GIP-(3-42) does not antagonize insulinotropic effects of GIP at physiological concentrations
GIP-(3-42) does not antagonize insulinotropic effects of GIP at physiological concentrations
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DOI：
10.1152/ajpendo.00577.2005
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发表时间：
2006-09-01
影响因子：
5.1
通讯作者：
Holst, Jens J.
中科院分区：
文献类型：
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作者：
Deacon, Carolyn F.;Plamboeck, Astrid;Holst, Jens J.
葡萄糖依赖性促胰岛素多肽[GIP-（1-42）]被二肽基肽酶IV（DPP IV）降解，形成GIP-（3-42）。在小鼠中，高浓度的合成GIP-（3-42）可作为GIP受体拮抗剂起作用，但尚不清楚这是否在生理浓度下发生。在用人GIP受体瞬时转染的COS-7细胞中，GIP-（1-42）和-（3-42）分别以5.2和22 nM的亲和力（IC 50）结合。GIP-（142）是一种有效的激动剂，刺激cAMP积累（EC 50，13.5 pM）;单独的GIP-（3-42）没有作用。当与天然GIP一起孵育时，GIP-（3-42）表现为弱拮抗剂（10 pM和1 nM天然GIP引起的cAMP积累抑制的IC 50分别为92和731 nM）。在分离的灌注大鼠胰腺中，单独的GIP-（3-42）对胰岛素输出没有影响，并且仅当以> 50倍摩尔过量（IC 50，138 nM）共输注时降低对GIP（1 nM）的反应。在静脉内给予葡萄糖的氯醛糖麻醉的猪中检查GIP-（3-42）影响GIP-（1-42）的抗高血糖或促胰岛素作用的能力。抑制内源性DPP IV活性以减少输注的GIP-（1-42）的降解，GIP-（1-42）单独输注和与GIP-（3-42）一起输注，速率足以模拟每种肽的餐后浓度。无论GIP-（1-42）是单独输注还是与GIP-（3-42）一起输注，葡萄糖、胰岛素和胰高血糖素反应都是相同的。我们的结论是，虽然GIP-（3-42）可以在体外弱拮抗cAMP的积累和胰岛素的输出，它不表现为在体内的生理拮抗剂。
Glucose-dependent insulinotropic polypeptide [GIP-(1-42)] is degraded by dipeptidyl peptidase IV (DPP IV), forming GIP-(3-42). In mice, high concentrations of synthetic GIP-(3-42) may function as a GIP receptor antagonist, but it is unclear whether this occurs at physiological concentrations. In COS-7 cells transiently transfected with the human GIP receptor, GIP-(1-42) and-(3-42) bind with affinities (IC50) of 5.2 and 22 nM, respectively. GIP-(142) was a potent agonist, stimulating cAMP accumulation (EC50, 13.5 pM); GIP-(3-42) alone had no effect. When incubated together with native GIP, GIP-(3-42) behaved as a weak antagonist (IC50, 92 and 731 nM for inhibition of cAMP accumulation elicited by 10 pM and 1 nM native GIP, respectively). In the isolated perfused rat pancreas, GIP-(3-42) alone had no effect on insulin output and only reduced the response to GIP (1 nM) when coinfused in > 50-fold molar excess (IC50, 138 nM). The ability of GIP-(3-42) to affect the antihyperglycemic or insulinotropic actions of GIP-(1-42) was examined in chloralose-anesthetized pigs given intravenous glucose. Endogenous DPP IV activity was inhibited to reduce degradation of the infused GIP-(1-42), which was infused alone and together with GIP-(3-42), at rates sufficient to mimic postprandial concentrations of each peptide. Glucose, insulin, and glucagon responses were identical irrespective of whether GIP-(1-42) was infused alone or together with GIP-(3-42). We conclude that, although GIP-(3-42) can weakly antagonize cAMP accumulation and insulin output in vitro, it does not behave as a physiological antagonist in vivo.