Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival.
Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival.
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DOI：
10.1016/j.molmet.2016.05.014
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发表时间：
2016-08
影响因子：
8.1
通讯作者：
Kieffer TJ
中科院分区：
文献类型：
--
作者：
Neumann UH;Ho JSS;Mojibian M;Covey SD;Charron MJ;Kieffer TJ
人们一直认为，胰岛素的消耗是糖尿病分解代谢后果的原因；然而，有证据表明胰高血糖素在糖尿病发病中也起作用。通过胰高血糖素受体（Gcgr）基因缺失、胰高血糖素免疫中和或Gcgr拮抗剂抑制胰高血糖素可以逆转或预防啮齿类动物的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由于化学或免疫介导的β细胞破坏而导致糖尿病，其中胰岛素消耗是不完全的。因此，胰高血糖素抑制是否能克服胰岛素完全缺乏的后果尚不清楚。为了直接验证这一点，我们对缺乏Gcgr和胰岛素基因（GcgrKO/InsKO）的小鼠进行了表征。在使用胰岛素治疗的P1幼崽和小鼠中，血糖和血浆酮适度正常化；然而，小鼠仅存活了6天，与GcgrHet/InsKO对照组相似。此外，与GcgrHet/InsKO对照组相比，Gcgr基因缺失无法使血浆瘦素水平、甘油三酯、脂肪酸或肝脏胆固醇积累正常化。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。Gcgr基因缺失不促进InsKO小鼠的存活。Gcgr基因缺失可适度降低InsKO小鼠的血糖和酮类。Gcgr基因缺失不能使InsKO小鼠的脂质代谢紊乱正常化。在完全缺乏胰岛素的情况下，Gcgr基因缺失并不能预防糖尿病。
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. To directly test this we characterized mice that lack the Gcgr and both insulin genes (GcgrKO/InsKO). 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. Therefore, the metabolic manifestations associated with a complete lack of insulin cannot be overcome by glucagon receptor gene inactivation. Gcgr gene deletion does not promote survival of InsKO mice. Gcgr gene deletion modestly reduces blood glucose and ketones in InsKO mice. Gcgr gene deletion does not normalize perturbed lipid metabolism in InsKO mice. Gcgr gene deletion does not prevent diabetes in the complete absence of insulin.