Department of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland.
Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.
Int J Obes (Lond). 2018 Apr;42(4):826-834. doi: 10.1038/ijo.2017.305. Epub 2017 Dec 13.
Glucose-dependent insulinotropic peptide (GIP) provides a novel link between the immune system and the gut, although results from different experimental and observational studies are contradictory, ranging from anti-inflammatory, through neutral to pro-inflammatory action of GIP. Thus, the aim of this study was to analyze inflammatory pathways on the level of gene expression and circulating inflammatory markers in relation to plasma GIP level.
SUBJECTS/METHODS: The study included 128 obese adults. Two groups of obese subjects were created according to fasting GIP levels, with cutoff point at the 66th percentile and compared in respect with molecular and circulating markers of inflammation. GIP, interleukin (IL)-6 and adipokines: leptin, adiponectin, visfatin were measured by enzyme-linked immunosorbent assay. Inflammatory markers: monocyte chemoattractant protein-1 (MCP-1), sE-Selectin, sVCAM-1, sPECAM-1 were studied at fasting and after nutrient challenges. Gene expression in blood cells was determined by human gene microarray.
Obese patients with high GIP levels had elevated fasting glucose (Q2 (Q1-Q3): 5.6 (5.0-6.0) vs 5.0 (4.8-5.4), P<0.001), homeostasis model assessment of insulin resistance (Q2 (Q1-Q3): 3.68 (2.72-5.42) vs 2.70 (2.13-4.33), P=0.021), thus increased markers of insulin resistance as well as elevated inflammatory markers Il-6 (Q2 (Q1-Q3): 1.34 (1.0-2.04) vs 1.12 (0.76-1.64), P=0.045), MCP-1 (Q2 (Q1-Q3): 363 (287-447) vs 323 (263-389), P=0.026). Leptin to adiponectin ratio was significantly associated with fasting plasma GIP levels (β (95% CI): 0.84 (0.10-1.59)) independently of glucose levels. sE-Selectin was found to be a factor influencing GIP response to oral glucose intake (β (95% CI): 0.47 (0.14-0.81)) and sVCAM was found to be a factor influencing GIP response to high-fat meal intake (β (95% CI): 0.19 (0.01-0.37)). We identified 32 genes of inflammatory pathways differentially expressed in subjects with a high plasma GIP level compared to low GIP. Most upregulated genes play a role in leukocyte chemotaxis and tissue infiltration.
These findings support the hypothesis that increased GIP signaling has a role in chronic low-grade inflammation.
葡萄糖依赖性胰岛素促分泌肽（GIP）在免疫系统和肠道之间提供了一个新的联系，尽管来自不同的实验和观察研究的结果相互矛盾，从抗炎作用到 GIP 的中性作用再到促炎作用。因此，本研究的目的是分析与血浆 GIP 水平相关的基因表达和循环炎症标志物的炎症途径。
受试者/方法：本研究纳入了 128 名肥胖成年人。根据空腹 GIP 水平将肥胖患者分为两组，以第 66 百分位数为截断点，并比较了两组患者在分子和循环炎症标志物方面的差异。采用酶联免疫吸附试验测定 GIP、白细胞介素（IL）-6 和脂肪因子：瘦素、脂联素、内脏脂肪素。空腹和营养负荷后研究了炎症标志物：单核细胞趋化蛋白-1（MCP-1）、可溶性 E-选择素（sE-Selectin）、可溶性血管细胞黏附分子-1（sVCAM-1）和可溶性血小板内皮细胞黏附分子-1（sPECAM-1）。通过人类基因微阵列测定血细胞中的基因表达。
高 GIP 水平的肥胖患者空腹血糖升高（Q2（Q1-Q3）：5.6（5.0-6.0）vs 5.0（4.8-5.4），P<0.001），胰岛素抵抗的稳态模型评估（Q2（Q1-Q3）：3.68（2.72-5.42）vs 2.70（2.13-4.33），P=0.021），因此胰岛素抵抗标志物以及炎症标志物 IL-6 也升高（Q2（Q1-Q3）：1.34（1.0-2.04）vs 1.12（0.76-1.64），P=0.045）、MCP-1（Q2（Q1-Q3）：363（287-447）vs 323（263-389），P=0.026）。瘦素与脂联素的比值与空腹血浆 GIP 水平显著相关（β（95%CI）：0.84（0.10-1.59）），独立于血糖水平。发现 sE-Selectin 是影响口服葡萄糖摄入后 GIP 反应的因素（β（95%CI）：0.47（0.14-0.81）），sVCAM 是影响高脂肪餐摄入后 GIP 反应的因素（β（95%CI）：0.19（0.01-0.37））。与低 GIP 相比，我们在高 GIP 水平的受试者中鉴定出 32 个炎症途径的差异表达基因。大多数上调的基因在白细胞趋化和组织浸润中起作用。
这些发现支持了这样的假设，即增加的 GIP 信号转导在慢性低度炎症中起作用。
