Characterization of the insulin sensitivity of ghrelin receptor KO mice using glycemic clamps.
Characterization of the insulin sensitivity of ghrelin receptor KO mice using glycemic clamps.
复制标题
DOI：
10.1186/1472-6793-11-1
复制
发表时间：
2011-01-06
期刊：
影响因子：
--
通讯作者：
Geddes BJ
中科院分区：
文献类型：
--
作者：
Qi Y;Longo KA;Giuliana DJ;Gagne S;McDonagh T;Govek E;Nolan A;Zou C;Morgan K;Hixon J;Saunders JO;Distefano PS;Geddes BJ
我们和其他人先前已经证明，相对于WT同窝出生的小鼠，喂食高脂肪饮食（HFD）的生长素释放肽受体（GhrR）敲除（KO）小鼠具有增加的胰岛素敏感性和代谢灵活性。HFD喂养的GhrR KO小鼠的显著特征是肝脂肪变性的显著减少。为了进一步表征GhrR KO小鼠中葡萄糖稳态的潜在机制，我们进行了高血糖（HG）和高胰岛素-正常血糖（HI-E）钳夹。此外，我们研究了组织葡萄糖摄取，并特别检查了肝脏胰岛素敏感性。与葡萄糖耐受性测试数据一致，在HG钳夹实验中，相对于WT同窝出生的小鼠，GhrR KO小鼠显示葡萄糖刺激的胰岛素释放减少。尽管如此，仍然实现了稳健的第1相胰岛素分泌，表明维持了健康的β细胞应答。此外，GhrR KO小鼠表现出显著增加的葡萄糖输注速率和显著降低的用于维持HG钳夹的胰岛素需求，这与它们的相对胰岛素敏感性一致。在HI-E钳夹中，LFD喂养和HFD喂养的GhrR KO小鼠均显示出相对于WT同窝小鼠更高的外周胰岛素敏感性，如胰岛素刺激的葡萄糖处置（Rd）显著增加和肝葡萄糖产生（HGP）降低所示。HFD喂养的GhrR KO小鼠在多种组织中显示出外周组织葡萄糖摄取的显著增加，包括骨骼肌、棕色脂肪组织和白色脂肪组织。喂食HFD的GhrR KO小鼠也显示丙酮酸转化为葡萄糖的适度但显著的降低，如如果这些小鼠显示出增加的肝脏胰岛素敏感性所预期的。此外，相对于WT小鼠，GhrR KO小鼠肝脏和BAT中的UCP 2和UCP 1水平分别降低。这些结果表明，相对于WT对照，GhrR KO小鼠的葡萄糖稳态改善的特征是在正常和代谢挑战状态下葡萄糖处理的稳健改善。GhrR KO小鼠具有完整的第1时相胰岛素反应，但需要显著更少的胰岛素用于葡萄糖处置。我们的实验表明，GhrR基因敲除小鼠的胰岛素敏感性是由于体重的独立和依赖因素。我们还提供了几条证据，证明GhrR KO小鼠的一个关键特征是在代谢挑战期间维持肝脏胰岛素敏感性。
We and others have demonstrated previously that ghrelin receptor (GhrR) knock out (KO) mice fed a high fat diet (HFD) have increased insulin sensitivity and metabolic flexibility relative to WT littermates. A striking feature of the HFD-fed GhrR KO mouse is the dramatic decrease in hepatic steatosis. To characterize further the underlying mechanisms of glucose homeostasis in GhrR KO mice, we conducted both hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI-E) clamps. Additionally, we investigated tissue glucose uptake and specifically examined liver insulin sensitivity. Consistent with glucose tolerance-test data, in HG clamp experiments, GhrR KO mice showed a reduction in glucose-stimulated insulin release relative to WT littermates. Nevertheless, a robust 1st phase insulin secretion was still achieved, indicating that a healthy β-cell response is maintained. Additionally, GhrR KO mice demonstrated both a significantly increased glucose infusion rate and significantly reduced insulin requirement for maintenance of the HG clamp, consistent with their relative insulin sensitivity. In HI-E clamps, both LFD-fed and HFD-fed GhrR KO mice showed higher peripheral insulin sensitivity relative to WT littermates as indicated by a significant increase in insulin-stimulated glucose disposal (Rd), and decreased hepatic glucose production (HGP). HFD-fed GhrR KO mice showed a marked increase in peripheral tissue glucose uptake in a variety of tissues, including skeletal muscle, brown adipose tissue and white adipose tissue. GhrR KO mice fed a HFD also showed a modest, but significant decrease in conversion of pyruvate to glucose, as would be anticipated if these mice displayed increased liver insulin sensitivity. Additionally, the levels of UCP2 and UCP1 were reduced in the liver and BAT, respectively, in GhrR KO mice relative to WT mice. These results indicate that improved glucose homeostasis of GhrR KO mice is characterized by robust improvements of glucose disposal in both normal and metabolically challenged states, relative to WT controls. GhrR KO mice have an intact 1st phase insulin response but require significantly less insulin for glucose disposal. Our experiments reveal that the insulin sensitivity of GhrR KO mice is due to both BW independent and dependent factors. We also provide several lines of evidence that a key feature of the GhrR KO mouse is maintenance of hepatic insulin sensitivity during metabolic challenge.