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Abstract：
OBJECTIVE: It has been thought that the depletion of insulin is responsible for the catabolic consequences of diabetes; however, evidence suggests that glucagon also plays a role in diabetes pathogenesis. Glucagon suppression by glucagon receptor (Gcgr) gene deletion, glucagon immunoneutralization, or Gcgr antagonist can reverse or prevent type 1 diabetes in rodents suggesting that dysregulated glucagon is also required for development of diabetic symptoms. However, the models used in these studies were rendered diabetic by chemical- or immune-mediated β-cell destruction, in which insulin depletion is incomplete. Therefore, it is unclear whether glucagon suppression could overcome the consequence of the complete lack of insulin.
METHODS: To directly test this we characterized mice that lack the Gcgr and both insulin genes (GcgrKO/InsKO).
RESULTS: In both P1 pups and mice that were kept alive to young adulthood using insulin therapy, blood glucose and plasma ketones were modestly normalized; however, mice survived for only up to 6 days, similar to GcgrHet/InsKO controls. In addition, Gcgr gene deletion was unable to normalize plasma leptin levels, triglycerides, fatty acids, or hepatic cholesterol accumulation compared to GcgrHet/InsKO controls.
CONCLUSIONS: Therefore, the metabolic manifestations associated with a complete lack of insulin cannot be overcome by glucagon receptor gene inactivation.
METHODS: To directly test this we characterized mice that lack the Gcgr and both insulin genes (GcgrKO/InsKO).
RESULTS: In both P1 pups and mice that were kept alive to young adulthood using insulin therapy, blood glucose and plasma ketones were modestly normalized; however, mice survived for only up to 6 days, similar to GcgrHet/InsKO controls. In addition, Gcgr gene deletion was unable to normalize plasma leptin levels, triglycerides, fatty acids, or hepatic cholesterol accumulation compared to GcgrHet/InsKO controls.
CONCLUSIONS: Therefore, the metabolic manifestations associated with a complete lack of insulin cannot be overcome by glucagon receptor gene inactivation.
摘要：
目的：人们一直认为胰岛素的消耗是糖尿病分解代谢的原因；然而，有证据表明胰高血糖素在糖尿病发病机制中也起作用.胰高血糖素受体(Gcgr)基因缺失对胰高血糖素的抑制,胰高血糖素免疫中和,或Gcgr拮抗剂可以逆转或预防啮齿动物的1型糖尿病，这表明胰高血糖素失调也是糖尿病症状发展所必需的。然而,这些研究中使用的模型通过化学或免疫介导的β细胞破坏而成为糖尿病，其中胰岛素消耗不完全。因此,目前尚不清楚胰高血糖素抑制能否克服胰岛素完全缺乏的后果.
方法：为了直接测试，我们表征了缺乏Gcgr和两种胰岛素基因（GcgrKO/InsKO）的小鼠。
结果：在P1幼崽和使用胰岛素治疗存活至成年的小鼠中，血糖和血浆酮适度正常化；然而，小鼠只存活了6天,类似于GcgrHet/InsKO控件。此外,Gcgr基因缺失无法使血浆瘦素水平正常化，甘油三酯，脂肪酸，或与GcgrHet/InsKO对照相比的肝胆固醇积累。
结论：因此，与胰岛素完全缺乏相关的代谢表现不能通过胰高血糖素受体基因失活来克服.
方法：为了直接测试，我们表征了缺乏Gcgr和两种胰岛素基因（GcgrKO/InsKO）的小鼠。
结果：在P1幼崽和使用胰岛素治疗存活至成年的小鼠中，血糖和血浆酮适度正常化；然而，小鼠只存活了6天,类似于GcgrHet/InsKO控件。此外,Gcgr基因缺失无法使血浆瘦素水平正常化，甘油三酯，脂肪酸，或与GcgrHet/InsKO对照相比的肝胆固醇积累。
结论：因此，与胰岛素完全缺乏相关的代谢表现不能通过胰高血糖素受体基因失活来克服.
