Combined Influence of Puberty and Obesity on Insulin Resistance in Adolescents
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 104
- 试验地点
- 1
- 主要终点
- Insulin Sensitivity
研究概览
简要总结
The Health Influences of Puberty (HIP) Study is designed to explore the relationships between puberty and the onset of type 2 diabetes in adolescents. The results of this study will help us better understand how to prevent type 2 diabetes in these youth. Children go through many changes during puberty, including important hormonal and behavioral alterations. Among these changes, it has long been known that, during puberty, insulin does not work as well as it does before and after puberty. This is called physiologic insulin resistance. In healthy children, this does not cause diabetes or affect blood sugar in any way because the body is able to compensate by making more insulin. Indeed, this is thought to be an important part of the adolescent growth spurt. However, in some children with increased risk for developing type 2 diabetes due to obesity and genetics, the worsening insulin resistance of puberty cannot be compensated for and these youth get diabetes early. The investigators believe this is because type 2 diabetes is rarely, if ever, seen before puberty begins, and the peak of diabetes onset in adolescents occurs at the time of the worst insulin resistance. This specific research project has two goals: 1. To examine effects of obesity on how well the body's insulin works during puberty, and 2. To see if treatment of obese children during this critical period of puberty with a medication that improves insulin resistance (metformin) will help prevent early onset type 2 diabetes.
详细描述
Specific Aims:
Pediatric insulin resistance and related disorders, such as type 2 diabetes mellitus (T2DM), are increasing in prevalence, and portend significant end-organ and cardiovascular morbidity and mortality. Thus, measures aimed at understanding its causes and preventing its onset are critical. The physiologic decrease in insulin sensitivity in all adolescents during puberty is well-established. It is also known that obese adolescents start out less insulin sensitive at the onset of puberty than lean adolescents, and that their insulin sensitivity worsens as puberty progresses. While there are both longitudinal and cross-sectional data confirming the natural recovery of pre-pubertal insulin sensitivity in normal weight adolescents after puberty is completed, it is unknown whether obese adolescents recover their pre-pubertal insulin sensitivity. Failure to regain pre-pubertal insulin sensitivity at the end of puberty, and failure of compensatory insulin secretion, may accelerate progression from obesity to insulin resistance to T2DM in at-risk youth and contribute to long-term cardiovascular risk.
In addition, obesity and insulin resistance are associated with earlier onset of puberty and premature adrenarche in females. Insulin resistance also contributes to the gonadal dysfunction of polycystic ovarian disease in fully pubertal females and is associated with hypogonadism in older adult males. Little is known about effects of obesity and insulin resistance on gonadal function in young males. However, persistent metabolic changes at the end of puberty may contribute to gonadal dysfunction in obese youth. Currently, there are few longitudinal studies in either sex that evaluate the interactions among obesity, insulin resistance and gonadal function during puberty.
The investigators' long-term goal is to better understand the metabolic changes that occur during puberty, their underlying mechanisms, and their potential contribution to adult disease. The overall aim is to evaluate the effects of obesity on the evolution of insulin sensitivity and gonadal function during puberty. In addition, because improvement in insulin action during puberty may slow β-cell deterioration, the investigators will evaluate whether compensatory insulin secretion is also affected in obese adolescents and whether treatment with metformin improves β-cell response.
HYPOTHESES:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 9 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •BMI ≥ 95th percentile
- •At least Tanner 2, but no more than Tanner 3
- •Age ≥ 9 years
- •Absence of impaired glucose tolerance (IGT), impaired fasting glucose (IFG) or Type 2 diabetes mellitus (T2DM)
排除标准
- •Presence of T2DM, IGT or IFG
- •Any disorder or medication known to effect glucose tolerance;
- •Hypertension or hyperlipidemia requiring pharmacological intervention;
- •Weight >300lbs. due to limits of imaging tables.
- •Chronic illness
研究组 & 干预措施
Obese metformin arm
Double-blinded placebo-controlled trial of metformin during puberty, treatment arm Dosage form: Metformin 1000 mg tablets Dosage: 1000 mg by mouth twice daily Duration: From early puberty (Tanner 2-3) until puberty completion (Tanner 5), approximately 3 years
干预措施: Metformin (Drug)
Obese placebo arm
Double-blinded placebo-controlled trial of metformin during puberty, placebo arm Dosage form: Placebo stamped to match 1000 mg metformin tablets Placebo comparator: Stamped placebo pill matching metformin dose Dosage: 1000 mg by mouth twice daily Duration: From early puberty (Tanner 2-3) until puberty completion (Tanner 5), approximately 3 years
干预措施: Placebo (Drug)
结局指标
主要结局
Insulin Sensitivity
时间窗: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline
As measured by in intravenous glucose tolerance test (IVGTT) as calculated by Bergman's minimal model. Higher numbers indicate a better outcome. Patients are randomized to receive metformin or placebo at Tanner stage 2-3 of puberty. They are reassessed at Tanner 4 and again at Tanner 5. At that point, the treatment is stopped and they are reassessed 6 months after stopping treatment to see if effects of treatment persist.
次要结局
- Insulin-like Growth Factor 1(Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline)
- Dehydroepiandrosterone Sulfate(Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline)
- Alanine Transaminase (ALT)(Baseline (Tanner 2-3), Tanner 4, Tanner 5)
- High Density Lipoprotein(Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline)
- Insulin Secretion (Acute Insulin Response to Glucose, AIRg)(Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline)
- Disposition Index(Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline)
- Low Density Lipoprotein(Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline)
- Aspartate Aminotransferase (AST)(Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline)
- Change in Urinary Follicle-stimulating Hormone(Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline)
- Change in Urinary Estradiol Metabolites(Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline)
- Hemoglobin A1c(Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline)
- Percent Body Fat(Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline)
- Total Testosterone(Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline)
- Estradiol(Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline)
- Sex Hormone Binding Globulin(Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline)
- High Sensitivity C-reactive Protein(Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline)
- Leptin(Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline)
- Liver Adipose(Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline)
- Change in Urinary Luteinizing Hormone(Baseline, every 6 months during the trial, Final visit (average 3 yrs after baseline))
- Visceral Adipose(Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline)