Boushey Robin P, Abadir Amir, Flamez Daisy, Baggio Laurie L, Li Yazhou, Berger Veerle, Marshall Bess A, Finegood Diane, Wang Timothy C, Schuit Frans, Drucker Daniel J
Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
Gastroenterology. 2003 Oct;125(4):1164-74. doi: 10.1016/s0016-5085(03)01195-8.
Both cholecystokinin (CCK)-A and CCK-B receptors are expressed in the pancreas, and exogenous gastrin administration stimulates glucagon secretion from human islets. Although gastrin action has been linked to islet neogenesis, transdifferentiation, and beta-cell regeneration, an essential physiologic role(s) for gastrin in the pancreas has not been established.
We examined glucose homeostasis, glucagon gene expression, glucagon secretion, and islet mass in mice with a targeted gastrin gene disruption.
Gastrin -/- mice exhibit fasting hypoglycemia and significantly reduced glycemic excursion following glucose challenge. Insulin sensitivity was normal and levels of circulating insulin and insulin messenger RNA transcripts were appropriately reduced in gastrin -/- mice. In contrast, levels of circulating glucagon and pancreatic glucagon messenger RNA transcripts were not up-regulated in hypoglycemic gastrin -/- mice. Furthermore, the glucagon response to epinephrine in isolated perifused islets was moderately impaired in gastrin -/- versus gastrin +/+ islets (40% reduction; P < 0.01, gastrin +/+ vs. gastrin -/- mice). Moreover, the glucagon response but not the epinephrine response to hypoglycemia was significantly attenuated in gastrin -/- compared with gastrin +/+ mice (P < 0.05). Despite gastrin expression in the developing fetal pancreas, beta-cell area, islet topography, and the islet proliferative response to experimental injury were normal in gastrin -/- mice.
These findings show an essential physiologic role for gastrin in glucose homeostasis; however, the gastrin gene is not essential for murine islet development or the adaptive islet proliferative response to beta-cell injury.
胆囊收缩素（CCK）-A受体和CCK-B受体均在胰腺中表达，外源性胃泌素给药可刺激人胰岛分泌胰高血糖素。尽管胃泌素的作用与胰岛新生、转分化及β细胞再生有关，但胃泌素在胰腺中的重要生理作用尚未确立。
我们研究了胃泌素基因靶向敲除小鼠的葡萄糖稳态、胰高血糖素基因表达、胰高血糖素分泌及胰岛质量。
胃泌素基因敲除（Gastrin -/-）小鼠表现出空腹低血糖，葡萄糖激发后血糖波动显著降低。胰岛素敏感性正常，Gastrin -/-小鼠循环胰岛素水平及胰岛素信使核糖核酸转录物水平相应降低。相反，低血糖的Gastrin -/-小鼠循环胰高血糖素水平及胰腺胰高血糖素信使核糖核酸转录物水平未上调。此外，与野生型（Gastrin +/+）胰岛相比，Gastrin -/-胰岛对肾上腺素刺激的胰高血糖素反应中度受损（降低40%；P < 0.01，Gastrin +/+ 与Gastrin -/-小鼠相比）。而且，与Gastrin +/+小鼠相比，Gastrin -/-小鼠对低血糖刺激的胰高血糖素反应显著减弱，但对肾上腺素反应无明显减弱（P < 0.05）。尽管在发育中的胎儿胰腺中有胃泌素表达，但Gastrin -/-小鼠的β细胞面积、胰岛形态以及胰岛对实验性损伤的增殖反应均正常。
这些发现表明胃泌素在葡萄糖稳态中起重要生理作用；然而，胃泌素基因对小鼠胰岛发育或胰岛对β细胞损伤的适应性增殖反应并非必需。
