Increased Arterial Stiffness in Adolescents With Obesity.

Increased arterial stiffness (AS) is an early sign of cardiovascular disease. Influence of weight, puberty, and insulin resistance (IR) on AS in adolescents is unclear. Therefore, this study compared AS, assessed with pulse wave velocity (PWV) and augmentation index (AIx), of adolescents with and without obesity and evaluated the influence of puberty and IR on AS. Sixty-two lean and 61 adolescents with obesity were included. Significantly higher PWV was observed in adolescents with obesity (4.1 ms-1 [2.4 to 5.6 ms-1] vs 3.6 ms-1 [0.4 to 6.1 ms-1]; P = .01), while AIx was not significant different. However, significantly higher AIx was observed in adolescents with obesity and IR (3.0 [-17.5% to 28.5%] vs -3.0 [-19.0% to 13.0%]; P = .01). For Tanner stages, no differences were observed. The higher PWV in adolescents with obesity and higher AIx in adolescents with obesity and IR both indicate an increased AS. Consequently, measurement of AS should be considered in adolescents with obesity and IR as part of cardiovascular risk assessment.

Increased Metformin Clearance in Overweight and Obese Adolescents: A Pharmacokinetic Substudy of a Randomized Controlled Trial.

BACKGROUND: In view of the increased use of metformin in obese adolescents, the aim of this study was to determine the pharmacokinetics of metformin in overweight and obese adolescents. METHODS: In overweight and obese adolescents receiving metformin 500 or 1000 mg twice daily for 37 weeks during a clinical trial, blood samples were collected over 8 h during an oral glucose tolerance test. Population pharmacokinetic modeling was performed using NONMEM. RESULTS: Data for 22 overweight and obese adolescents with a mean total body weight (TBW) of 79.3 kg (range 54.7-104.9), body mass index (BMI) of 29.1 kg/m2 (range 22.9-39.3), and age of 15.9 years (range 11.1-17.5) were analysed. In the model, oral clearance (CL/F) of metformin (1.17 l/min [relative standard error of 6%]) increased significantly with TBW (p < 0.01). More specifically, CL/F increased with both developmental weight (WTfor age and length) and excess body weight (WTexcess), for which an excess weight covariate model was proposed. CONCLUSION: The CL/F of metformin in obese adolescents (1.17 l/min) is larger than that in non-obese children (0.55 l/min) and similar to that in adults (1.3 l/min) as reported in the literature. This increase may potentially be explained by increased tubular secretion of metformin. These results appear to indicate that adult dosages of metformin could be considered in obese adolescents if pediatric dosages have been therapeutically ineffective. CLINICALTRIALS.GOV: NCT01487993.

Definition of insulin resistance affects prevalence rate in pediatric patients: a systematic review and call for consensus.

BACKGROUND: As a result of the rising prevalence of childhood obesity, there is an increasing interest in the type 2 diabetes mellitus precursor insulin resistance (IR). The aim of this study is to review definitions (methods and cutoff values) to define IR in children and to apply these definitions to a previously described obese pediatric population. METHODS: A systematic literature review on prevalence and/or incidence rates in children was performed. The extracted definitions were applied to an obese pediatric population. RESULTS: In the 103 identified articles, 146 IR definitions were reported based on 14 different methods. Fasted definitions were used 137 times, whereas oral/intravenous glucose tolerance test-derived methods were used nine times. The homeostasis model for the assessment of insulin resistance (HOMA-IR) and fasted plasma insulin (FPI) were the most frequently used fasted methods (83 and 37 times, respectively). A wide range in cutoff values to define IR was observed, resulting in prevalence rates in the predefined obese pediatric population between 5.5% (FPI>30 mU/L) and 72.3% (insulin sensitivity indexMatsuda≤7.2). CONCLUSIONS: To compare IR incidence and prevalence rates in pediatric populations, a uniform definition of IR should be defined.

The Effect of Eighteen-Month Metformin Treatment in Obese Adolescents: Comparison of Results Obtained in Daily Practice with Results from a Clinical Trial.

Background. In a recent randomized controlled trial (RCT) in obese adolescents, 18 month-treatment with metformin versus placebo was reported to lead to stabilisation of the BMI. This study aimed to compare the effect of metformin on BMI in obese adolescents in daily practice versus results obtained in an RCT. Methods. Obese adolescents treated off label with metformin in daily practice in an outpatient clinic with a follow-up of ≥18 months were identified. Anthropometric and biochemical data were collected at baseline and at 18 months. Patients treated with metformin for 18 months in an RCT were used for comparison. BMI was compared between the two groups. Results. Nineteen patients (median age 14.3 (interquartile range 11.7-15.7) years, BMI 31.3 (28.8-33.8) kg/m2) treated in daily practice were compared to 23 patients receiving metformin in the RCT (age 13.6 (12.6-15.3) years, BMI 29.8 (28.1-34.5) kg/m2). BMI change after 18 months was -0.36 (-2.10-1.58) versus +0.22 (-2.87-1.27) kg/m2 for the two groups, respectively. In the multivariable model, BMI change was not statistically significantly different between the two groups (p = 0.61). Conclusion. Treatment with metformin in obese adolescents in daily practice resulted in a comparable change in BMI as observed in an RCT. This trial is registered with ClinicalTrials.gov number: NCT01487993.

A Follow-up Study on BMI-SDS and Insulin Resistance in Overweight and Obese Children at Risk for Type 2 Diabetes Mellitus.

Objectives. To evaluate body mass index standard deviation score (BMI-SDS), insulin sensitivity, and progression to type 2 diabetes mellitus (T2DM) in children at risk for T2DM approximately 3 years after being diagnosed with overweight/obesity and insulin resistance (measured by Homeostasis Model Assessment of Insulin Resistance [HOMA-IR]). Methods. Out of 86 invited children, 44 (mean age 15.4 ± 3.6 years) participated. Medical history, physical examination, and laboratory workup were performed. Results. While the mean BMI-SDS significantly increased from 2.9 to 3.4, the mean HOMA-IR significantly decreased from 5.5 to 4.6 (baseline vs follow-up visit). Change in HOMA-IR was only due to a decrease in mean fasting plasma insulin (24.1 vs 21.1, P = .073). Conclusions. Although increase in BMI-SDS in these children is worrisome, the American Diabetes Association recommended screening interval of 3 years for children at risk for T2DM is not too long based on the fact that none of our study participants developed T2DM.

METFORMIN: an efficacy, safety and pharmacokinetic study on the short-term and long-term use in obese children and adolescents - study protocol of a randomized controlled study.

BACKGROUND: The prevalence of childhood obesity and insulin resistance is rising, increasing the risk of diabetes mellitus type 2. To prevent these complications, lifestyle intervention is the corner stone in treatment. However, long-term efficacy of lifestyle intervention is questionable. In addition to lifestyle intervention, pharmacological treatments have been explored. Metformin has been shown to be moderately effective to reduce BMI in obese adolescents with hyperinsulinemia. However, data on pharmacokinetics and long-term efficacy and safety are lacking as well as an evidence-based dosing regimen for this age group. The primary objective of the METFORMIN study is to determine the effect of adding metformin treatment to lifestyle intervention in reducing BMI in obese adolescents with insulin resistance. In addition, the pharmacokinetics of metformin in obese adolescents will be studied. METHODS/DESIGN: The METFORMIN study is a multi-centre prospective study that consists of two 18-month phases: a double-blind randomized placebo-controlled trial (part 1) and an open-label follow-up study (part 2). During part 1, the participants will be given metformin 1,000 mg or placebo twice daily and will be offered a lifestyle intervention programme; 144 participants will be included, 72 in each arm. Primary endpoints are reduction in body mass index, insulin resistance, and percentage body fat. DISCUSSION: This study will provide data on short- and long-term efficacy and safety of metformin and on the pharmacokinetics of metformin in obese adolescents. TRIAL REGISTRATION: ClinicalTrials.gov number NCT01487993; EudraCT nr. 2010-023980-17. Registration date: 06-01-2011.

How to screen obese children at risk for type 2 diabetes mellitus?

BACKGROUND: Recommended screening to identify children at risk for diabetes and its precursors impaired glucose tolerance (IGT) and insulin resistance (IR) is fasted plasma glucose (FPG). This study evaluates the added value of fasted plasma insulin (FPI). METHODS: This study analyzed routinely collected data of an oral glucose tolerance test (OGTT) of 311 obese children (age 10.8 ± 3.2 years). Diabetes and IGT were defined according to the American Diabetes Association criteria, IR as homeostasis model assessment (HOMA)-IR ≥3.4. RESULTS: Cases diagnosed with an OGTT if FPG ≥5.6 mmol/L, compared with an OGTT performed if FPG ≥5.6 mmol/L or HOMA-IR ≥3.4, were, respectively, 4 (80%) versus 5 (100%) with diabetes, 7 (28%) versus 16 (64%) with IGT, and 0 (0%) versus 93 (100%) with IR. CONCLUSIONS: Screening with FPG and FPI has equal burden compared with screening with FPG alone, identifies all patients with diabetes, and identifies more patients with precursors of diabetes.