on the Child Behavior Checklist (all p < 0.05). Adolescents with type 2 diabetes scored below the population mean in academic achievement, most notably calculation. Working memory and processing speed were negatively correlated with duration of diabetes (r = -0.50 and -0.47, respectively, p < 0.05). CONCLUSIONS: Obese youth with type 2 diabetes score poorly compared with controls on multiple assessments of cognitive function and adaptive behavior. Further work is needed to determine if these effects are driven by obesity, diabetes or other demographic and socioeconomic risk factors.

Suboptimal Clinical Documentation in Young Children with Severe Obesity at Tertiary Care Centers.

Background and Objectives. The prevalence of severe obesity in children has doubled in the past decade. The objective of this study is to identify the clinical documentation of obesity in young children with a BMI ≥ 99th percentile at two large tertiary care pediatric hospitals. Methods. We used a standardized algorithm utilizing data from electronic health records to identify children with severe early onset obesity (BMI ≥ 99th percentile at age <6 years). We extracted descriptive terms and ICD-9 codes to evaluate documentation of obesity at Boston Children's Hospital and Cincinnati Children's Hospital and Medical Center between 2007 and 2014. Results. A total of 9887 visit records of 2588 children with severe early onset obesity were identified. Based on predefined criteria for documentation of obesity, 21.5% of children (13.5% of visits) had positive documentation, which varied by institution. Documentation in children first seen under 2 years of age was lower than in older children (15% versus 26%). Documentation was significantly higher in girls (29% versus 17%, p < 0.001), African American children (27% versus 19% in whites, p < 0.001), and the obesity focused specialty clinics (70% versus 15% in primary care and 9% in other subspecialty clinics, p < 0.001). Conclusions. There is significant opportunity for improvement in documentation of obesity in young children, even years after the 2007 AAP guidelines for management of obesity.

Developing an Algorithm to Detect Early Childhood Obesity in Two Tertiary Pediatric Medical Centers.

OBJECTIVE: The objective of this study is to develop an algorithm to accurately identify children with severe early onset childhood obesity (ages 1-5.99 years) using structured and unstructured data from the electronic health record (EHR). INTRODUCTION: Childhood obesity increases risk factors for cardiovascular morbidity and vascular disease. Accurate definition of a high precision phenotype through a standardize tool is critical to the success of large-scale genomic studies and validating rare monogenic variants causing severe early onset obesity. DATA AND METHODS: Rule based and machine learning based algorithms were developed using structured and unstructured data from two EHR databases from Boston Children's Hospital (BCH) and Cincinnati Children's Hospital and Medical Center (CCHMC). Exclusion criteria including medications or comorbid diagnoses were defined. Machine learning algorithms were developed using cross-site training and testing in addition to experimenting with natural language processing features. RESULTS: Precision was emphasized for a high fidelity cohort. The rule-based algorithm performed the best overall, 0.895 (CCHMC) and 0.770 (BCH). The best feature set for machine learning employed Unified Medical Language System (UMLS) concept unique identifiers (CUIs), ICD-9 codes, and RxNorm codes. CONCLUSIONS: Detecting severe early childhood obesity is essential for the intervention potential in children at the highest long-term risk of developing comorbidities related to obesity and excluding patients with underlying pathological and non-syndromic causes of obesity assists in developing a high-precision cohort for genetic study. Further such phenotyping efforts inform future practical application in health care environments utilizing clinical decision support.

A novel case of compound heterozygous congenital hyperinsulinism without high insulin levels.

BACKGROUND: Congenital hyperinsulinism leads to unregulated insulin secretion and hypoglycemia. Diagnosis can be difficult and genetic testing may be warranted. CASE: This patient initially presented at 11 months with seizure activity secondary to severe hypoglycemia. Her diagnostic evaluation included genetic studies, which confirmed congenital hyperinsulinism. A novel combination of mutations in the ABCC8 gene leading to diffuse, diazoxide-unresponsive congenital hyperinsulinism was identified. Mutation analysis of ABCC8 showed three variants (R1215W - paternal, pathogenic; W739C - maternal, variant of unknown significance; R1393L - maternal, variant of unknown significance). Her clinical course continues to be complicated by severe, refractory hypoglycemia at age 3 years. CONCLUSION: We describe a novel compound heterozygous mutation leading to diffuse, diazoxide-unresponsive congenital hyperinsulinism. This case illustrates challenges associated with diagnosing and managing congenital hyperinsulinism and the importance of genetic testing.