Glucagon is a critical regulator of glucose homeostasis; however, mechanisms regulating glucagon action and a-cell function and number are incompletely understood. To elucidate the role of the hepatic glucagon receptor (Gcgr) in glucagon action, we generated mice with hepatocyte-speciflc deletion of the glucagon receptor. Gcgrffep~/~ mice exhibited reductions in fasting blood glucose and improvements in insulin sensitivity and glucose tolerance compared with wild-type controls, similar in magnitude to changes observed in Gcgr~'~ mice. Despite preservation of islet Gcgr signaling, Gcgr" mice developed hyperglucagonemia and a-cell hyperplasia. To investigate mechanisms by which signaling through the Gcgr regulates a-cell mass, wild-type islets were transplanted into Gcgr~f~ or GcgyfIep~'~ mice. Wild-type islets beneath the renal capsule of Gcgr~y~ or GcgrHep~/~ mice exhibited an increased rate of a-cell proliferation and expansion of a-cell area, consistent with changes exhibited by endogenous a-cells in Gcgr~'~ and GcgrHep~/~ pancreata. These results suggest that a circulating factor generated after disruption of hepatic Gcgr signaling can increase a-cell proliferation independent of direct pancreatic input. Identification of novel factors regulating a-cell proliferation and mass may facilitate the generation and expansion of a-cells for transdifferentiation into beta-cells and the treatment of diabetes.
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机译：胰高血糖素是葡萄糖稳态的关键调节因子;然而，调节胰高血糖素作用和 A 细胞功能和数量的机制尚不完全清楚。为了阐明肝胰高血糖素受体（Gcgr）在胰高血糖素作用中的作用，我们生成了胰高血糖素受体肝细胞特异性缺失的小鼠。与野生型对照组相比，Gcgrffep~/~小鼠的空腹血糖降低，胰岛素敏感性和葡萄糖耐量改善，其幅度与Gcgr~'~小鼠的变化相似。尽管胰岛 Gcgr 信号传导得以保留，但 Gcgr“ 小鼠出现了高胰高血糖素血症和 A 细胞增生。为了研究通过 Gcgr 信号转导调节 a 细胞质量的机制，将野生型胰岛移植到 Gcgr~f~ 或 GcgyfIep~'~ 小鼠中。Gcgr~y~或GcgrHep~/~小鼠肾囊下的野生型胰岛表现出A细胞增殖速率增加和a细胞面积扩增，与Gcgr~'~和GcgrHep~/~胰腺中内源性a细胞的变化一致。这些结果表明，肝脏 Gcgr 信号传导中断后产生的循环因子可以增加 A 细胞增殖，而与直接胰腺输入无关。鉴定调节 a 细胞增殖和质量的新因子可能有助于 a 细胞的产生和扩增，以便转分化为 β 细胞和治疗糖尿病。
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