Pediatric Extrapolation in Type 2 Diabetes: Future Implications of a Workshop.

Extrapolation from adults to youth with type 2 diabetes (T2D) is challenged by differences in disease progression and manifestation. This manuscript presents the results of a mock-team workshop focused on examining the typical team-based decision process used to propose a pediatric development plan for T2D addressing the viability of extrapolation. The workshop was held at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) in Orlando, Florida on March 21, 2018.

Acute effects of betahistine hydrochloride on food intake and appetite in obese women: a randomized, placebo-controlled trial.

BACKGROUND: Central nervous system histaminergic tone is thought to play a role in appetite regulation. In animal models, histamine receptor 1 (HRH1) agonists and histamine receptor 3 (HRH3) antagonists decrease food intake. OBJECTIVE: The objective of this study was to examine the acute effects of betahistine hydrochloride (an HRH1 agonist and HRH3 antagonist) on food intakes and appetites. DESIGN: The study was a proof-of-concept, randomized, double-blinded, placebo-controlled, dose-ranging study performed to examine the effects of betahistine in women with class I or II obesity [body mass index (BMI; in kg/m²) of 30-39.99]. After a 24-h placebo run-in period, subjects received a placebo (n = 19) or 48 (n = 19), 96 (n = 17), or 144 (n = 21) mg betahistine/d for 24 h. Treatment was followed by a buffet test meal to assess energy intake. Hunger, satiety, and desire to eat were measured after consuming the meal by using visual analog scales. Data were analyzed by using regression models with the assumption that there would be an increasing effect of betahistine doses. Analyses were adjusted for age, log fat and lean mass, food preferences, and intake during a buffet test meal obtained during the placebo run-in period. RESULTS: Of the 79 obese women (mean ± SD age: 42 ± 11 y; BMI: 35 ± 3) enrolled in the study, 76 women completed the study. The betahistine dose did not significantly change intakes from those observed during the run-in period of the buffet test meal (P = 0.78). Hunger, fullness, and desire to eat (all P > 0.62) similarly showed no differences according to the betahistine dose. CONCLUSIONS: Betahistine did not produce an effect on food intakes or appetites. More potent histaminergic modulators may be required to elucidate the possible role of histaminergic pathways in human obesity. This trial was registered at clinicaltrials.gov as NCT00459992.

Psychological symptoms and insulin sensitivity in adolescents.

PURPOSE: Symptoms of psychological distress have been linked to low insulin sensitivity in adults; however, little is known about this relationship in pediatric samples. We therefore examined symptoms of depression and anxiety in relation to insulin sensitivity in adolescents. METHODS: Participants were 136 non-treatment-seeking, healthy adolescents (53.2% female) of all weight strata (BMI-z = 1.08 +/- 1.08) between the ages of 12 and 18 years (M = 15.16,SD = 1.55). Adolescents completed questionnaire measures assessing depression and anxiety symptoms. Fasting blood samples for serum insulin and plasma glucose were obtained to estimate insulin sensitivity with the quantitative insulin sensitivity check index. Fat mass and fat-free mass were measured with air displacement plethysmography or dual-energy X-ray absorptiometry. RESULTS: Depressive symptoms were associated with higher fasting insulin and decreased insulin sensitivity even after controlling for fat mass, fat-free mass, height, age, pubertal status, race, and sex (p < 0.01). CONCLUSIONS: As has been described for adults, depressive symptoms are associated with low insulin sensitivity among healthy adolescents. Further experimental and prospective studies are required to determine the directionality of this link.

The stability of metabolic syndrome in children and adolescents.

CONTEXT: Some studies suggest the presence of metabolic syndrome before adulthood may identify those at high risk for later cardiovascular morbidity, but there are few data examining the reliability of pediatric metabolic syndrome. OBJECTIVE: To examine the short- and long-term stability of pediatric metabolic syndrome. DESIGN: Metabolic syndrome was defined as having at least three of the following: waist circumference, blood pressure, and fasting serum triglycerides in the 90th or higher percentile for age/sex; high-density lipoprotein-cholesterol 10th or lower percentile for age/sex; and fasting serum glucose of at least 100 mg/dl. Short-term metabolic syndrome stability (repeated measurements within 60 d) was assessed in obese youth ages 6-17 yr. Long-term metabolic syndrome stability (repeated measurements more than 1.5 yr apart) was studied in 146 obese and nonobese children age 6-12 yr at baseline. PATIENTS AND SETTING: Convenience samples of obese and nonobese youth ages 6-17 yr participating in research studies were collected at a clinical research hospital. RESULTS: Short-term metabolic syndrome stability (repeat measurements performed 19.7 +/- 13.1 d apart) was assessed in 220 children. The diagnosis of metabolic syndrome was unstable in 31.6% of cases. At their short-term follow-up visit, incidence of metabolic syndrome among participants who did not have metabolic syndrome at baseline was 24%. In the long term (repeat measurements performed 5.6 +/- 1.9 yr apart), the diagnosis of metabolic syndrome was unstable in 45.5% of cases. CONCLUSIONS: Cutoff-point-based definitions for pediatric metabolic syndrome have substantial instability in the short and long term. The value of making a cutoff-point-based diagnosis of metabolic syndrome during childhood or adolescence remains in question.

Effects of calcium supplementation on body weight and adiposity in overweight and obese adults: a randomized trial.

BACKGROUND: Some data suggest that increasing calcium intake may help prevent weight gain. OBJECTIVE: To test the hypothesis that calcium supplementation can prevent weight gain in persons who are overweight or obese. DESIGN: Randomized, placebo-controlled trial. Randomization was computer-generated, and allocation was assigned by pharmacy personnel who prepared intervention and placebo capsules. Participants, providers, and those who assessed outcomes were blinded to study group assignment. SETTING: Single research center. PARTICIPANTS: 340 overweight (body mass index [BMI], 25 to <30 kg/m(2)) and obese (BMI > or =30 kg/m(2)) adults (mean age, 38.8 years [SD, 10.5]). INTERVENTION: Calcium carbonate (elemental calcium, 1500 mg/d) (n = 170) or placebo (n = 170) with meals for 2 years. MEASUREMENTS: Changes in body weight and fat mass (primary outcomes). RESULTS: Seventy-five percent of participants completed the trial (78% received calcium; 73% received placebo). There were no statistically or clinically significant differences between the calcium and placebo groups in change in body weight (difference, 0.02 kg [95% CI, -1.64 to 1.69 kg]; P = 0.98), BMI (difference, 0.32 kg/m(2) [CI, -0.41 to 1.02 kg/m(2)]; P = 0.39), or body fat mass (difference, 0.39 kg [CI, -1.04 to 1.92 kg]; P = 0.55). Parathyroid hormone concentrations decreased in the calcium group compared with the placebo group (difference, -0.71 pmol/L [CI, -1.28 to -0.13 pmol/L]). LIMITATION: The study took place at a research center, and its sample was mostly women. CONCLUSION: Dietary supplementation with elemental calcium, 1500 mg/d, for 2 years had no statistically or clinically significant effects on weight in overweight and obese adults. Calcium supplementation is unlikely to have clinically significant efficacy as a preventive measure against weight gain in such patients.

Disordered-eating attitudes in relation to bone mineral density and markers of bone turnover in overweight adolescents.

PURPOSE: To examine the relationships between cognitive eating restraint and both bone mineral density (BMD) and markers of bone turnover in overweight adolescents. METHODS: One hundred thirty-seven overweight (BMI 39.1 +/- 6.8 kg/m(2)) African American and Caucasian adolescent (age = 14.4 +/- 1.4 years) girls (66.4%) and boys were administered the Eating Disorder Examination (EDE) interview and Eating Inventory (EI) questionnaire and underwent dual energy X-ray absorptiometry (DXA) to measure total lumbar spine BMD. Markers of bone formation (serum bone specific alkaline phosphatase and osteocalcin), bone resorption (24-hour urine N-telopeptides), and stress (urine free cortisol) were measured. RESULTS: After accounting for the contribution of demographics, height, weight, serum 25-hydroxyvitamin D, and depressive symptoms, adolescents' weight concern, as assessed by interview, was a significant contributor to the model of urine free cortisol (beta = .30, p < .05). Shape concern, as also assessed by interview, was significantly associated with lumbar spine bone mineral density (beta = -.15, p < .05). Dietary restraint was not a significant predictor in any of these models. CONCLUSIONS: These findings suggest that among severely overweight adolescents, dissatisfaction with shape and weight may be salient stressors. Future research is required to illuminate the relationship between bone health and disordered-eating attitudes in overweight adolescents.

Obesity-related hypoferremia is not explained by differences in reported intake of heme and nonheme iron or intake of dietary factors that can affect iron absorption.

Hypoferremia is more prevalent in obese than nonobese adults, but the reason for this phenomenon is unknown. To elucidate the role dietary factors play in obesity-related hypoferremia, the intake of heme and nonheme iron and the intake of other dietary factors known to affect iron absorption were compared cross-sectionally from April 2002 to December 2003 in a convenience sample of 207 obese and 177 nonobese adults. Subjects completed 7-day food records, underwent phlebotomy for serum iron measurement, and had body composition assessed by dual-energy x-ray absorptiometry, during a 21-month period. Data were analyzed by analysis of covariance and multiple linear regression. Serum iron (mean+/-standard deviation) was significantly lower in obese than nonobese individuals (72.0+/-61.7 vs 85.3+/-58.1 microg/dL [12.888+/-11.0443 vs 15.2687+/-10.3999 micromol/L]; P<0.001). The obese cohort reported consuming more animal protein (63.6+/-34.5 vs 55.7+/-32.5 g/day; P<0.001) and more heme iron (3.6+/-2.8 vs 2.7+/-2.6 mg/day; P<0.001). Groups did not differ, however, in total daily iron consumption, including supplements. Obese subjects reported consuming less vitamin C (77.2+/-94.9 vs 91.8+/-89.5 mg/day; P=0.01), which may increase absorption of nonheme iron, and less calcium (766.2+/-665.0 vs 849.0+/-627.2 mg/day; P=0.038), which may decrease nonheme iron absorption, than nonobese subjects. Groups did not significantly differ in intake of other dietary factors that can impact absorption of iron, including phytic acid, oxalic acid, eggs, coffee, tea, zinc, vegetable protein, or copper. After accounting for demographic covariates and dietary factors expected to affect iron absorption, fat mass (P=0.007) remained a statistically significant negative predictor of serum iron. This cross-sectional, exploratory study suggests that obesity-related hypoferremia is not associated with differences in reported intake of heme and nonheme iron or intake of dietary factors that can affect iron absorption.

Oxygen-uptake efficiency slope as a determinant of fitness in overweight adolescents.

PURPOSE: Peak oxygen uptake (VO2peak) is frequently difficult to assess in overweight individuals; therefore, submaximal measures that predict VO2peak are proposed as substitutes. Oxygen uptake efficiency slope (OUES) has been suggested as a submaximal measurement of cardiorespiratory fitness that is independent of exercise intensity. There are few data examining its value as a predictor of V O2peak in severely overweight adolescents. METHODS: One hundred seven severely overweight (BMI Z 2.50 +/- 0.34) and 43 nonoverweight (BMI Z 0.13 +/- 0.84) adolescents, performed a maximal cycle ergometer test with respiratory gas-exchange measurements. OUES was calculated through three exercise intensities: lactate inflection point (OUES LI), 150% of lactate inflection point (OUES 150), and VO2peak (OUES PEAK). RESULTS: When adjusted for lean body mass, VO2peak and OUES at all exercise intensities were lower in overweight subjects (VO2peak: 35.3 +/- 6.4 vs 46.8 +/- 7.9 mL.kg(-1) LBM.min(-1), P < 0.001; OUES LI: 37.9 +/- 10.0 vs 43.7 +/- 9.2 mL.kg(-1) LBM.min(-1).logL(-1) P < 0.001; OUES 150: 41.6 +/- 9.0 vs 49.8 +/- 11.1 mL.kg(-1) LBM.min(-1).logL(-1) P < 0.001; and OUES PEAK: 45.1 +/- 8.7 vs 52.8 +/- 9.6 mL.kg(-1) LBM.min(-1).logL(-1) P < 0.001). There was a significant increase in OUES with increasing exercise intensity in both groups (P < 0.001). OUES at all exercise intensities was a significant predictor of VO2peak for both groups (r2 = 0.35-0.83, P < 0.0001). However, limits of agreement for predicted VO2peak relative to actual VO2peak were wide (+/- 478 to +/- 670 mL.min(-1)). CONCLUSIONS: OUES differs significantly in overweight and nonoverweight adolescents. The wide interindividual variation and the exercise intensity dependence of OUES preclude its use in clinical practice as a predictor of VO2peak.

Validation of three food frequency questionnaires to assess dietary calcium intake in adults.

OBJECTIVE: To assess the accuracy of three self-administered food frequency questionnaires (FFQs) to measure dietary calcium intake in healthy adults. DESIGN: Estimates of dietary calcium intake from one previously validated and two recently developed FFQs were compared with those from 7-day food records. SUBJECTS/SETTING: Healthy adults enrolled in an outpatient study of calcium supplementation completed the 36-page Dietary History Questionnaire (DHQ), a 3-page Calcium Questionnaire, and a 1-page Short Calcium Questionnaire. Subjects then completed a 7-day food record. MAIN OUTCOME MEASURES: Differences between calcium intake reported on FFQs and calcium intake from food records were compared. STATISTICAL ANALYSES: Spearman correlations were used to measure associations among variables; Bland-Altman pairwise comparisons were conducted to assess systematic and magnitude biases. RESULTS: We studied 341 subjects, 74.5% female, mean (+/-standard deviation) age of 38+/-11 years and body mass index (calculated as kg/m(2)) of 31.8+/-7.1. Mean (+/-standard deviation) food record calcium intake was 896+/-380 mg/day; data from all three FFQs were positively related to food record calcium intake, but accounted for <40% of the variance in food record dietary calcium intake (DHQ: r(2)=0.21; Calcium Questionnaire: r(2)=0.33; Short Calcium Questionnaire: r(2)=0.37; all P<0.001). The DHQ underestimated daily calcium intake (systematic bias: -94 mg/day, P<0.001; magnitude bias r=-0.40; P<0.001), whereas the Calcium Questionnaire overestimated calcium intake (systematic bias +177 mg/day, P<0.001), but had no significant magnitude bias (r=-0.09; P=0.11). The Short Calcium Questionnaire showed minimal systematic bias (+34 mg/day, P=0.09), but had magnitude bias (r=-0.33; P<0.001). CONCLUSIONS: All three FFQs performed reasonably well at estimating dietary calcium intake compared to food records; each may be appropriate for use in select clinical and research settings.

Effects of ovarian failure and X-chromosome deletion on body composition and insulin sensitivity in young women.

OBJECTIVE: Menopause is associated with increased visceral adiposity and reduced insulin sensitivity. It remains unclear whether these changes are due primarily to ovarian failure or aging. The aim of this study was to clarify the impact of ovarian failure on body composition and insulin sensitivity in young women. DESIGN: In a cross-sectional study, we compared main outcome measures (body mass index, body composition by dual-energy x-ray absorptiometry, and insulin sensitivity by Quantitative Insulin Sensitivity Check Index) in three groups: women with 46,XX premature ovarian failure (POF), women with premature ovarian failure associated with 45,X or Turner syndrome (TS), and normal control women (NC). Participants were enrolled in National Institutes of Health Clinical Center protocols between years 2000 and 2005. RESULTS: Mean body mass index (+/- SD) was lower in women with POF (n = 398): 24.3 +/- 5 kg/m versus 27.8 +/- 7 for women with TS (n = 131) and 26.6 +/- 4 for controls (n = 73) (both P < 0.001). Only 33% of women with POF were overweight or obese, compared with 56% of those with TS and 67% of NC women (P < 0.0001 for both). Despite less obesity, women with POF had lower insulin sensitivity (0.367 +/- 0.03) compared with those with TS (0.378 +/- 0.03, P = 0.003) and NC women (0.376 +/- 0.03, P = 0.04). In groups selected for similar age and body mass index, women with POF (n = 89), women with TS (n = 48), and NC women (n = 40) had similar total body and trunk adiposity. After adjustment for age and truncal adiposity, women with POF had significantly lower insulin sensitivity than women with TS (P = 0.03) and NC women (P = 0.049). CONCLUSIONS: In contrast to observations in middle-aged postmenopausal women, ovarian failure in young women is not associated with increased total or central adiposity. In fact, women with TS were similar to NC women, whereas women with POF were leaner. The lower insulin sensitivity observed in women with POF deserves further investigation.

The prevalence of hypovitaminosis D and secondary hyperparathyroidism in obese Black Americans.

CONTEXT: Both obesity (body mass index, BMI > or = 30 kg/m2) and Black race are associated with a higher risk of vitamin D deficiency and secondary hyperparathyroidism. We hypothesized the risk of hypovitaminosis D would therefore be extraordinarily high in obese Black adults. OBJECTIVE: To study the effects of race and adiposity on 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (iPTH). DESIGN, SETTING AND PARTICIPANTS: Cross-sectional study of 379 Black and White adults from the Washington D.C. area. BMI ranged from 19.9 to 58.2 kg/m2. MAIN OUTCOME MEASURES: Prevalence of hypovitaminosis D [25(OH)D < 37.5 nmol/l] and secondary hyperparathyroidism [25(OH)D < 37.5 nmol/l with iPTH > 4.2 pmol/l]. RESULTS: Obese Black subjects had lower mean 25(OH)D, 40.3 (SD, 20.3) nmol/l, compared with obese Whites, 64.5 (29.7), P < 0.001, nonobese Blacks, 53.3 (26.0), P = 0.0025 and nonobese Whites, 78.0 (33.5), P < 0.001. The prevalence of hypovitaminosis D increased with increasing BMI, and was greater (P < 0.001) in Blacks than Whites within all BMI categories examined. Among subjects with BMI > or = 35 kg/m2, 59% of Blacks vs 18% of Whites had hypovitaminosis D (odds ratio 6.5, 95% confidence interval 3.0-14.2). iPTH was negatively correlated with 25(OH)D (r = -0.31, P < 0.0001), suggesting those with hypovitaminosis D had clinically important vitamin D deficiency with secondary hyperparathyroidism. For secondary hyperparathyroidism 35.2% of Blacks met the criteria, compared to 9.7% of Whites (OR 3.6, CI 1.5-98.8). CONCLUSIONS: Obese Black Americans are at particularly high risk for vitamin D deficiency and secondary hyperparathyroidism. Physicians should consider routinely supplementing such patients with vitamin D or screening them for hypovitaminosis D.

Influence of excess adiposity on exercise fitness and performance in overweight children and adolescents.

OBJECTIVE: Relatively little is known about how excess body mass affects adolescents' capacity to perform sustained exercise. We hypothesized that most of the difficulty that severely overweight adolescents have with sustained exercise occurs because the metabolic costs of moving excess mass result in use of a high proportion of their total oxygen reserve. METHODS: We compared results from a maximal cycle ergometry fitness test in 129 severely overweight adolescents who had BMIs of 41.5 +/- 9.7 kg/m2 and ages of 14.5 +/- 1.8 years (range: 12.1-17.8 years) and 34 nonoverweight adolescents who had BMIs of 20.1 +/- 2.9 kg/m2 and ages of 14.5 +/- 1.5 years (range: 12.0-18.1 years). Oxygen uptake (Vo2) was compared at 3 times: during a 4-minute period of unloaded cycling (ULVo2), at the lactate threshold estimated by gas exchange (LTVo2), and at maximal exertion (Vo2 max). Heart rate was obtained at rest and at Vo2 max. Participants also completed a 12-minute walk/run performance test to obtain distance traveled (D12) and heart rate. RESULTS: Absolute LTVo2 and Vo2 max and LTVo2 as a percentage of Vo2 max were not different in overweight and nonoverweight adolescents during the cycle test. However, absolute ULVo2 was significantly greater in overweight adolescents: ULVo2 accounted for 35 +/- 8% of Vo2 max (and 63 +/- 15% of LTVo2) in overweight adolescents but only 20 +/- 5% of Vo2 max (and 39 +/- 12% of LTVo2) in nonoverweight adolescents. Resting heart rate before initiating the cycle test was significantly greater in overweight than nonoverweight adolescents (94 +/- 14 vs 82 +/- 15 beats per minute). However, maximal heart rate during the cycle test was significantly lower in overweight adolescents (186 +/- 13 vs 196 +/- 11 beats per minute). During the walk/run test, mean D12 was significantly shorter for overweight than for nonoverweight adolescents (1983 +/- 323 vs 1159 +/- 194 m). D12 was negatively related to BMI SDS (r = -0.81) and to ULVo2 (r = -0.98). DISCUSSION: Overweight and nonoverweight adolescents had similar absolute Vo2 at the lactate threshold and at maximal exertion, suggesting that overweight adolescents are more limited by the increased cardiorespiratory effort required to move their larger body mass through space than by cardiorespiratory deconditioning. The higher percentage of oxygen consumed during submaximal exercise indicates that overweight adolescents are burdened by the metabolic cost of their excess mass. Their greater oxygen demand during an unloaded task predicted poorer performance during sustained exercise. Exercise prescriptions for overweight adolescents should account for the limited exercise tolerance imposed by excess body mass, focusing on activities that keep demands below lactate threshold so that exercise can be sustained.