CIBER de Fisiopatología de la Obesidad y la Nutrición (CIBERobn-Instituto de Salud Carlos III, 28029 Madrid, Spain) and Hospital Universitario Virgen de la Victoria (V.C.-M., L.G.-S., F.J.T.), 29010 Málaga, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM-Instituto de Salud Carlos III, 28029 Madrid, Spain) (X.D., G.P., K.R., N.V., J.V., S.F.-V.) and Hospital Universitari de Tarragona Joan XXIII-Institut d Investigació Sanitária Pere Virgili-Universitat Rovira i Virgili (G.P., K.R., V.V., J.V., S.F.-V.), 43007 Tarragona, Spain; and Hospital Universitari de Bellvitge (N.V., J.P.), 08907 Barcelona, Spain.
J Clin Endocrinol Metab. 2014 May;99(5):E908-19. doi: 10.1210/jc.2013-3350. Epub 2014 Feb 10.
Glucose-dependent insulinotropic peptide (GIP) has a central role in glucose homeostasis through its amplification of insulin secretion; however, its physiological role in adipose tissue is unclear.
Our objective was to define the function of GIP in human adipose tissue in relation to obesity and insulin resistance.
GIP receptor (GIPR) expression was analyzed in human sc adipose tissue (SAT) and visceral adipose (VAT) from lean and obese subjects in 3 independent cohorts. GIPR expression was associated with anthropometric and biochemical variables. GIP responsiveness on insulin sensitivity was analyzed in human adipocyte cell lines in normoxic and hypoxic environments as well as in adipose-derived stem cells obtained from lean and obese patients.
GIPR expression was downregulated in SAT from obese patients and correlated negatively with body mass index, waist circumference, systolic blood pressure, and glucose and triglyceride levels. Furthermore, homeostasis model assessment of insulin resistance, glucose, and G protein-coupled receptor kinase 2 (GRK2) emerged as variables strongly associated with GIPR expression in SAT. Glucose uptake studies and insulin signaling in human adipocytes revealed GIP as an insulin-sensitizer incretin. Immunoprecipitation experiments suggested that GIP promotes the interaction of GRK2 with GIPR and decreases the association of GRK2 to insulin receptor substrate 1. These effects of GIP observed under normoxia were lost in human fat cells cultured in hypoxia. In support of this, GIP increased insulin sensitivity in human adipose-derived stem cells from lean patients. GIP also induced GIPR expression, which was concomitant with a downregulation of the incretin-degrading enzyme dipeptidyl peptidase 4. None of the physiological effects of GIP were detected in human fat cells obtained from an obese environment with reduced levels of GIPR.
GIP/GIPR signaling is disrupted in insulin-resistant states, such as obesity, and normalizing this function might represent a potential therapy in the treatment of obesity-associated metabolic disorders.
葡萄糖依赖性胰岛素促分泌多肽（GIP）通过放大胰岛素分泌在葡萄糖稳态中发挥核心作用；然而，其在脂肪组织中的生理作用尚不清楚。
我们的目的是确定 GIP 在肥胖和胰岛素抵抗相关的人类脂肪组织中的功能。
在 3 个独立队列中，分析了瘦人和肥胖个体的人皮下脂肪组织（SAT）和内脏脂肪（VAT）中的 GIP 受体（GIPR）表达。GIPR 表达与人体测量学和生化变量相关。在常氧和低氧环境以及从瘦人和肥胖患者获得的脂肪来源干细胞中，分析 GIP 在人脂肪细胞系中的胰岛素敏感性反应。
肥胖患者的 SAT 中 GIPR 表达下调，与体重指数、腰围、收缩压以及葡萄糖和甘油三酯水平呈负相关。此外，稳态模型评估的胰岛素抵抗、葡萄糖和 G 蛋白偶联受体激酶 2（GRK2）是与 SAT 中 GIPR 表达密切相关的变量。葡萄糖摄取研究和人脂肪细胞中的胰岛素信号表明，GIP 是一种胰岛素增敏的肠促胰岛素。免疫沉淀实验表明，GIP 促进 GRK2 与 GIPR 的相互作用，并减少 GRK2 与胰岛素受体底物 1 的结合。这些在常氧下观察到的 GIP 作用在低氧培养的人脂肪细胞中丧失。支持这一观点的是，GIP 增加了来自瘦患者的人脂肪来源干细胞的胰岛素敏感性。GIP 还诱导 GIPR 表达，同时下调肠促胰岛素降解酶二肽基肽酶 4。在肥胖环境中，GIPR 水平降低，从肥胖环境中获得的人脂肪细胞中未检测到 GIP 的任何生理作用。
在肥胖等胰岛素抵抗状态下，GIP/GIPR 信号被破坏，使这种功能正常化可能是治疗肥胖相关代谢紊乱的一种潜在疗法。
