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

MANATEE-T1D：二甲双胍和自动胰岛素输送系统对 1 型糖尿病青年肾血管阻力、胰岛素敏感性和心脏代谢功能的影响

• 批准号: 10469560
• 负责人: Kalie L Tommerdahl
• 金额: $ 18.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469560
• 关键词: Address; Adipose tissue; Adopted; Affect; Algorithms; American; Artificial Pancreas; Attenuated; Biometry; Biopsy; Blood Vessels; Body Composition; Body fat; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Caring; Cessation of life; Childhood; Clinical Trials; Complex; Data Analyses; Data Collection; Development Plans; Diabetes Mellitus; Diabetic Nephropathy; Disease; Dose; Endocrinology; Endothelial Cells; Endothelium; Environment; Exposure to; Fatty acid glycerol esters; Foundations; Functional disorder; Funding; Future; Glomerular Filtration Rate; Glucose Clamp; Goals; Gold; Grant; Hematocrit procedure; Hepatic; Hybrids; Hyperglycemia; Hypoglycemia; Immunofluorescence Immunologic; Incidence; Individual; Infusion procedures; Injections; Insulin; Insulin Infusion Systems; Insulin Resistance; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Intervention; Iohexol; Kidney; Longevity; Measures; Mentorship; Metabolic; Metabolic dysfunction; Metformin; Methods; Morbidity - disease rate; Nephrology; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Performance; Peripheral; Personnel Management; Persons; Pharmacology; Publications; Randomized; Regimen; Renal Plasma Flow; Research; Research Design; Research Methodology; Risk; Sampling; System; Technology; Testing; Time; Training; Translational Research; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Vascular resistance; Weight Gain; Work; Youth; aged; arterial stiffness; attenuation; cardiometabolism; cardiovascular disorder risk; career; career development; cell injury; double-blind placebo controlled trial; endothelial dysfunction; euglycemia; experience; fasting glucose; glucose monitor; glycemic control; high risk; improved; improved functioning; in vivo; innovation; instructor; insulin sensitivity; insulin sensitizing drugs; kidney dysfunction; kidney vascular structure; mortality; multidisciplinary; new technology; patient oriented research; peer; pressure; professor; protein expression; randomized placebo controlled trial; research study; resistance factors; standard measure; therapeutic development; Address; Adipose tissue; Adopted; Affect; Algorithms; American; Artificial Pancreas; Attenuated; Biometry; Biopsy; Blood Vessels; Body Composition; Body fat; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Caring; Cessation of life; Childhood; Clinical Trials; Complex; Data Analyses; Data Collection; Development Plans; Diabetes Mellitus; Diabetic Nephropathy; Disease; Dose; Endocrinology; Endothelial Cells; Endothelium; Environment; Exposure to; Fatty acid glycerol esters; Foundations; Functional disorder; Funding; Future; Glomerular Filtration Rate; Glucose Clamp; Goals; Gold; Grant; Hematocrit procedure; Hepatic; Hybrids; Hyperglycemia; Hypoglycemia; Immunofluorescence Immunologic; Incidence; Individual; Infusion procedures; Injections; Insulin; Insulin Infusion Systems; Insulin Resistance; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Intervention; Iohexol; Kidney; Longevity; Measures; Mentorship; Metabolic; Metabolic dysfunction; Metformin; Methods; Morbidity - disease rate; Nephrology; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Performance; Peripheral; Personnel Management; Persons; Pharmacology; Publications; Randomized; Regimen; Renal Plasma Flow; Research; Research Design; Research Methodology; Risk; Sampling; System; Technology; Testing; Time; Training; Translational Research; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Vascular resistance; Weight Gain; Work; Youth; aged; arterial stiffness; attenuation; cardiometabolism; cardiovascular disorder risk; career; career development; cell injury; double-blind placebo controlled trial; endothelial dysfunction; euglycemia; experience; fasting glucose; glucose monitor; glycemic control; high risk; improved; improved functioning; in vivo; innovation; instructor; insulin sensitivity; insulin sensitizing drugs; kidney dysfunction; kidney vascular structure; mortality; multidisciplinary; new technology; patient oriented research; peer; pressure; professor; protein expression; randomized placebo controlled trial; research study; resistance factors; standard measure; therapeutic development

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.

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型糖尿病患者的死亡率（T1D），糖尿病持续时间更长 外部目标血糖范围。然而，T1D是一种复杂的疾病，具有病理生理学，延伸超出细胞 损伤和胰岛素缺乏，包括胰岛素抵抗（IR）和肾血管耐药性（RVR），这些因素 加速CVD风险。我们已经表明，二甲双胍改善了周围胰岛素敏感性（IS）和血管 T1D的年轻人在多次每日胰岛素注射（MDI）或标准胰岛素泵上的僵硬。然而， 二甲双胍对肾脏和内皮结果的影响以及T1D技术的影响 在任何简历或肾脏结果上，二甲双胍仍然未知。自动胰岛素输送（AID）系统 结合胰岛素泵，连续葡萄糖监测器（CGM）和控制算法以调节背景 胰岛素输送并减少周围胰岛素暴露，同时改善目标范围的时间并减少 低血糖。我们假设该辅助系统，尤其是与二甲双胍结合时，可能会调节 RVR，从而影响心脏代谢功能。 Manatee-T1D是一个随机的双盲， 安慰剂对照试验4个月的二甲双胍每天2,000毫克，年龄在30岁的年轻人中，辅助T1D 系统vs. 15在MDI/CGM上具有T1D的控制青年，该系统将评估计算的RVR和Gold的变化 全身和脂肪的标准度量是动脉刚度和内皮功能。 作为儿科内分泌学的讲师/研究员，具有强大的出版物和赠款记录，我是 通过开发一个独特的利基研究来研究T1D技术的水伤领域 糖尿病技术的影响，无论有没有组合药物疗法，IS和肾脏和肾脏的影响 T1D青年的心血管并发症。 K23将支持以下研究目标：1）定义 p-氨基磷酸清除率在RVR方面的纵向差异，并且是高胰岛素 - 埃格血糖夹 在二甲双胍和辅助系统的T1D青年中，2）测试RVR和IS之间的关联，3）评估 体内和外体内皮功能随二甲双胍和辅助系统的变化。我的职业发展计划 包括专用时间到1）训练黄金标准翻译研究的性能和分析 RVR的方法，IS，动脉刚度和内皮功能，2）获得以患者为导向的经验 研究研究，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，肾脏学和生物统计学专家的多学科团队合作， 4）建立旨在开发新技术的独立研究职业的基础 利用现有疗法来减轻整个生命周期中DKD和CVD的风险。我的训练 DRS的指导力量将是杰出的环境。克里斯汀·纳多（Kristen Nadeau）（ped。内分泌学教授） 杰西卡·肯德里克（Jessica Kendrick）（肾脏科教授），临床试验专家，糖尿病，DKD和CVD。