Taylor Simeon I, Montasser May E, Yuen Ashley H, Fan Hubert, Yazdi Zhinoosossadat Shahidzadeh, Whitlatch Hilary B, Mitchell Braxton D, Shuldiner Alan R, Muniyappa Ranganath, Streeten Elizabeth A, Beitelshees Amber L
Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Diabetes, Endocrinology, and Obesity Branch, National institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
medRxiv. 2023 May 3:2023.03.15.23287166. doi: 10.1101/2023.03.15.23287166.
GLP1R agonists provide multiple benefits to patients with type 2 diabetes - including improved glycemic control, weight loss, and decreased risk of major adverse cardiovascular events. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses.
Exenatide (5 µg, sc) or saline (0.2 mL, sc) was administered to 62 healthy volunteers. Frequently sampled intravenous glucose tolerance tests were conducted to assess the impact of exenatide on insulin secretion and insulin action. This pilot study was designed as a crossover study in which participants received exenatide and saline in random order.
Exenatide increased first phase insulin secretion 1.9-fold (p=1.9×10 ) and accelerated the rate of glucose disappearance 2.4-fold (p=2×10 ). Minimal model analysis demonstrated that exenatide increased glucose effectiveness (S ) by 32% (p=0.0008) but did not significantly affect insulin sensitivity (S ). The exenatide-induced increase in insulin secretion made the largest contribution to inter-individual variation in exenatide-induced acceleration of glucose disappearance while inter-individual variation in the drug effect on S contributed to a lesser extent (β=0.58 or 0.27, respectively).
This pilot study provides validation for the value of an FSIGT (including minimal model analysis) to provide primary data for our ongoing pharmacogenomic study of pharmacodynamic effects of semaglutide ( NCT05071898 ). Three endpoints provide quantitative assessments of GLP1R agonists' effects on glucose metabolism: first phase insulin secretion, glucose disappearance rates, and glucose effectiveness.
NCT02462421 (clinicaltrials.gov).
American Diabetes Association (1-16-ICTS-112); National Institute of Diabetes and Digestive and Kidney Disease (R01DK130238, T32DK098107, P30DK072488).
胰高血糖素样肽-1受体（GLP1R）激动剂为2型糖尿病患者带来多种益处，包括改善血糖控制、减轻体重以及降低主要不良心血管事件风险。由于个体对药物的反应存在差异，我们开展了相关研究以确定与药物反应程度相关的基因变异。
对62名健康志愿者皮下注射艾塞那肽（5微克）或生理盐水（0.2毫升）。进行频繁采样的静脉葡萄糖耐量试验，以评估艾塞那肽对胰岛素分泌和胰岛素作用的影响。这项初步研究设计为交叉研究，参与者随机接受艾塞那肽和生理盐水。
艾塞那肽使第一相胰岛素分泌增加1.9倍（p = 1.9×10 ），并使葡萄糖消失速率加快2.4倍（p = 2×10 ）。最小模型分析表明，艾塞那肽使葡萄糖效能（S ）提高32%（p = 0.0008），但对胰岛素敏感性（S ）无显著影响。艾塞那肽诱导的胰岛素分泌增加对艾塞那肽诱导的葡萄糖消失个体间差异贡献最大，而药物对S 的个体间差异贡献较小（β分别为0.58或
