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

项目总结/摘要： 糖尿病肾病（DKD）和心血管疾病（CVD）仍然是发病的主要原因， 1型糖尿病（T1 D）患者的死亡率，并随着糖尿病持续时间的延长和时间的延长而加剧 超出目标血糖范围。然而，T1 D是一种复杂的疾病，其病理生理学超出了细胞免疫学。 损伤和胰岛素缺乏包括胰岛素抵抗（IR）和肾血管抵抗（RVR）， 增加CVD风险。我们已经证明二甲双胍可以改善外周胰岛素敏感性（IS）和血管 T1 D青年患者在每日多次胰岛素注射（MDI）或标准胰岛素泵治疗时的僵硬。然而，在这方面， 二甲双胍对肾脏和内皮结局的影响，以及T1 D技术的影响，伴或不伴 二甲双胍对任何CV或肾脏结局的影响仍未知。自动胰岛素输注（AID）系统 将胰岛素泵、连续葡萄糖监测器（CGM）和控制算法组合联合收割机以调节背景 胰岛素输送和降低外周胰岛素暴露，同时改善目标范围内的时间并降低 低血糖我们假设AID系统，特别是与二甲双胍联合使用时， RVR和IS，从而影响心脏代谢功能。MANATEE-T1 D是一种随机、双盲、 一项在30名接受AID治疗的12-21岁T1 D青年中进行的为期4个月二甲双胍2，000 mg每日一次的安慰剂对照试验 系统与15名对照T1 D青少年接受MDI/CGM，将评估计算的RVR和黄金的变化 全身和脂肪IS、动脉硬度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，我有很好的出版和资助记录， 通过发展一个独特的利基研究，在T1 D技术的新兴领域建立自己的地位， 糖尿病技术（联合或不联合药物治疗）对IS和肾脏的影响， T1 D青年患者的心血管并发症。K23将支持以下研究目标：1）定义 对氨基马尿酸清除法测定的RVR和高胰岛素-正葡萄糖钳夹法测定的IS的纵向差异 在接受二甲双胍和AID系统治疗的T1 D青年中，2）检测RVR和IS之间的相关性，3）评估 二甲双胍和AID系统的体内和离体内皮功能变化。我的职业发展计划 包括专门的时间来1）培训金标准转化研究的表现和分析 RVR、IS、动脉僵硬度和内皮功能的方法，2）获得进行以患者为导向的 研究，包括研究设计和执行、数据收集和分析以及人员 管理，3）与内分泌学，肾脏病学和生物统计学的多学科专家团队合作， 四是为自主研发新技术奠定基础 同时利用现有的治疗方法来降低整个生命周期中DKD和CVD的风险。我的训练 环境将是杰出的导师博士克里斯汀纳多（教授，儿科。内分泌学） 和Jessica Kendrick（肾脏病学教授），临床试验、糖尿病、IS、DKD和CVD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.