Megan M. Kelsey

Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria

Background: Mutations in the E-cadherin (CDH1) gene are a well documented cause of hereditary diffuse gastric cancer (HDGC). Development of evidence based guidelines for CDH1 screening for HDGC have been complicated by its rarity, variable penetrance, and lack of founder mutations. Methods: Forty three new gastric cancer (GC) families were ascertained from multiple sources. In 42 of these families at least one gastric cancer was pathologically confirmed to be a diffuse gastric cancer (DGC); the other family had intestinal type gastric cancers. Screening of the entire coding region of the CDH1 gene and all intron/exon boundaries was performed by bi-directional sequencing. Results: Novel mutations were found in 13 of the 42 DGC families (31% overall). Twelve of these mutations occur among the 25 families with multiple cases of gastric cancer and with pathologic confirmation of diffuse gastric cancer phenotype in at least one individual under the age of 50 years. The mutations found include small insertions and deletions, splice site mutations, and three non-conservative amino acid substitutions (A298T, W409R, and R732Q). All three missense mutations conferred loss of E-cadherin function in in vitro assays. Multiple cases of breast cancers including pathologically confirmed lobular breast cancers were observed both in mutation positive and negative families. Conclusion: Germline truncating CDH1 mutations are found in 48% of families with multiple cases of gastric cancer and at least one documented case of DGC in an individual under 50 years of age. We recommend that these criteria be used for selecting families for CDH1 mutational analysis.

Age-related consequences of childhood obesity.

The severity and frequency of childhood obesity has increased significantly over the past three to four decades. The health effects of increased body mass index as a child may significantly impact obese youth as they age. However, many of the long-term outcomes of childhood obesity have yet to be studied. This article examines the currently available longitudinal data evaluating the effects of childhood obesity on adult outcomes. Consequences of obesity include an increased risk of developing the metabolic syndrome, cardiovascular disease, type 2 diabetes and its associated retinal and renal complications, nonalcoholic fatty liver disease, obstructive sleep apnea, polycystic ovarian syndrome, infertility, asthma, orthopedic complications, psychiatric disease, and increased rates of cancer, among others. These disorders can start as early as childhood, and such early onset increases the likelihood of early morbidity and mortality. Being obese as a child also increases the likelihood of being obese as an adult, and obesity in adulthood also leads to obesity-related complications. This review outlines the evidence for childhood obesity as a predictor of adult obesity and obesity-related disorders, thereby emphasizing the importance of early intervention to prevent the onset of obesity in childhood.

Sedentary Behavior and Physical Activity in Youth With Recent Onset of Type 2 Diabetes

OBJECTIVE: With the rise of type 2 diabetes in youth, it is critical to investigate factors such as physical activity (PA) and time spent sedentary that may be contributing to this public health problem. This article describes PA and sedentary time in a large cohort of youth with type 2 diabetes and compares these levels with other large-scale investigations. METHODS: The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) trial is a study in 699 youth, recruited from 15 US clinical centers, aged 10 to 17 years with <2 years of type 2 diabetes and a BMI ≥85th percentile. RESULTS: In comparison with the subset of the NHANES cohort who were obese (BMI ≥95th percentile), TODAY youth spent significantly more time being sedentary (difference averaging 56 minutes per day; P < .001) as assessed by accelerometry. Although moderate to vigorous activity levels in both obese cohorts for all age groups were exceptionally low, younger TODAY boys were still significantly less active than similarly aged NHANES youth. Comparisons between the TODAY girls and other investigations suggest that the TODAY girls also had relatively lower PA and fitness levels. CONCLUSIONS: Adolescents with type 2 diabetes from the large TODAY cohort appear to be less physically active and tend to spend more time being sedentary than similarly aged youth without diabetes identified from other large national investigations. Treatment efforts in adolescents with type 2 diabetes should include decreasing sitting along with efforts to increase PA levels.

Continuous Glucose Monitoring and its Relationship to Hemoglobin A1c and Oral Glucose Tolerance Testing in Obese and Prediabetic Youth

CONTEXT The optimal screening test for diabetes and prediabetes in obese youth is controversial. OBJECTIVE We examined whether glycosylated hemoglobin (HbA1c) or the oral glucose tolerance test (OGTT) is a better predictor of free-living glycemia as measured by continuous glucose monitoring (CGM). DESIGN This was a cross-sectional study of youth 10-18 years old, body mass index (BMI) 85th percentile or greater, with diabetes risk factors. SETTING AND PARTICIPANTS Participants (n = 118) with BMI 85th percentile or greater, not on medications for glucose management, were recruited from primary care and pediatric endocrinology clinics around Denver, Colorado. INTERVENTION HbA1c, fasting plasma glucose, and 2-hour glucose were collected and all participants wore a blinded CGM for 72 hours. MAIN OUTCOME MEASURES CGM outcomes were determined and descriptive statistics calculated. Performance characteristics at current American Diabetes Association cutpoints were compared with CGM outcomes. RESULTS CGM data were successfully collected on 98 obese youth. Those with prediabetes had significantly higher average glucose, area under the curve (AUC), peak glucose, and time greater than 120 and greater than 140 mg/dL (P < .01) on CGM than youth with normal HbA1c or OGTT. HbA1c had a greater magnitude of correlation to CGM average glucose, AUC, and minimum glucose; 2-hour glucose had a greater magnitude of correlation to CGM SD, peak glucose, and time greater than 140 and greater than 200 mg/dL. However, there were no overall differences in the strength comparisons between 2-hour glucose and HbA1c correlations to CGM outcomes. CONCLUSIONS In obese youth, HbA1c and 2-hour glucose performed equally well at predicting free-living glycemia on CGM, suggesting that both are valid tests for dysglycemia screening.

Screening for type 2 diabetes and prediabetes in obese youth: evaluating alternate markers of glycemia – 1,5‐anhydroglucitol, fructosamine, and glycated albumin

Hemoglobin A1c (HbA1c) is increasingly performed over the oral glucose tolerance test (OGTT) as the initial screening test for type 2 diabetes in youth. However, the optimal strategy for identifying type 2 diabetes in youth remains controversial. Alternate glycemic markers have been proposed as potentially useful tools for diabetes screening. We examined the relationships among fructosamine (FA), glycated albumin (GA), and 1,5‐anhydroglucitol (1,5‐AG) with traditional screening tests, HbA1c and OGTT. Youth 10–18 yrs, BMI ≥85th‰, and HbA1c <7.5% had a single visit with measurement of HbA1c, 1,5‐AG, FA, GA, and a standard OGTT. Distributions of FA, GA, and 1,5‐AG by HbA1c and 2‐hour glucose (2hG) categories were compared. Receiver operating characteristic (ROC)‐curves were generated to determine the cut points at which alternate markers maximized sensitivity and specificity for predicting prediabetes and diabetes. One hundred and seventeen, 62% female, 59% Hispanic, 22% White, 17% black, median 14.1 yr, and body mass index (BMI) z‐score 2.3 participated. Median values of each alternate marker differed significantly between prediabetes and diabetes HbA1c and 2hG categories (p < 0.017). Only GA medians differed (p = 0.006) between normal and prediabetes HbA1c. Area under the receiver operating characteristic curves (ROC‐AUCs) for alternate markers as predictors of prediabetes (0.5–0.66) were low; however, alternate marker ROC‐AUCs for identifying diabetes (0.82–0.98) were excellent. Although the alternate markers were poor predictors of prediabetes, they all performed well predicting diabetes by 2hG and HbA1c. Whereas the usefulness of these markers for identifying prediabetes is limited, they may be useful in certain scenarios as second line screening tools for diabetes in overweight/obese youth.

Relationship Between Parental Diabetes and Presentation of Metabolic and Glycemic Function in Youth With Type 2 Diabetes: Baseline Findings From the TODAY Trial

OBJECTIVE Children whose parents have diabetes are at increased risk for developing type 2 diabetes. This report assessed relationships between parental diabetes status and baseline demographics, anthropometrics, metabolic measurements, insulin sensitivity, and β-cell function in children recently diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS The sample included 632 youth (aged 10–17 years) diagnosed with type 2 diabetes for <2 years who participated in the TODAY clinical trial. Medical history data were collected at baseline by self-report from parents and family members. Youth baseline measurements included an oral glucose tolerance test and other measures collected by trained study staff. RESULTS Youth exposed to maternal diabetes during pregnancy (whether the mother was diagnosed with diabetes prior to pregnancy or had gestational diabetes mellitus) were diagnosed at younger ages (by 0.6 years on average), had greater dysglycemia at baseline (HbA1c increased by 0.3% [3.4 mmol/mol]), and had reduced β-cell function compared with those not exposed (C-peptide index 0.063 vs. 0.092). The effect of maternal diabetes on β-cell function was observed in non-Hispanic blacks and Hispanics but not whites. Relationships with paternal diabetes status were minimal. CONCLUSIONS Maternal diabetes prior to or during pregnancy was associated with poorer glycemic control and β-cell function overall but particularly in non-Hispanic black and Hispanic youth, supporting the hypothesis that fetal exposure to aberrant metabolism may have long-term effects. More targeted research is needed to understand whether the impact of maternal diabetes is modified by racial/ethnic factors or whether the pathway to youth-onset type 2 diabetes differs by race/ethnicity.

Self-Reported Dietary Intake of Youth with Recent Onset of Type 2 Diabetes: Results from the TODAY Study

Despite the widely recognized importance of diet in managing diabetes, few studies have documented usual dietary intake in young people with type 2 diabetes. The objectives of our study were to assess dietary intake among a large, ethnically diverse cohort of young people with type 2 diabetes and compare intake to current recommendations. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study is a multicenter randomized clinical trial of 699 youth aged 10 to 17 years. At baseline, following a run-in period that included standard diabetes education, diet was assessed using a food frequency questionnaire between 2004 and 2009. Analysis of variance and nonparametric tests were used to compare mean and median nutrient intakes; logistic regression was used to compare the odds of meeting predefined dietary intake recommendation cutpoints between subgroups of age, sex, and race-ethnicity. Percent of energy from saturated fat was consistently 13% to 14% across all subgroups-substantially exceeding national recommendations. Overall, only 12% of youth met Healthy People 2010 guidelines for intake of <10% of energy from saturated fat and only 1% of youth met American Diabetes Association recommendations for intake of <7% of energy from saturated fat. Dietary intake fell substantially below other Healthy People 2010 targets; only 3% met calcium intake goals, 11% met fruit consumption goals, 5% met vegetable consumption goals, and 67% met grain intake goals. Overall, dietary intake in this large cohort of young people with type 2 diabetes fell substantially short of recommendations, in ways that were consistent by sex, age, and race-ethnicity. The data suggest a critical need for better approaches to improve dietary intake of these young people.

Psychological functioning in adolescents with obesity co-morbidities.

BACKGROUND An understanding of the relationships among obesity severity, medical co-morbidities, and psychological complications is important in the design of interventions to encourage overweight youth and families to accomplish healthy lifestyle changes. METHODS We evaluated associations among psychological status, diagnosed medical co-morbidities consistent with components of the metabolic syndrome, and BMI among 166 obese adolescents (11-18 years) referred for endocrinology consultation. We hypothesized that there would be higher levels of psychological distress among youth with more diagnosed components of the metabolic syndrome (i.e., more medical co-morbidities associated with obesity). RESULTS Contrary to expectation, we found that meeting criteria for extreme obesity alone was more predictive of psychological difficulties. CONCLUSIONS The degree of obesity may be more relevant than the number of associated medical co-morbidities in impacting psychological health. It is important to recognize individual differences between patients in terms of identifying motivating goals for accomplishing weight management.

Alternate glycemic markers reflect glycemic variability in continuous glucose monitoring in youth with prediabetes and type 2 diabetes

To determine whether the alternate glycemic markers, fructosamine (FA), glycated albumin (GA), and 1,5‐anhydroglucitol (1,5AG), predict glycemic variability captured by continuous glucose monitoring (CGM) in obese youth with prediabetes and type 2 diabetes (T2D).

Testosterone concentration and insulin sensitivity in young men with type 1 and type 2 diabetes

Reduced testosterone, a recognized comorbidity of reduced insulin sensitivity (IS) and type 2 diabetes (T2D), has also been reported in adult males with type 1 diabetes (T1D). However, there are limited data on how early reduced testosterone occurs, and whether it is related to the reduced IS in T1D. Leptin, a modulator of the HPG‐axis, may also influence testosterone in T1D. We hypothesized that IS and leptin would be associated with total testosterone (TT), and free androgen index (FAI) in adolescent males with T1D.