Restoring vasodilator actions of insulin in patients with type 2 diabetes

恢复胰岛素对 2 型糖尿病患者的血管扩张作用

• 批准号: 10210288
• 负责人: Jaume Padilla
• 金额: $ 49.14万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-20 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10210288
• 关键词: Animals; Area; Arteries; Attention; Beds; Biopsy; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Clinical Research; Data; Defect; Diabetes Mellitus; Doppler Ultrasound; Down-Regulation; Endothelial Cells; Endothelin-1; Endothelium; Equilibrium; Exhibits; Exposure to; Glucose; Glucose Clamp; Goals; Harvest; Heating; Human; Hyperglycemia; Impairment; Insulin; Insulin Resistance; Intervention; Investigation; Lead; Leg; Mediating; Metabolic; Molecular; Nitric Oxide; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathogenesis; Patients; Pharmacology; Phenotype; Physical activity; Physiological; Precipitating Factors; Prevalence; Production; Protein Isoforms; Protein Kinase C; Research; Resistance; Rodent; Role; Signal Transduction; Skeletal Muscle; Stimulus; Testing; Transducers; United States; Up-Regulation; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Visceral; Walking; Work; bariatric surgery; base; blood glucose regulation; experimental study; glucose uptake; glycemic control; improved; loss of function; sedentary; shear stress; therapeutic development

PROJECT SUMMARY/ABSTRACT In type 2 diabetes (T2D), insulin-stimulated blood flow to skeletal muscle is markedly blunted which significantly limits glucose uptake, thus contributing to impaired glucose homeostasis. A detailed understanding of the precipitating factors and mechanisms underlying the defects in vasodilator actions of insulin is critical for the development of therapeutic strategies aimed at improving glycemic control and protecting against cardiovascular disease. Based on our prior work and most recent preliminary data, we propose that in hyperglycemic T2D patients, protein kinase C (PKC) activation drives the upregulation of endothelin-1 (ET-1) and consequent impairment in insulin-induced dilation. Furthermore, we hypothesize that increased vascular exposure to shear stress, associated with physical activity, mitigates these toxic molecular effects of hyperglycemia on endothelial cells and lead to substantial improvements in insulin-induced dilation in T2D. Specifically, we will test the overarching hypothesis that endothelial PKC activation mediates the upregulation of ET-1 and impairment in insulin-induced dilation in patients with T2D, a defect that can be corrected with increased physical activity and shear stress. In Aims 1 and 2, ex vivo functional studies will be performed in isolated visceral resistance arteries from obese T2D and obese non-T2D patients undergoing Roux-en-Y gastric bypass surgery. Through gain- and loss-of-function experiments, we will examine the role of PKC activation in mediating impaired insulin-induced dilation in arteries from T2D patients as well as the role of hyperglycemia and shear stress in modulating insulin-induced dilation. In Aim 3, we will perform a clinical study in patients with T2D to determine the effects of increased walking and shear stress on insulin-stimulated leg blood flow. In particular, we will test the hypothesis that increased walking for 8 weeks decreases vascular PKC activation and ET-1 production, thus leading to an improvement in insulin-stimulated leg blood flow. Leg blood flow via Doppler ultrasound will be assessed during a hyperinsulinemic-euglycemic clamp. Skeletal muscle biopsies will be performed for vascular phenotypic characterization. Furthermore, we will determine if increased leg vascular shear stress using a non-exercise stimulus (i.e., leg heating intervention for 8 weeks) recapitulates the beneficial vascular effects of increased walking. Targeting PKC activation and ET-1, pharmacologically or through an increase in shear stress, may be key for correction of vascular insulin resistance and ultimately improvement of metabolic and cardiovascular outcomes in patients with T2D. Indeed, our research team is poised to move cardiovascular and diabetes research forward in an area currently receiving little attention, despite its importance and clear need for investigation.

项目总结/摘要 在2型糖尿病（T2 D）中，胰岛素刺激的流向骨骼肌的血流明显减弱， 显著限制葡萄糖摄取，从而导致葡萄糖稳态受损。详细 了解促发因素和机制的缺陷，在血管扩张作用的 胰岛素对于旨在改善血糖控制的治疗策略的发展是至关重要的， 预防心血管疾病。根据我们先前的工作和最新的初步数据，我们 提出在高血糖T2 D患者中，蛋白激酶C（PKC）激活驱动了 内皮素-1（ET-1）和随之而来的胰岛素诱导的扩张受损。此外，我们假设， 与体力活动相关的血管暴露于剪切应力的增加减轻了这些毒性分子 高血糖对内皮细胞的影响，并导致胰岛素诱导的血管扩张的实质性改善， 2型糖尿病具体来说，我们将检验内皮细胞PKC激活介导细胞凋亡的总体假设。 2型糖尿病患者ET-1的上调和胰岛素诱导的血管扩张功能的受损， 通过增加体力活动和剪切应力进行校正。在目标1和2中，将进行离体功能研究。 在肥胖T2 D和肥胖非T2 D患者的分离内脏阻力动脉中进行， Roux-en-Y胃旁路手术通过功能获得和功能丧失实验，我们将研究 PKC激活在介导2型糖尿病患者动脉胰岛素诱导扩张受损中的作用以及 高血糖和剪切应力在调节胰岛素诱导的扩张。在目标3中，我们将进行临床 在T2 D患者中进行的一项研究，旨在确定步行和剪切应力增加对胰岛素刺激的 腿部血流特别是，我们将检验增加步行8周减少血管生成的假设。 PKC激活和ET-1产生，从而导致胰岛素刺激的腿部血流量的改善。腿 在高胰岛素-正常血糖钳夹期间通过多普勒超声评估血流。骨骼 将进行肌肉活组织检查以进行血管表型表征。此外，我们将确定，如果 使用非运动刺激增加腿部血管剪切应力（即，腿部加热干预8周） 概括了增加步行对血管的有益作用。靶向PKC激活和ET-1， 通过增加剪切应力，可能是纠正血管胰岛素的关键 抵抗，并最终改善T2 D患者的代谢和心血管结局。 事实上，我们的研究团队正准备在一个领域推动心血管和糖尿病研究向前发展， 目前很少受到关注，尽管它的重要性和明确的调查需要。

项目成果

Role of Endothelin-1 Receptors in Limiting Leg Blood Flow and Glucose Uptake During Hyperinsulinemia in Type 2 Diabetes.

内皮素 1 受体在限制 2 型糖尿病高胰岛素血症期间腿部血流量和葡萄糖摄取中的作用。

• DOI: 10.1210/endocr/bqac008
• 发表时间: 2022
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Young,BenjaminE;Padilla,Jaume;Finsen,StineH;Fadel,PaulJ;Mortensen,StefanP
• 通讯作者: Mortensen,StefanP

Leg Fidgeting During Prolonged Sitting Improves Postprandial Glycemic Control in People with Obesity.

• DOI: 10.1002/oby.23173
• 发表时间: 2021-07
• 期刊: Obesity (Silver Spring, Md.)
• 作者: Pettit-Mee RJ;Ready ST;Padilla J;Kanaley JA
• 通讯作者: Kanaley JA

Metabolic Implications of Diet and Energy Intake during Physical Inactivity.

缺乏身体活动期间饮食和能量摄入的代谢影响。

• DOI: 10.1249/mss.0000000000001892
• 发表时间: 2019
• 期刊: Medicine and science in sports and exercise
• 影响因子: 4.1
• 作者: Winn,NathanC;Pettit-Mee,Ryan;Walsh,LaurenK;Restaino,RobertM;Ready,SeanT;Padilla,Jaume;Kanaley,JillA
• 通讯作者: Kanaley,JillA

When gain is greater than loss: effects of physical activity on insulin sensitivity after short-term inactivity in older subjects.

当收获大于损失时：老年受试者短期不活动后体力活动对胰岛素敏感性的影响。

• DOI: 10.1113/jp277110
• 发表时间: 2018
• 期刊: The Journal of physiology
• 作者: Padilla,Jaume;Winn,NathanC;Walsh,LaurenK
• 通讯作者: Walsh,LaurenK