Differential antidiabetic efficacy of incretin agonists versus DPP-4 inhibition in high fat-fed mice
Differential antidiabetic efficacy of incretin agonists versus DPP-4 inhibition in high fat-fed mice
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DOI：
10.2337/db07-1202
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发表时间：
2008-01-01
期刊：
影响因子：
7.7
通讯作者：
Drucker, Daniel J.
中科院分区：
文献类型：
--
作者：
Lamont, Benjamin J.;Drucker, Daniel J.
目的：我们研究了长期给予高血糖素样多肽1(GLP-1)受体激动剂Exendin-4(Ex-4)、葡萄糖依赖的胰岛素依赖型多肽(GIP)受体激动剂D-Ala(2)-GIP(DA-GIP)或二肽基多肽酶-4(DPP-4)抑制剂(DPP-4I)Des-Fuco-Sitagliptin是否能在高脂喂养的小鼠中产生类似的抗糖尿病作用。结果与结论：单独用赋形剂或DA-GIP处理的小鼠出现进行性体重增加，而用Ex-4或DPP4i处理则阻止体重增加。虽然Ex4改善了口服葡萄糖耐量试验(IPGTT)后的口服葡萄糖耐量和胰岛素/葡萄糖比率，但DPP-4i在IPGTT后没有显著影响，但改善了口服葡萄糖耐量试验后的血糖漂移和胰岛素水平。持续抑制DPP4对血糖控制的改善程度更持久，在给药9小时后血糖控制明显丧失，DPP4i组的A1C显著降低，但DA-GIP或Ex-4治疗组则没有。DA-GIP与胰岛素敏感性受损以及血浆瘦素和抵抗素水平升高相关，而与EX4或DPP-4I无关。虽然所有治疗都没有增加P细胞质量，但只有前L治疗组的小鼠表现出胰腺IRS2、EGFR和GCK的转录增加。这些发现凸显了内源性GLP-1和GIP通过抑制DPP4而增强内源性GLP-1和GIP之间的显著差异。
OBJECTIVE-We examined whether chronic administration of a glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 (Ex-4), a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist D-Ala(2)-GIP (DA-GIP), or a dipeptidyl peptidase-4 (DPP-4) inhibitor (DPP-4i) des-fluoro-sitagliptin produced comparable antidiabetic actions in high fat-fed mice.RESEARCH DESIGN AND METHODS-High fat-fed mice were administered twice-daily injections of Ex4, DA-GIP, vehicle (saline), or vehicle with the addition of des-fluoro-sitagliptin (DPP4i) in food to produce sustained inhibition of DPP4 activity.RESULTS AND CONCLUSIONS-Mice treated with vehicle alone or DA-GIP exhibited progressive weight gain, whereas treatment with Ex-4 or DPP4i prevented weight gain. Although Ex4 improved oral glucose tolerance and insulin-to-glucose ratios after an intraperitoneal glucose tolerance test (IPGTT), DPP-4i had no significant effect after IPGTT but improved glucose excursion and insulin levels after an oral glucose tolerance test. The extent of improvement in glycemic control was more sustained with continuous DPP4 inhibition, as evidenced by loss of glucose control evident 9 h after peptide administration and a significant reduction in A1C observed with DPP4i but not with DA-GIP or Ex-4 therapy. DA-GIP, but not Ex4 or DPP-4i, was associated with impairment in insulin sensitivity and increased levels of plasma leptin and resistin. Although none of the therapies increased P-cell mass, only Ex-l-treated mice exhibited increased pancreatic mRNA transcripts for Irs2, Egfr, and Gck. These findings highlight significant differences between pharmacological administration of incretin receptor agonists and potentiation of endogenous GLP-1 and GIP via DPP4 inhibition.