Role of the skeletal muscle/pancreatic axis in type 2 diabetes

骨骼肌/胰轴在 2 型糖尿病中的作用

基本信息

批准号：
9014518
负责人：
JOHN P. KIRWAN
金额：
$ 17.32万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-13 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9014518
关键词：
Affect Age Bathing Beta Cell Biochemical Biopsy Specimen Brefeldin A Cell Culture Techniques Cell physiology Cells Chemicals Conditioned Culture Media Contracts Coupling Data Disease Economic Burden Electrophoresis Endocrine Glands Endoplasmic Reticulum Exercise Gender Glucose Goals Golgi Apparatus Health Human Immunoassay Incubated Individual Insulin Resistance Interleukin-6 Islets of Langerhans Lead Link Liquid substance Mass Spectrum Analysis Measures Mediating Metabolic Metabolic Pathway Metabolism Molecular Muscle Muscle Cells Muscle Contraction Muscle Fibers Newly Diagnosed Non-Insulin-Dependent Diabetes Mellitus Outcome Pancreas Pathway interactions Patients Peptides Phenotype Physiologic pulse Physiological Play Population Primary Cell Cultures Protein Isoforms Proteins Proteomics Public Health Regulation Reporting Rest Role Sampling Skeletal Muscle Small Interfering RNA Stimulus System Testing Validation Vesicle Work base blood glucose regulation clinically relevant diabetes management diabetic drug development drug discovery exercise training genetic regulatory protein glucose metabolism health economics immunocytochemistry improved in vitro Model inhibitor/antagonist insulin secretion islet non-diabetic novel pancreatic islet function response skeletal vastus lateralis

Affect Age Bathing Beta Cell Biochemical Biopsy Specimen Brefeldin A Cell Culture Techniques Cell physiology Cells Chemicals Conditioned Culture Media Contracts Coupling Data Disease Economic Burden Electrophoresis Endocrine Glands Endoplasmic Reticulum Exercise Gender Glucose Goals Golgi Apparatus Health Human Immunoassay Incubated Individual Insulin Resistance Interleukin-6 Islets of Langerhans Lead Link Liquid substance Mass Spectrum Analysis Measures Mediating Metabolic Metabolic Pathway Metabolism Molecular Muscle Muscle Cells Muscle Contraction Muscle Fibers Newly Diagnosed Non-Insulin-Dependent Diabetes Mellitus Outcome Pancreas Pathway interactions Patients Peptides Phenotype Physiologic pulse Physiological Play Population Primary Cell Cultures Protein Isoforms Proteins Proteomics Public Health Regulation Reporting Rest Role Sampling Skeletal Muscle Small Interfering RNA Stimulus System Testing Validation Vesicle Work base blood glucose regulation clinically relevant diabetes management diabetic drug development drug discovery exercise training genetic regulatory protein glucose metabolism health economics immunocytochemistry improved in vitro Model inhibitor/antagonist insulin secretion islet non-diabetic novel pancreatic islet function response skeletal vastus lateralis

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项目摘要

DESCRIPTION (provided by applicant): Type 2 diabetes affects 366 million people globally, and 25.8 million in the US alone. It is one of the major public health and economic burdens of the 21st century. Despite the scale of the problem our fundamental understanding of the disease itself is incomplete. In patients with type 2 diabetes, exercise reduces insulin resistance in muscle and increases glucose sensitivity in the pancreas. The objective of this R21 application is to explore the cellular and molecular links between skeletal muscle contraction and downstream regulation of pancreatic insulin secretion. Our central hypothesis is that contracting skeletal muscle secretes myokines that target β-cells and participate in the regulation of glucose stimulated insulin secretion. To test this hypothesis we will generate primary cell cultures from vastus lateralis muscle of newly diagnosed patients with type 2 diabetes and non-diabetic age and gender matched controls, and measure the myokine secretome response to contraction using electrical pulse stimulation (EPS). We will utilize state-of-the-art proteomic analyses, including 2D electrophoresis and mass spectrometry to identify non-targeted myokines, and immunoassays to identify a targeted myokine signature in the media from muscle cells that undergo contraction. We will use computational filtering to identify the secreted myokines. Global physiological validation of our findings will be assessed from the collective effect of these myokines on glucose stimulated insulin secretion from isolated human pancreatic islets. Based on our preliminary human studies in type 2 diabetes, insulin secretion was increased after exercise training. We expect that glucose stimulated insulin secretion and stimulus-secretory- coupling will be increased in islets incubated in media from EPS-conditioned cells. It is expected that myokines secreted during EPS mediate increased pancreatic insulin secretion. We will use chemical inhibition, siRNA and immunocytochemistry to explore the endoplasmic reticulum-Golgi network as a likely secretory pathway for contraction-induced myokine secretion. These studies will provide the initial steps towards a comprehensive and complementary analysis of a biochemical link between skeletal muscle contraction and downstream pancreatic insulin secretion in a clinically relevant population of individuals with type 2 diabetes. We expect that these proof-of-principle studies will lead to the identification of specific myokines that can be used for drug development and diabetes management. The discoveries will also further our understanding of skeletal muscle as an endocrine organ and its role in the regulation of glucose metabolism and insulin secretion in type 2 diabetes.

描述（由适用提供）：2型糖尿病会影响全球3.66亿人，仅在美国，就会影响2580万。它是21世纪的主要公共卫生和经济伯恩斯之一。尽管有问题的规模，但我们对疾病本身的基本理解是不完整的。在2型糖尿病患者中，运动可降低胰岛素抵抗在肌肉中增加胰腺中的葡萄糖敏感性。 R21应用的目的是探索骨骼肌收缩与胰岛分泌的下游调节之间的细胞和分子联系。我们的核心假设是，骨骼肌秘密会诱使靶向β细胞并参与葡萄糖刺激的胰岛素分泌的调节。为了检验这一假设，我们将从新诊断的2型糖尿病患者和非糖尿病年龄和性别匹配的对照组中产生原代细胞培养物，并测量使用电脉冲刺激（EPS）对收缩的肌动物分泌组反应。我们将利用最先进的蛋白质组学分析，包括2D电泳和质谱法来鉴定非靶向的肌动物，并免疫测定识别来自肌肉细胞中培养基中有针对性的肌动物签名，这些肌肉细胞中的肌肉细胞中的肌肉细胞受到了摄取的肌肉细胞。我们将使用计算过滤来识别分泌的肌动物。从这些肌动物对葡萄糖刺激的胰岛素分泌的集体作用中，将评估我们发现的全球物理验证。基于我们在2型糖尿病的人类初步研究，运动训练后胰岛素分泌增加。我们预计，在EPS条件细胞中孵育的胰岛中，葡萄糖刺激的胰岛素分泌和刺激 - 分泌 - 偶联将增加。预计在EPS媒体上分泌的Myokines会增加胰腺胰岛素分泌。我们将使用化学抑制作用，siRNA和免疫细胞化学探索内质网络网络，这可能是合同引起的肌动物分泌的秘密途径。这些研究将提供对骨骼肌收缩与下游胰腺胰岛素分泌之间在临床上相关的2型糖尿病患者中的生物化学联系的全面和完整分析的初步步骤。我们希望这些原则研究将导致识别可用于药物开发和糖尿病管理的特定肌动物。这些发现还将进一步理解骨骼肌作为内分泌器官及其在2型糖尿病中葡萄糖代谢和胰岛素分泌的作用中的作用。