Surgical or Medical Treatment for Pediatric Type 2 Diabetes (ST2OMP)

小儿 2 型糖尿病的手术或药物治疗 (ST2OMP)

• 批准号: 10247673
• 负责人: MICHAEL A. HELMRATH
• 金额: $ 66.15万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247673
• 关键词: Adipose tissue; Adolescent; Adult; Affect; Age; Alpha Cell; Beta Cell; Body mass index; Caring; Cell physiology; Childhood; Clinical; Data; Dependence; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease remission; Dyslipidemias; Enrollment; Functional disorder; Future; Gastrectomy; Gastric Bypass; Glycosylated hemoglobin A; Goals; Hepatic; Hormone secretion; Hypertension; Incidence; Insulin; Insulin Resistance; Islets of Langerhans; Knowledge; Literature; Measures; Medical; Metabolic; Metabolism; Metformin; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Outcome; Pancreas; Participant; Pathway interactions; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Procedures; Prognosis; Prospective Studies; Site; Son; Structure of beta Cell of islet; Testing; Time; Tissues; Uncontrolled Study; Youth; bariatric surgery; blood glucose regulation; cohort; comorbidity; experience; glucose production; glycemic control; health care service utilization; improved; incretin hormone; innovation; insulin secretion; insulin sensitivity; lipid metabolism; liver metabolism; mortality; non-alcoholic fatty liver disease; primary endpoint; primary outcome; prospective; recruit; response; rosiglitazone; secondary endpoint; secondary outcome; sex; surgery outcome

PROJECT SUMMARY Youth-onset type 2 diabetes (T2D) leads to early dependence on exogenous insulin and progression of T2D co-morbidities, including dyslipidemia, hypertension, non-alcoholic fatty liver disease and diabetic kidney dis- ease. The pathophysiology of T2D in youth differs considerably from adults and current treatment approaches are inadequate for youth. Thus, exploration of innovative approaches to reduce co-morbidities is critical. Meta- bolic bariatric surgery (MBS) significantly improves multiple outcomes in adults with T2D. Initial small, uncon- trolled studies of Roux-en-Y gastric bypass also suggest beneficial effects in youth with T2D, but definitive studies and understanding of mechanisms in youth-onset T2D are lacking, especially with the now more com- mon form of MBS, vertical sleeve gastrectomy (VSG). Our long-term goal is to improve the treatment of youth- onset T2D to reduce morbidity and mortality. Our central hypothesis is that VSG will be more effective in reduc- ing glycemia and comorbidities than the best currently available medical treatment: advanced medical therapy (AMT), via pancreatic, enterohepatic and/or metabolic changes. To test this hypothesis, we will enroll 90 ado- lescents with T2D across two sites and compare the effects of VSG vs. AMT on glycemic control and T2D-as- sociated comorbidities, as well as underlying mechanisms. Our sites have collaborative pediatric medical and surgical expertise, including use of non-invasive metabolic measures in MBS and T2D and collectively have a large, diverse adolescent T2D cohort, making us uniquely positioned to accomplish these aims. Our rationale is that 1) there is a critical need to determine the impact of VSG over AMT in youth-onset T2D, and 2) im- proved knowledge of the mechanisms underlying the impact of MBS will direct future non-surgical approaches to mimic MBS less invasively. Aim 1 will evaluate the effects of VSG vs. AMT on glycemic control and T2D- associated co-morbidities. We hypothesize that a higher proportion of youth with T2D receiving VSG vs. AMT will achieve the primary endpoint of HbA1c <6% with higher rates of remission (lower incidence) of comorbidi- ties at 1 and 2 years. We will also explore the impact of T2D duration, BMI, sex and initial HbA1c on the pri- mary outcome. Aim 2 will elucidate mechanisms by which VSG & AMT influence pancreatic islet cell function, enterohepatic metabolism and tissue-specific insulin sensitivity, and their contributions to glycemic control in youth with T2D. We hypothesize that the primary outcome of β-cell function will improve in T2D youth undergo- ing VSG vs. AMT at 1 and 2 years. Secondary endpoints include whole-body IR, tissue-specific IR, incretin re- sponse and α-cell function to understand mechanisms underlying improvements. These results will determine whether MBS is more effective than AMT in promoting glycemic control and reducing co-morbidities in youth- onset T2D, an outcome that would dramatically improve the lives of youth who currently have a dismal progno- sis. Further, this proposal will help understand the mechanisms underlying MBS in youth, to guide the develop- ment of future treatments that could target these same pathways without the need for surgery.

项目摘要 青年发病的2型糖尿病（T2 D）导致早期依赖外源性胰岛素和T2 D进展 合并症，包括血脂异常、高血压、非酒精性脂肪肝和糖尿病肾病， 放松。青年T2 D的病理生理学与成人和目前的治疗方法有很大不同 不适合年轻人。因此，探索创新方法以减少合并症至关重要。Meta- 弯曲减肥手术（MBS）显著改善了成人T2 D患者的多种结局。最初的小，uncon- Roux-en-Y胃旁路术的控制性研究也表明对T2 D青年患者有益， 缺乏对青年发病的T2 D机制的研究和理解，特别是随着现在越来越多的共同点， 垂直袖状胃切除术（VSG）。我们的长期目标是改善青少年的待遇- 2型糖尿病发病，以降低发病率和死亡率。我们的中心假设是，VSG将更有效地减少- 与目前最好的药物治疗相比， (AMT)通过胰腺、肠肝和/或代谢变化。为了验证这一假设，我们将招募90名ado- 两个研究中心的T2 D患者，并比较VSG与AMT对血糖控制和T2 D-as- 相关的合并症，以及潜在的机制。我们的网站有协作儿科医疗和 外科专业知识，包括在MBS和T2 D中使用非侵入性代谢措施， 庞大、多样化的青少年T2 D队列，使我们处于实现这些目标的独特地位。我们的理据 1）迫切需要确定VSG相对于AMT在青年发作的T2 D中的影响，以及2）IM- 对MBS影响的潜在机制的已证实的知识将指导未来的非手术方法 以更少的侵入性模仿MBS。目的1将评价VSG与AMT对血糖控制和T2 D的影响。 相关合并症。我们假设接受VSG的T2 D青年患者比例高于AMT 将达到HbA 1c <6%的主要终点，合并症的缓解率更高（发生率更低）， 1年和2年的关系。我们还将探讨T2 D病程、BMI、性别和初始HbA 1c对原发性高血压的影响。 玛丽的结局。目的2阐明VSG和AMT影响胰岛细胞功能的机制， 肝肠代谢和组织特异性胰岛素敏感性，以及它们对糖尿病患者血糖控制的作用 青少年T2 D我们假设，β细胞功能的主要结果将改善2型糖尿病青年接受- 在1年和2年时比较VSG与AMT。次要终点包括全身IR、组织特异性IR、肠促胰岛素再摄取、 sponse和α-细胞功能，以了解改善的机制。这些结果将决定 MBS在促进血糖控制和减少青年合并症方面是否比AMT更有效- 发病T2 D，这一结果将大大改善目前患有抑郁症的年轻人的生活， 姐此外，这一建议将有助于了解青年MBS的机制，以指导发展- 未来的治疗方法，可以针对这些相同的途径，而不需要手术。