The role of GIP and pancreatic GLP-1 in the glucoregulatory effect of DPP-4 inhibition in mice.
The role of GIP and pancreatic GLP-1 in the glucoregulatory effect of DPP-4 inhibition in mice.
复制标题
GIP 和胰腺 GLP-1 在小鼠 DPP-4 抑制的葡萄糖调节作用中的作用。
DOI：
10.1007/s00125-019-4963-5
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发表时间：
2019
期刊：
影响因子：
8.2
通讯作者：
Sandoval,DarleenA
中科院分区：
文献类型：
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作者：
Hutch,ChelseaR;Roelofs,Karen;Haller,April;Sorrell,Joyce;Leix,Kyle;D'Alessio,DavidD;Augustin,Robert;Seeley,RandyJ;Klein,Thomas;Sandoval,DarleenA
目的/假设胰高血糖素样肽-1 （GLP-1）和葡萄糖依赖性胰岛素性多肽（GIP）是两种促进胰岛素分泌的肽。二肽基肽酶-4 （DPP-4）抑制剂增加GLP-1和GIP的生物利用度，但教条仍然是GLP-1的增加有助于改善葡萄糖稳态。我们之前已经证明胰腺而不是肠道GLP-1是改善小鼠葡萄糖稳态所必需的。因此，我们假设胰GLP-1和GIP的结合对于DPP-4抑制剂对葡萄糖稳态的充分影响是必要的。方法采用基因工程的小鼠系，在这些小鼠系中，胰高血糖素前原基因（Gcg）在全身缺失（GcgRAΔNull）或仅在肠道（GcgRAΔVilCre）或胰腺和十二指肠（GcgRAΔPDX1Cre）中表达。这些小鼠被用来检测口服葡萄糖耐量和GLP-1和GIP对DPP-4抑制剂单独或与肠促胰岛素受体拮抗剂联合的反应。结果给予DPP-4抑制剂利格列汀可改善小鼠葡萄糖耐量inGcgRAΔNullmice和对照幼崽inGcgRAΔVilCreandGcgRAΔPDX1Cremice。有效的GLP-1受体拮抗剂exendin-[9-39] （Ex9）减弱了利格列汀处理的对照小鼠和inGcgRAΔPDX1Cremice的糖耐量改善。Ex9对linagliptin-treatedGcgRAΔNullor inGcgRAΔVilCremice的糖耐量没有影响。除了GLP-1外，利格列汀还在所有基因型中以相似的程度增加餐后血浆GIP水平。当利格列汀与gip拮抗抗体联合使用时，利格列汀在野生型小鼠中的作用部分减弱，并完全阻断inGcgRAΔNullmice。综上所述，这些数据表明胰腺GLP-1和GIP的增加对于DPP-4抑制剂对葡萄糖耐量的充分影响是必要的。
Aims/hypothesisGlucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two peptides that function to promote insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase the bioavailability of both GLP-1 and GIP but the dogma continues to be that it is the increase in GLP-1 that contributes to the improved glucose homeostasis. We have previously demonstrated that pancreatic rather than intestinal GLP-1 is necessary for improvements in glucose homeostasis in mice. Therefore, we hypothesise that a combination of pancreatic GLP-1 and GIP is necessary for the full effect of DPP-4 inhibitors on glucose homeostasis.MethodsWe have genetically engineered mouse lines in which the preproglucagon gene (Gcg) is absent in the entire body (GcgRAΔNull) or is expressed exclusively in the intestine (GcgRAΔVilCre) or pancreas and duodenum (GcgRAΔPDX1Cre). These mice were used to examine oral glucose tolerance and GLP-1 and GIP responses to a DPP-4 inhibitor alone, or in combination with incretin receptor antagonists.ResultsAdministration of the DPP-4 inhibitor, linagliptin, improved glucose tolerance inGcgRAΔNullmice and control littermates and inGcgRAΔVilCreandGcgRAΔPDX1Cremice. The potent GLP-1 receptor antagonist, exendin-[9–39] (Ex9), blunted improvements in glucose tolerance in linagliptin-treated control mice and inGcgRAΔPDX1Cremice. Ex9 had no effect on glucose tolerance in linagliptin-treatedGcgRAΔNullor inGcgRAΔVilCremice. In addition to GLP-1, linagliptin also increased postprandial plasma levels of GIP to a similar degree in all genotypes. When linagliptin was co-administered with a GIP-antagonising antibody, the impact of linagliptin was partially blunted in wild-type mice and was fully blocked inGcgRAΔNullmice.Conclusions/interpretationTaken together, these data suggest that increases in pancreatic GLP-1 and GIP are necessary for the full effect of DPP-4 inhibitors on glucose tolerance.