Regulation of glucose homeostasis by intestinal macronutrients and surgery

描述(申请人提供)：肥胖、2型糖尿病(T2D)和代谢综合征的日益流行是现代社会最具挑战性和代价最高的医学疾病之一，这增加了改善血糖控制和预防相关并存疾病的新战略的必要性。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，阻碍了更有效的治疗方案的开发。葡萄糖效率(Gel Efficiency，GE)是指葡萄糖独立于胰岛素促进自身代谢的能力，在葡萄糖代谢中的作用与胰岛素大致相当，但其调节机制尚不清楚。由于GE在肥胖和T2D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，胃肠激素成纤维细胞生长因子-19(FGF19)的中枢作用是通过快速而有效地增加GE来降低血糖，这支持了脑中心糖调节系统(BCGs)与胰岛合作调节血糖的证据。BCG的作用也与肠道营养素和减肥手术激活肠-脑-肝(IBL)轴的抗糖尿病效应有关。我们建议使用最先进的手术方法，结合复杂的FSIGT/最小建模、代谢组学和示踪稀释高血糖钳夹技术来确定中枢调节的GE增加是否有助于其中任何一种激活的能力 IBL轴或减肥手术(或两者兼而有之)以改善血糖稳态。此外，我们还将确定特定的常量营养素注入肠腔调节TE分泌FGF15的能力，FGF15是啮齿动物的FGF19同源物。最终，这些研究有望通过肠道营养素激活IBL轴和通过BCG参与的机制激活减肥手术中的葡萄糖来建立GE降低血糖的生理学机制。这一结果将是我们对葡萄糖稳态理解的重大进步，并表明可以通过干预增加GE来补充不需要手术破坏胃肠道的以胰岛为中心的治疗，从而改善T2D的管理。拟议的项目结合了申请者的临床胃肠病学、肝病和营养学兴趣和研究技能，以及该机构相当多的多学科资源，以增进对糖尿病病理生理学的了解，并为未来糖尿病治疗的进展打开大门。

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.