Regulation of the biological activity of glucagon-like peptide 2 in vivo by dipeptidyl peptidase IV
Regulation of the biological activity of glucagon-like peptide 2 in vivo by dipeptidyl peptidase IV
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DOI：
10.1038/nbt0797-673
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发表时间：
1997-07-01
影响因子：
46.9
通讯作者：
Brubaker, PL
中科院分区：
文献类型：
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作者：
Drucker, DJ;Shi, Q;Brubaker, PL
多肽酶失活的物种特异性差异是评估治疗效果的重要考虑因素。我们证明胰高血糖素样肽2 （GLP-2）在小鼠中具有高度的肠营养作用，促进肠绒毛高度的增加，但对大鼠的小肠重量没有营养作用。大鼠体内GLP-5的肠营养活性降低是由于二肽基肽酶IV （DPP-IV）的失活，GLP-2（1-33）在与人胎盘DPP-IV或大鼠血清孵育后被降解为GLP-2(3-33)，而与DPP-IV缺陷大鼠血清孵育后则没有。给DPP-IV缺陷大鼠注射大鼠GLP-2与大鼠GLP-2的生物活性显著增加相关，导致小肠重量显著增加。合成的GLP-2类似物r[Gly(2)]GLP-2在2位由丙氨酸取代为甘氨酸，在体外抗DPP-IV和大鼠血清的裂解。用r[Gly(2)]GLP-2治疗野生型大鼠，小肠体积增加具有统计学意义。dpp - iv介导的GLP-5失活是GLP-2生长因子样特性的关键决定因素。
Species-specific differences in the enzymatic inactivation of peptides is an important consideration in the evaluation of therapeutic efficacy. We demonstrate that glucagon-like peptide 2 (GLP-2), shown to be highly intestinotrophic in mice, promotes an increase in intestinal villus height but has no trophic effect on small bowel weight in rats. The reduced intestinotrophic activity of GLP-5 in rats is attributable to inactivation by the enzyme dipeptidyl peptidase IV (DPP-IV), GLP-2(1-33) was degraded to GLP-2(3-33) following incubation with human placental DPP-IV or rat serum but not by serum from DPP-IV-deficient rats, Administration of rat GLP-2 to DPP-IV-deficient rats was associated with markedly increased bioactivity of rat GLP-2 resulting in a significant increase in small bowel weight. A synthetic GLP-2 analog, r[Gly(2)]GLP-2, with an alanine to glycine substitution at position 2, was resistant to cleavage by both DPP-IV and rat serum in vitro. Treatment of wild-type rats with r[Gly(2)]GLP-2 produced a statistically significant increase in small bowel mass. DPP-IV-mediated inactivation of GLP-5 is a critical determinant of the growth factor-like properties of GLP-2.