Duodenal nutrient exclusion enhances glucose metabolism via CNS regulation

十二指肠营养排除通过中枢神经系统调节增强葡萄糖代谢

• 批准号: 8699565
• 负责人: Kirk Michael Habegger
• 金额: $ 15.2万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699565
• 关键词: Bariatrics; Body Weight; Body Weight decreased; Body fat; Brain Stem; Carbohydrates; Chronic; Clinical; Communication; Comorbidity; Data; Devices; Diet; Duodenum; Elements; Energy Metabolism; Euglycemic Clamping; Excision; Exclusion; Fatty acid glycerol esters; Foundations; Future; Gastric Bypass; Glucose; Glucose Clamp; Glutamates; Gold; Hepatic; Hormones; Human; Hyperglycemia; Implant; Individual; Intestines; Lipids; Macronutrients Nutrition; Measurement; Measures; Mediating; Melanocortin 4 Receptor; Metabolic; Metabolic syndrome; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuraxis; Neuroanatomy; Neurons; Neurosecretory Systems; Nodose Ganglion; Non-Insulin-Dependent Diabetes Mellitus; Nucleus solitarius; Nutrient; Obesity; Operative Surgical Procedures; Patients; Pharmacology; Population; Procedures; Process; Proteins; Rattus; Receptor Signaling; Regulation; Research Personnel; Resolution; Rodent; Rodent Model; Role; Secondary to; Signal Transduction; Small Intestines; Solid; Stomach; System; Systems Biology; Testing; Training; Viral; Work; base; blood glucose regulation; detection of nutrient; diabetic; feeding; glucose disposal; glucose metabolism; glucose production; glucose tolerance; hindbrain; improved; insight; insulin secretion; melanocortin receptor; operation; pre-clinical; prevent; public health relevance; research study; response; skills; small hairpin RNA; therapy development; transmission process

DESCRIPTION (provided by applicant): Several bariatric operations are currently used to produce sustained weight loss and treat obesity- related comorbidities. Currently considered the gold standard in bariatric surgical procedures, Roux-en-Y Gastric Bypass (RYGB) stimulates a considerable and sustained weight-loss in obese individuals. This reduced adiposity is often accompanied by profound improvement in glucose control of type 2 diabetic subjects. While some of the effects of RYGB on glucose control are secondary to reduced body weight, dramatic changes in gut nutrient sensing/presentation and hormone profile may contribute to the resolution of T2D in many individuals. Accumulating evidence indicates that duodenal nutrient exclusion (DNE) may be an important contributor to the metabolic benefits of RYGB. We can directly test such DNE without gastric restriction or altering the path of ingested nutrients using duodenal, barrier-endolumenal sleeves (DES) that prevent ingested nutrients from interacting with the upper intestine. Early pre-clinical experiments in rodents and clinical experiments in humans point to beneficial effects of DES in individuals with impaired glucose homeostasis. We have successfully established a rodent model of a DES that will allow for the careful mechanistic testing of DES that is not possible in humans. In our hands, we observe that DES results in a small in fat mass and a clear improvement in glucose tolerance, which is above and beyond the effect of the weight loss alone. This proposal will dissect components of glucose handling via hyperinsulinemic-euglycemic clamps. It will also investigate the role of the vagus and the central nervous system in the DES-enhancement of glucose metabolism. Together these studies will test the hypothesis that duodenal nutrient exclusion restores the ability of this nutrient-sensing circuitry to regulate glucose homeostasis.

描述（由申请人提供）：目前有几种减肥手术用于持续减肥和治疗肥胖相关的合并症。Roux-en-Y胃旁路术（RYGB）目前被认为是减肥外科手术的黄金标准，它能刺激肥胖个体显著且持续的减肥。这种肥胖的减少通常伴随着2型糖尿病患者血糖控制的显著改善。虽然RYGB对葡萄糖控制的一些影响是继发于体重减轻，但肠道营养感知/呈现和激素谱的巨大变化可能有助于许多个体的T2D的解决。越来越多的证据表明，十二指肠营养排除（DNE）可能是RYGB代谢益处的重要贡献者。我们可以直接测试这种DNE，而不需要胃限制或改变摄入营养物质的途径