Valverde Isabel, Wang Gen-Sheng, Burghardt Karolina, Kauri Lisa M, Redondo Araceli, Acitores Alicia, Villanueva-Peñacarrillo Maria L, Courtois Philippe, Sener Abdullah, Cancelas Jesús, Malaisse Willy J, Scott Fraser W
Fundación Jiménez Díaz, Madrid, Spain.
Endocrine. 2004 Feb;23(1):77-84. doi: 10.1385/ENDO:23:1:77.
Glucagon-like peptide-1 (GLP-1) is the most insulinogenic of the glucagon-like peptides secreted mainly by L cells in the small and large intestine in response to the ingestion of nutrients. It binds to a specific GLP-1 receptor (GLP-1R) on beta-cells and can increase islet neogenesis and beta-cell mass. It is not clear whether the transmission of information from the gut to islet beta-cells by messengers such as GLP-1 is different in individuals who develop autoimmune diabetes. In the present study the expression of bioactive GLP-1 protein in the gut and its receptor in the pancreas was examined in diabetes-prone BioBreeding (BBdp) rats in the period before overt diabetes and in age-matched control, non-diabetes-prone BB (BBc) rats. An N-terminal directed antibody specific for the bioactive forms of GLP-1 (GLP-1(7-37) and GLP-1(7-36amide)) was used to mea-sure GLP-1 by radioimmunoassay in proximal, median, and distal gut. Pancreas GLP-1R area fraction, GLP-1R gene expression, and insulin content were analyzed, as were plasma GLP-1, glucose, and insulin. The concentration of GLP-1 protein in the jejunum and ileum of BBdp rats was lower than in BBc rats. Although these animals maintained normal blood glucose, there was impaired pancreatic endocrine function, characterized by low baseline insulin concentration in plasma and pancreas. GLP-1R mRNA expression was threefold less in islets isolated from BBdp rats, and GLP-1R+ islet area fraction in pancreas sections was decreased. When injected iv with GLP-1, BBdp rats displayed lower second-phase insulin response (and insulin/glucose ratios) compared with BBc rats. Thus, young BBdp rats displayed decreased concentrations of bioactive GLP-1 in jejunum and ileum, reduced GLP-1R in islets, and lower second-phase insulin response to iv GLP-1 than controls. The decrease in insulinogenic and islet beta-cell mass-promoting signal from GLP-1 in BBdp rats may contribute to impaired glucoregulation and ineffective maintenance of normal islet mass that shifts islet homeostasis in favor of development of diabetes.
胰高血糖素样肽-1（GLP-1）是最具促胰岛素分泌作用的胰高血糖素样肽，主要由小肠和大肠的L细胞在摄入营养物质后分泌。它与β细胞上的特异性GLP-1受体（GLP-1R）结合，可增加胰岛新生和β细胞量。尚不清楚在发生自身免疫性糖尿病的个体中，像GLP-1这样的信使从肠道向胰岛β细胞传递信息的过程是否存在差异。在本研究中，对易患糖尿病的BioBreeding（BBdp）大鼠在显性糖尿病发生前的阶段以及年龄匹配的对照、不易患糖尿病的BB（BBc）大鼠，检测了肠道中生物活性GLP-1蛋白及其胰腺中受体的表达。使用一种针对GLP-1生物活性形式（GLP-1(7-37)和GLP-1(7-36酰胺)）的N端定向抗体，通过放射免疫分析法测定近端、中段和远端肠道中的GLP-1。分析了胰腺GLP-1R面积分数、GLP-1R基因表达和胰岛素含量以及血浆GLP-1、葡萄糖和胰岛素。BBdp大鼠空肠和回肠中GLP-1蛋白的浓度低于BBc大鼠。尽管这些动物维持正常血糖，但胰腺内分泌功能受损，其特征为血浆和胰腺中基础胰岛素浓度较低。从BBdp大鼠分离的胰岛中GLP-1R mRNA表达减少了三倍，胰腺切片中GLP-1R+胰岛面积分数降低。与BBc大鼠相比，静脉注射GLP-1时，BBdp大鼠的第二相胰岛素反应（以及胰岛素/葡萄糖比值）较低。因此，年轻的BBdp大鼠空肠和回肠中生物活性GLP-1浓度降低，胰岛中GLP-1R减少，对静脉注射GLP-1的第二相胰岛素反应低于对照组。BBdp大鼠中来自GLP-1的促胰岛素分泌和促进胰岛β细胞量的信号减少，可能导致血糖调节受损以及无法有效维持正常胰岛量，从而使胰岛内环境稳态向有利于糖尿病发展的方向转变。
