Regulation of glucose homeostasis by intestinal macronutrients and surgery

肠道大量营养素和手术对葡萄糖稳态的调节

• 批准号: 9017811
• 负责人: Jarrad M Scarlett
• 金额: $ 6.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9017811
• 关键词: Bariatrics; Blood; Blood Circulation; Blood Glucose; Body Weight decreased; Brain; Bypass; Carbohydrates; Catheters; Clinical; Comorbidity; Complement; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Diet; Disease; Duodenum; Effectiveness; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Functional disorder; Future; Gastrectomy; Gastric Bypass; Gastroenterology; Gastrointestinal Hormones; Gastrointestinal tract structure; Glucose; Glucose Intolerance; Goals; Hepatic; Hepatology; Homologous Gene; Hormonal; Hormones; Human; Hyperglycemia; Implant; Infusion procedures; Institution; Insulin; Intervention; Intestines; Islets of Langerhans; Lipids; Liver; Location; Macronutrients Nutrition; Measures; Mediating; Medical; Metabolic; Metabolic syndrome; Methods; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Obesity; Operative Surgical Procedures; Outcome; Outcome Study; Pancreas; Pathogenesis; Physiological; Plasma; Positioning Attribute; Prevalence; Prevention; Procedures; Process; Proteins; Rattus; Receptor Signaling; Regimen; Regulation; Reporting; Research; Resources; Rodent; Role; Saline; Sampling; Societies; System; Techniques; Testing; Therapeutic; Therapeutic Effect; Tissues; Tracer; Translating; Vagotomy; Work; bariatric surgery; base; blood glucose regulation; diabetic; diabetic rat; glucose disposal; glucose metabolism; glucose production; glucose tolerance; glucose uptake; glycemic control; improved; insulin secretion; insulin sensitivity; interest; intravenous glucose tolerance test; islet; metabolomics; nerve supply; nutrition; prevent; public health relevance; relating to nervous system; response; skills; uptake

DESCRIPTION (provided by applicant): The increasing prevalence of obesity, type 2 diabetes (T2D), and metabolic syndrome are among the most challenging and costly medical disorders of modern society, heightening the need for new strategies for improving glycemic control and prevention of associated co-morbidities. Hyperglycemia is the primary cause of the many complications of diabetes, but the development of more effect therapeutic regimens has been hampered by our limited understanding of the mechanisms of diabetes pathogenesis. Glucose effectiveness (GE), the ability of glucose to promote its own disposal independently of insulin, makes a contribution approximately equal to that of insulin in glucose disposal, however the mechanisms that regulate GE remain poorly understood. As GE is markedly impaired in obesity and T2D, strategies based on increasing GE have important therapeutic potential. Our recent finding that the central action of the gastrointestinal hormone Fibroblast growth factor-19 (FGF19) lowers blood glucose by rapidly and potently increasing GE supports evidence of a brain-centered glucoregulatory system (BCGS) that works cooperatively with pancreatic islets to regulate blood glucose. A role for the BCGS has also been implicated for the anti-diabetic effect of activation of the intestine-brain-liver (IBL) axis by intestinal nutrients and bariatric surgery We propose to use state-of- the art surgical approaches in combination with sophisticated FSIGT/Minimal Modeling, metabolomics and tracer dilution hyperglycemic clamp techniques to determine if a centrally mediated increase of GE contributes to the ability of either activation of the IBL axis or bariatric surgery (or both) to improve glucose homeostasis. In addition, we will characterize the ability of specific macronutrients infused into the intestinal lumen to regulate te secretion FGF15, the rodent homologue of human FGF19. Ultimately, these studies are anticipated to establish a physiological for GE in the lowering of blood gluocose by activation of the IBL axis by intestinal nutrients and bariatric surgery glucose via a mechanism involving the BCGS. This outcome would constitute a significant advance of our understanding of glucose homeostasis and suggest that improved management of T2D may be achievable through interventions that increase GE to complement islet-centered therapies that would not require surgical disruption of the gastrointestinal tract. The proposed project unites the clinical gastroenterology, hepatology and nutrition interests and research skills of the applicant as well as the considerable multi-disciplinary resources of the institution to advance understanding of the pathophysiology of diabetes and open the door for future advances in diabetes treatment.

描述（由申请人提供）：肥胖、2型糖尿病（T2 D）和代谢综合征的患病率不断增加，是现代社会最具挑战性和最昂贵的医学疾病之一，因此需要新的策略来改善血糖控制和预防相关的合并症。高血糖是糖尿病许多并发症的主要原因，但由于我们对糖尿病发病机制的了解有限，阻碍了更有效治疗方案的开发。葡萄糖有效性（GE），葡萄糖促进其自身处置独立于胰岛素的能力，在葡萄糖处置中的贡献大致等于胰岛素的贡献，然而调节GE的机制仍然知之甚少。由于GE在肥胖和T2 D中明显受损，因此基于增加GE的策略具有重要的治疗潜力。我们最近发现，胃肠道激素成纤维细胞生长因子-19（FGF 19）的中枢作用通过快速有效地增加GE来降低血糖，这支持了以脑为中心的葡萄糖调节系统（BCGS）与胰岛合作调节血糖的证据。BCGS的作用还涉及通过肠营养和减肥手术激活脑-脑-肝（IBL）轴的抗糖尿病作用。我们建议使用最先进的手术方法与复杂的FSIGT/最小建模、代谢组学和示踪剂稀释高血糖钳夹技术相结合，以确定中枢介导的GE增加是否有助于通过肠营养和减肥手术激活脑-脑-肝（IBL）轴。 IBL轴或减肥手术（或两者），以改善葡萄糖稳态。此外，我们将表征注入肠腔的特定常量营养素调节TE分泌FGF 15（人FGF 19的啮齿动物同源物）的能力。最终，预计这些研究将通过涉及BCGS的机制，通过肠道营养素和减肥手术葡萄糖激活IBL轴，确定GE降低血糖的生理学作用。这一结果将构成我们对葡萄糖稳态的理解的一个重大进步，并表明通过增加GE的干预来补充不需要手术破坏胃肠道的胰岛中心疗法，可以改善T2 D的管理。该项目将临床胃肠病学，肝病学和营养学的兴趣和申请人的研究技能以及该机构的大量多学科资源结合起来，以促进对糖尿病病理生理学的理解，并为糖尿病治疗的未来进展打开大门。