Inflammation in human obesity and type 2 diabetes

人类肥胖和 2 型糖尿病中的炎症

• 批准号: 9128227
• 负责人: Caroline M Apovian
• 金额: $ 74.04万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128227
• 关键词: Address; Affect; Agreement; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Biological Markers; Blood; Boston; Cardiovascular Diseases; Categories; Cell physiology; Cells; Chronic; Clinic; Clinical; Clinical Research; Clinical Trials; Coupled; Cytokine Network Pathway; Development; Disease; Etiology; Future; Genes; Health; Human; Immune; Individual; Inflammation; Inflammatory; Insulin Resistance; Intervention; Logistic Regressions; Measures; Mediating; Medical center; Metabolic; Minority; Modeling; Modification; Monitor; Mus; Myeloid Cells; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathogenesis; Pharmaceutical Preparations; Plasma; Play; Population; Positioning Attribute; Prediabetes syndrome; Recruitment Activity; Regression Analysis; Research; Role; Route; Sampling; Source; Staging; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Validation; Work; clinical practice; cytokine; diabetogenic; follow-up; glycemic control; improved; mathematical methods; meetings; monocyte; network models; predictive marker; prevent; public health relevance; response; targeted treatment

 DESCRIPTION (provided by applicant): Inflammation is generally required for the development of insulin resistance in obese animals, consistent with demonstrations that inflammation predisposes obese people to be metabolically unhealthy. In contrast, obese people with negligible inflammation are often metabolically healthy. The role of inflammation as an accelerator of obesity-associated metabolic decline indicates that an inflammatory signature can predict the transition from obese/metabolically healthy to obese/insulin resistant/type 2 diabetes (T2D). Our proposed work will comprehensively define inflammatory signature(s) during T2D etiology and pathogenesis to fill critical gaps in 1. Identifying people most likely to transition to T2D in response to obesity; 2. Pinpointing treatments to new targets thus improve the currently modest efficacy of anti-inflammatory drugs in T2D; and 3. Using targeted therapies to uncouple obesity from inflammatory-mediated complications such as T2D and cardiovascular disease. We have used a multivariate mathematical approach to identify a previously unappreciated inflammatory signature that differentiates obese/non-T2D, obese/pre-T2D and obese/T2D subjects. This signature includes multiple T cell cytokines, many of which are preferentially produced by the Th17 or Th1 T cell subsets. Our identification of a human T cell inflammatory signature coupled with the proposed extention of the analyses to additional putative sources of "diabetogenic" inflammation provide unique opportunities to address important outstanding questions in the relationship between inflammation and T2D pathogenesis. We will test the hypothesis that a T cell signature that distinguishes T2D from non-T2D subjects is a predictive biomarker for T2D pathogenesis through a longitudinal multiple-PI project involving experts in human immunometabolism, cytokine network modeling and clinical research in obesity. The possibility that a cytokine signature validated by the proposed work will identify people who require more intensive monitoring, intervention or new anti-inflammatory drugs to delay or prevent obesity-associated T2D has tremendous potential to change clinical practice, emphasizing both the impact and the urgency of the project.