Ghrelin differentially affects hepatic and peripheral insulin sensitivity in mice
Ghrelin differentially affects hepatic and peripheral insulin sensitivity in mice
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DOI：
10.1007/s00125-006-0138-2
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发表时间：
2006-04-01
期刊：
影响因子：
8.2
通讯作者：
Corssmit, EPM
中科院分区：
文献类型：
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作者：
Heijboer, AC;van den Hoek, AM;Corssmit, EPM
目的/假设：本研究旨在评估胃饥饿素（ghrelin）对小鼠胰岛素抑制内源性葡萄糖生成和促进葡萄糖处置能力的影响。为了确定生长激素促分泌素（GHS）受体是否可以介导ghrelin对胰岛素的作用，我们还测定了生长激素释放肽6 （GHRP-6）的代谢作用，GHS受体的特异性激动剂。此外，我们在这个实验背景下探讨了去酰化胃饥饿素（去酰化胃饥饿素）的生物学意义。材料和方法：将培养液（n=8）、胃促生长素（n=9）、GHRP-6 （n=9）、去-胃促生长素（n=8）或去-胃促生长素和胃促生长素的组合（n=7）静脉滴注3 h。同时，在高胰岛素-血糖钳夹期间，用c- 14-葡萄糖稀释法测定内源性葡萄糖的产生和处置。使用h -3-2-脱氧葡萄糖测量肌肉和脂肪组织的组织特异性葡萄糖摄取。结果：高胰岛素血症时，胃促生长素处理小鼠的葡萄糖消耗量比对照小鼠高31%（分别为77 +/- 16和59 +/- 8 mu mol kg(-1) h(-1)), p < 0.05）。这与胃饥饿素治疗动物肌肉中2-脱氧葡萄糖摄取增强一致。相比之下，在胃饥饿素输注期间，胰岛素抑制内源性葡萄糖产生的效果较差（对照组为46 +/- 22%，对照组为71 +/- 11%，p < 0.05）。GHRP-6不影响胰岛素的作用。Des-ghrelin阻碍了胰岛素抑制内源性葡萄糖产生的能力，而不影响葡萄糖的处理。去胃饥饿素和胃饥饿素对肝脏胰岛素作用的抑制作用在同时给药时被消除。结论/解释：Ghrelin阻碍胰岛素抑制内源性葡萄糖产生的能力，而它加强胰岛素对葡萄糖处理的作用，独立于食物摄入量和体重。这些代谢作用不太可能由GHS受体介导。此外，同时给予去胃饥饿素可消除胃饥饿素对肝脏胰岛素作用的抑制作用。
Aims/hypothesis: This study was conducted to evaluate the effects of ghrelin on insulin's capacity to suppress endogenous glucose production and promote glucose disposal in mice. To establish whether the growth hormone secretagogue (GHS) receptor can mediate the putative effect of ghrelin on the action of insulin, we also determined the metabolic effects of growth hormone releasing peptide 6 (GHRP-6), a specific GHS receptor agonist. In addition, we explored the biological significance of des-ghrelin (unacylated ghrelin) in this experimental context. Materials and methods: Vehicle (n=8), ghrelin (n=9), GHRP-6 (n=9), des-ghrelin (n=8) or a combination of des-ghrelin and ghrelin (n=7) were infused i.v. for 3 h. Simultaneously, endogenous glucose production and glucose disposal were measured by C-14-glucose dilution during a hyperinsulinaemic-euglycaemic clamp. Tissue-specific glucose uptake in muscle and adipose tissue was measured using H-3-2-deoxyglucose. Results: During hyperinsulinaemia, glucose disposal was 31% higher in mice treated with ghrelin than in those treated with vehicle (77 +/- 16 and 59 +/- 8 mu mol kg(-1) h(-1), respectively, p < 0.05). This was in accordance with enhanced 2-deoxyglucose uptake in muscle in ghrelin-treated animals. In contrast, endogenous glucose production was less effectively suppressed by insulin during ghrelin infusion (46 +/- 22 vs 71 +/- 11% in controls, p < 0.05). GHRP-6 did not affect insulin action. Des-ghrelin hampered insulin's capacity to inhibit endogenous glucose production, whereas it did not affect glucose disposal. The restraining effects of des-ghrelin and ghrelin on hepatic insulin action were abolished by simultaneous administration of both peptides. Conclusions/interpretation: Ghrelin hampers insulin's capacity to suppress endogenous glucose production, whereas it reinforces the action of insulin on glucose disposal, independently of food intake and body weight. These metabolic effects are unlikely to be mediated by the GHS receptor. Furthermore, simultaneous administration of des-ghrelin abolishes the inhibitory effect of ghrelin on hepatic insulin action.