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Pharmacogenomics of Gastric Function & Weight in Obesity

胃功能的药物基因组学

基本信息

批准号：
9098206
负责人：
MICHAEL L. CAMILLERI
金额：
$ 39.57万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9098206
关键词：
Address Adrenergic Agents Adult Affect Age Agonist Alleles Anticonvulsants Bile Acids Biological Markers Blood Glucose Body Weight Body Weight decreased Calories Candidate Disease Gene Cell physiology Characteristics Data Dose Drug Formulations Fasting Fatty acid glycerol esters Feeling Female Fibroblast Growth Factor Functional disorder Funding Gastric Emptying Gastroparesis Genes Genetic Predisposition to Disease Genotype Glucose Glycemic Index Health Healthcare Systems Human Hyperglycemia Individual Inherited Insulin Intake Lead Liquid substance Measurement Medication Management Metformin Mitochondria Motor Obesity Overweight Participant Pathway interactions Patients Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacotherapy Phenotype Phentermine Placebos Plasma Prevalence Public Health Satiation Solid Stomach Subgroup Sympathomimetic Amines TCF7L2 gene Testing United States Ursodeoxycholic Acid Variant Weight adrenergic base clinically relevant cost diabetic diabetic patient diet and exercise exenatide gastrointestinal gastrointestinal function genetic association glucagon-like peptide 1 improved increased appetite insulin secretion male mitochondrial uncoupling protein 3 noradrenergic obesity treatment placebo controlled study receptor response topiramate trait waist circumference

项目摘要

DESCRIPTION (provided by applicant): Obesity prevalence continues to increase worldwide; 69% of U.S. adults are overweight or obese. Despite advances in understanding obesity pathophysiology, weight loss with current non-surgical treatments (diet, exercise and medications) is highly variable, and predictors of weight loss with obesity pharmacotherapy are unknown. In two studies of 328 patients funded by DK67071, obesity was associated with greater fasting gastric volume, accelerated gastric emptying of solids, lower postprandial peak plasma PYY, higher postprandial peak plasma GLP-1, greater calories to achieve satiation [volume to fullness] and to evoke satiety with an ad-libitum meal.. Among candidate genes predisposing to obesity, variants in uncoupling protein (UCP)-3 gene (rs1626521, which influences human mitochondrial function) were associated with gastric motor function, satiation and satiety (significant with correction for testing 15 candidate genes). Our preliminary data shows (a) GLP-1 agonist delays gastric emptying, reduces calorie intake at ad-libitum meal, and weight loss is prominent in T allele carriers of TCF7L2 rs7903146; (b) calorie intake at ad-libitum meal predicted weight loss in response to phentermine-topiramate-ER; (c) ileocolonic delivery ursodeoxycholic acid (UDCA) reduced fasting and postprandial blood glucose, and a subgroup of patients had a marked postprandial insulin response consistent with the hypothesis of pharmacogenetic interaction between UDCA and TGR5 gene variation. We propose to test the overall hypothesis that weight loss with pharmacological agents may be individualized, based on specific abnormalities in quantitative traits, and genotype variation; each could be targeted by pharmacological actions of specific obesity medications. We propose specific aims in three different obesity phenotypes, assessing the potential for a quantitative trait and a related candidate gene to impact the response to treatment compared to placebo among overweight or obese patients: (a) the GLP-1 receptor agonist, exenatide, in those with accelerated gastric emptying, particularly in carriers of TCF7L2 rs7903146 (TT genotype); (b) the centrally acting combination noradrenergic sympathomimetic amine, phentermine, and anticonvulsant, topiramate, in those with reduced satiety (increased appetite), particularly in carriers of variant of UCP-3 rs1626521 genotype, which controls mitochondrial function and cellular energetics; (c) the ileo- colonic delivered UDCA, an activator of TGR5 receptors in obese patients with hyperglycemia treated with metformin, particularly in carriers of variants of TGR-5 rs11554825 genotype. Alternative strategies will be explored through measurements of all quantitative traits that differ between obese and normal weight individuals: gastric emptying of solids and liquids, fasting and postprandial gastric volume, satiation, satiety, postprandial PYY and GLP-1, and glycemic indices (postprandial glucose, insulin). Significance: Our study addresses the treatment of obesity, introducing an era of individualizing drug therapy for obesity based on quantitative biomarkers and pharmacogenomics. Therefore, it addresses an important public health challenge.

描述（由申请人提供）：全球肥胖患病率持续增加; 69%的美国成年人超重或肥胖。尽管在了解肥胖病理生理学方面取得了进展，但目前非手术治疗（饮食，运动和药物）的体重减轻是高度可变的，并且肥胖药物治疗的体重减轻的预测因素尚不清楚。在两项由DK 67071资助的328例患者的研究中，肥胖与空腹胃容量较大、固体胃排空加速、餐后血浆PYY峰值较低、餐后血浆GLP-1峰值较高、达到饱足感[体积与饱足感之比]的热量较高以及随意进食引起饱足感相关。在易患肥胖症的候选基因中，解偶联蛋白（UCP）-3基因（rs 1626521，影响人类线粒体功能）的变异与胃运动功能、饱足感和饱腹感相关（对15个候选基因进行校正后显著）。我们的初步数据显示：（a）GLP-1激动剂延迟胃排空，减少自由进食时的热量摄入，体重减轻在TCF 7 L2 rs7903146 T等位基因携带者中显著;（B）自由进食时的热量摄入膳食预测了对苯那英-托吡酯-ER反应的体重减轻;（c）回结肠递送熊去氧胆酸（UDCA）降低了空腹和餐后血糖，并且一个亚组的患者具有显著的餐后胰岛素反应，这与UDCA和TGR 5基因变异之间的药物遗传学相互作用的假设一致。我们建议测试的总体假设，药物减肥可能是个性化的，基于特定的数量性状异常，和基因型变异;每一个可以通过特定的肥胖药物的药理作用为目标。我们在三种不同的肥胖表型中提出了具体的目标，在超重或肥胖患者中评估与安慰剂相比，数量性状和相关候选基因影响治疗反应的潜力：（a）GLP-1受体激动剂艾塞那肽，在胃排空加速的患者中，特别是在TCF 7 L2 rs7903146携带者中（TT基因型）;（B）中枢作用组合去甲肾上腺素能拟交感神经胺，芬特明，抗惊厥药，托吡酯，在那些减少饱腹感（食欲增加），特别是在控制线粒体功能和细胞能量学的UCP-3 rs 1626521基因型变体的携带者中;（c）回结肠递送的UDCA，在用二甲双胍治疗的患有高血糖症的肥胖患者中，特别是在TGR-5 rs 11554825基因型变体的携带者中，UDCA是TGR 5受体的激活剂。将通过测量肥胖和正常体重个体之间不同的所有定量特征来探索替代策略：固体和液体的胃排空、空腹和餐后胃容量、饱腹感、饱腹感、餐后PYY和GLP-1以及血糖指数（餐后葡萄糖、胰岛素）。重要性：我们的研究解决了肥胖的治疗，介绍了一个时代的个性化药物治疗肥胖的基础上定量生物标志物和药物基因组学。因此，它解决了一个重要的公共卫生挑战。