MANATEE-T1D: Metformin ANd AutomaTEd insulin delivery system Effects on renal vascular resistance, insulin sensitivity, and cardiometabolic function in youth with Type 1 Diabetes

项目摘要/摘要： 糖尿病肾病(DKD)和心血管疾病(CVD)仍然是发病率和 1型糖尿病(T1D)患者的死亡率，并随着糖尿病病程和时间的延长而加剧 超出目标血糖范围。然而，T1D是一种复杂的疾病，其病理生理超越了细胞 损伤和胰岛素缺乏包括胰岛素抵抗(IR)和肾血管阻力(RVR)，这些因素 加速心血管疾病风险。我们已经证明，二甲双胍改善了外周胰岛素敏感性(IS)和血管 患有T1D的年轻人每天多次注射胰岛素(MDI)或标准胰岛素泵的僵硬。然而， 二甲双胍对肾脏和血管内皮细胞预后的影响以及T1D技术的影响 二甲双胍在任何简历或肾脏结果中的作用仍不清楚。胰岛素自动给药(AID)系统 结合胰岛素泵、连续血糖监测仪(CGM)和控制算法来调节背景 提供胰岛素并减少外周胰岛素暴露，同时改善在目标范围内的时间并减少 低血糖症。我们推测，AID系统，特别是与二甲双胍联合使用时，可能会调节 RVR和IS，从而影响心脏代谢功能。海牛-T1D是一种随机、双盲、 30名12-21岁艾滋病患者每日服用2,000 mg二甲双胍4个月的安慰剂对照试验 系统与15使用MDI/CGM上的T1D控制青年，这将评估计算的RVR和GOLD的变化 全身和脂肪、动脉僵硬和内皮功能的标准测量。 作为一名儿科内分泌学讲师/研究员，拥有良好的出版和拨款记录，我 通过开发一个独特的利基研究，在新兴的T1D技术领域建立自己的地位 糖尿病技术，无论有没有联合药物治疗，对IS和肾脏以及 青年T1D患者的心血管并发症。K23将支持以下研究目标：1)定义 对氨基马尿酸清除RVR与高胰岛素-正常血糖钳夹下RVR的纵向差异 在服用二甲双胍和AID系统的T1D青年中，2)测试RVR和IS之间的关联，3)评估 体内和体外血管内皮细胞功能随着二甲双胍和艾迪系统的改变而改变。我的职业发展计划 包括专门用于1)培训黄金标准翻译研究的绩效和分析的时间 方法RVR、IS、动脉僵硬和内皮功能，2)获得以患者为导向的指导经验 研究研究，包括研究设计和实施、数据收集和分析以及人员 管理，3)与内分泌学、肾脏病和生物统计学的多学科专家团队合作， 以及4)为旨在开发新技术的独立研究事业奠定基础 同时利用现有的治疗方法在整个生命周期内降低DKD和CVD的风险。我的训练 环境将在Kristen Nadeau博士(Ped教授)的指导下出类拔萃。内分泌学) 杰西卡·肯德里克(肾病学教授)，临床试验、糖尿病、IS、DKD和心血管疾病方面的专家。

PROJECT SUMMARY/ABSTRACT: Diabetic kidney disease (DKD) and cardiovascular disease (CVD) remain the leading causes of morbidity and mortality in people with type 1 diabetes (T1D) and are exacerbated with longer duration of diabetes and time outside goal glycemic range. Yet, T1D is a complex disease with pathophysiology that extends beyond -cell injury and insulin deficiency to include insulin resistance (IR) and renal vascular resistance (RVR), factors that accelerate CVD risk. We have shown that metformin improved peripheral insulin sensitivity (IS) and vascular stiffness in youth with T1D on multiple daily insulin injections (MDI) or standard insulin pumps. However, metformin’s effect on kidney and endothelial outcomes, and the effects of T1D technologies, with or without metformin, on any CV or kidney outcome, remains unknown. Automated insulin delivery (AID) systems combine an insulin pump, continuous glucose monitor (CGM), and control algorithm to modulate background insulin delivery and decrease peripheral insulin exposure while improving time in target range and reducing hypoglycemia. We hypothesize that AID systems, particularly when combined with metformin, may modulate RVR and IS, thereby impacting cardiometabolic function. MANATEE-T1D is a randomized, double-blind, placebo-controlled trial of 4 months of metformin 2,000 mg daily in 30 youth aged 12-21 years with T1D on AID systems vs. 15 control youth with T1D on MDI/CGM which will assess for changes in calculated RVR and gold standard measures of whole-body and adipose IS, arterial stiffness, and endothelial function. As an Instructor/Fellow in Pediatric Endocrinology with a strong publication and grant funding record, I am establishing myself in the burgeoning field of T1D technologies by developing a unique niche studying the effects of diabetes technologies, with or without combination pharmacological therapies, on IS and kidney and cardiovascular complications in youth with T1D. A K23 would support the following research goals: 1) define longitudinal differences in RVR by p-aminohippurate clearance and IS by hyperinsulinemic-euglycemic clamp in youth with T1D on metformin and AID systems, 2) test for associations between RVR and IS, 3) evaluate for in vivo and ex vivo endothelial function changes with metformin and AID systems. My career development plan includes dedicated time to 1) train in the performance and analysis of gold standard translational research methods for RVR, IS, arterial stiffness, and endothelial function, 2) gain experience conducting patient-oriented research studies including study design and execution, data collection and analysis, and personnel management, 3) work with a multidisciplinary team of experts in Endocrinology, Nephrology, and Biostatistics, and 4) establish the foundation for an independent research career aimed at developing novel technologies while leveraging existing therapies to mitigate the risk for DKD and CVD across the lifespan. My training environment will be outstanding with mentorship from Drs. Kristen Nadeau (Professor, Ped. Endocrinology) and Jessica Kendrick (Professor, Nephrology), experts in clinical trials, diabetes, IS, DKD, and CVD.