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: 10674617
• 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/10674617
• 关键词: Acceleration; Address; Adipose tissue; Adopted; Affect; Algorithms; American; Aorta; 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; Continuous Glucose Monitor; Data Analyses; Data Collection; Dedications; 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; Glucose Clamp; Goals; Grant; Hematocrit procedure; Hepatic; Hybrids; Hyperglycemia; Hyperinsulinism; 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; 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; glycemic control; high risk; improved; in vivo; innovation; instructor; insulin sensitivity; insulin sensitivity/resistance; kidney dysfunction; kidney vascular structure; mortality; multidisciplinary; new technology; patient oriented research; peer; pharmacologic; pressure; professor; protein expression; randomized placebo controlled trial; research study; risk mitigation; 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）仍然是发病率和死亡率的主要原因 1 型糖尿病 (T1D) 患者的死亡率随着糖尿病病程和时间的延长而加剧 然而，T1D 是一种复杂的疾病，其病理生理学范围超出了  细胞范围。 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 我们已经证明二甲双胍可改善外周胰岛素敏感性 (IS) 和血管。 患有 T1D 的青少年每天多次注射胰岛素 (MDI) 或标准胰岛素泵会出现僵硬现象。 二甲双胍对肾脏和内皮结果的影响，以及 T1D 技术的影响（有或没有） 二甲双胍对心血管或肾脏结果的影响仍然未知。 结合胰岛素泵、连续血糖监测仪 (CGM) 和控制算法来调节背景 胰岛素输送并减少外周胰岛素暴露，同时改善目标范围内的时间并减少 我们勇敢地承认 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 MANATEE-T1D 是一种随机、双盲、 对 30 名 12-21 岁患有 T1D 的青少年进行为期 4 个月的安慰剂对照试验，每天服用二甲双胍 2,000 毫克 系统与使用 MDI/CGM 的 15 名患有 T1D 的对照青年进行比较，这将评估计算出的 RVR 和黄金的变化 全身和脂肪 IS、动脉僵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，拥有强大的出版物和拨款记录，我 通过开发独特的利基研究，在 T1D 技术的新兴领域确立自己的地位 糖尿病技术（无论是否联合药物治疗）对 IS 和肾脏的影响 K23 将支持以下研究目标：1) 定义 T1D 青少年的心血管并发症。 通过p-氨基马尿酸清除率测定的RVR和通过高胰岛素-正常血糖钳夹测定的IS的纵向差异 使用二甲双胍和 AID 系统的 1D 青少年患者，2) 测试 RVR 和 IS 之间的关联，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 1) 培训黄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) 获得以患者为导向的经验 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、肾病学和生物统计学的多学科专家团队合作， 4）为旨在开发新技术的独立研究事业奠定基础 同时利用现有的疗法来降低整个生命周期中 DKD 和 CVD 的风险。 在 Kristen Nadeau 博士（内分泌学教授）的指导下，环境将非常出色。 Jessica Kendrick（肾病学教授），临床试验、糖尿病、IS、DKD 和 CVD 方面的专家。

项目成果

Pharmacological management of youth with type 2 diabetes and diabetic kidney disease: a comprehensive review of current treatments and future directions.

• DOI: 10.1080/14656566.2023.2203319
• 发表时间: 2023-06
• 期刊: EXPERT OPINION ON PHARMACOTHERAPY
• 影响因子: 3.2
• 作者: Tommerdahl, Kalie L.;Kula, Alexander J.;Bjornstad, Petter
• 通讯作者: Bjornstad, Petter

Response to Letter to the Editor Entitled "The Missing Link Between Coffee Consumption and AKI - Water".

• DOI: 10.1016/j.ekir.2022.09.015
• 发表时间: 2022-11
• 期刊: KIDNEY INTERNATIONAL REPORTS
• 影响因子: 6
• 作者: Tommerdahl, Kalie L.;Bjornstad, Petter;Rebholz, Casey M.;Parikh, Chirag R.
• 通讯作者: Parikh, Chirag R.

Coffee Consumption May Mitigate the Risk for Acute Kidney Injury: Results From the Atherosclerosis Risk in Communities Study.

• DOI: 10.1016/j.ekir.2022.04.091
• 发表时间: 2022-07
• 期刊: KIDNEY INTERNATIONAL REPORTS
• 影响因子: 6
• 作者: Tommerdahl, Kalie L.;Hu, Emily A.;Selvin, Elizabeth;Steffen, Lyn M.;Coresh, Josef;Grams, Morgan E.;Bjornstad, Petter;Rebholz, Casey M.;Parikh, Chirag R.
• 通讯作者: Parikh, Chirag R.

A Pilot Study of the Safety and Efficacy of Alkali Therapy on Vascular Function in Kidney Transplant Recipients.

• DOI: 10.1016/j.ekir.2021.06.006
• 发表时间: 2021-09
• 期刊: Kidney international reports
• 影响因子: 6
• 作者: Bohling R;Grafals M;Moreau K;You Z;Tommerdahl KL;Bjornstad P;Stenson EK;Andrews E;Ramirez-Renteria L;Kendrick J
• 通讯作者: Kendrick J

Leukotriene Antagonist Use is Associated With Lower Systolic Blood Pressure in Adults.

• DOI: 10.1016/j.ekir.2022.11.013
• 发表时间: 2023-03
• 期刊: KIDNEY INTERNATIONAL REPORTS
• 影响因子: 6
• 作者: Lai, Jennifer;Furgeson, Seth;Bjornstad, Petter;You, Zhiying;Tommerdahl, Kalie L.;Kendrick, Jessica
• 通讯作者: Kendrick, Jessica