de Heer J, Rasmussen C, Coy D H, Holst J J
Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark.
Diabetologia. 2008 Dec;51(12):2263-70. doi: 10.1007/s00125-008-1149-y. Epub 2008 Sep 16.
AIMS/HYPOTHESIS: The glucose-lowering effect of glucagon-like peptide-1 (GLP-1) is based not only upon its potent insulinotropic actions but also on its ability to restrain glucagon secretion. Surprisingly, the closely related glucose-dependent insulinotropic peptide (GIP) stimulates glucagon release. We examined whether the islet hormone somatostatin, which strongly inhibits glucagon secretion, is involved in this divergent behaviour.
At 1.5 mmol/l glucose and therefore minimal insulin secretion, the glucagon, insulin and somatostatin responses to 20 mmol/l glucose, GLP-1, GIP and somatostatin were studied in the presence of a high-affinity monoclonal somatostatin antibody and of a highly specific somatostatin receptor subtype 2 (SSTR2) antagonist (PRL-2903) in the isolated perfused rat pancreas.
In control experiments, GLP-1 at 1 and 10 nmol/l reduced glucagon secretion significantly to 59.0 +/- 6.3% (p < 0.004; n = 5; SSTR2 series; each vs pre-infusion level) and to 48.0 +/- 2.6% (p < 0.001; n = 6; somatostatin antibody series) respectively. During somatostatin antibody administration, GLP-1 still inhibited glucagon secretion significantly, but the effect was less pronounced than in control experiments (p < 0.018). Co-infusion of the SSTR2 antagonist completely abolished the GLP-1-induced suppression of glucagon secretion. In contrast, neither the GIP-induced stimulation of glucagon release nor its inhibition by 20 mmol/l glucose was altered by somatostatin antibody or SSTR2 antagonist administration.
CONCLUSIONS/INTERPRETATION: We conclude that GLP-1 is capable of inhibiting glucagon secretion even in the absence of secretory products from the beta cell. It is highly likely that this is mediated via somatostatin interacting with SSTR2 on rat alpha cells. In contrast, GIP and glucose seem to influence the alpha cell independently of somatostatin secretion.
目的/假设：胰高血糖素样肽-1（GLP-1）的降糖作用不仅基于其强大的促胰岛素作用，还基于其抑制胰高血糖素分泌的能力。令人惊讶的是，密切相关的葡萄糖依赖性促胰岛素多肽（GIP）会刺激胰高血糖素释放。我们研究了强烈抑制胰高血糖素分泌的胰岛激素生长抑素是否参与了这种不同的行为。
在葡萄糖浓度为1.5 mmol/l且胰岛素分泌极少的情况下，在分离灌注的大鼠胰腺中，研究了在存在高亲和力单克隆生长抑素抗体和高度特异性生长抑素受体2型（SSTR2）拮抗剂（PRL-2903）的情况下，胰高血糖素、胰岛素和生长抑素对20 mmol/l葡萄糖、GLP-1、GIP和生长抑素的反应。
在对照实验中，1和10 nmol/l的GLP-1分别将胰高血糖素分泌显著降低至59.0±6.3%（p<0.004；n = 5；SSTR2系列；各与输注前水平相比）和48.0±2.6%（p<0.001；n = 6；生长抑素抗体系列）。在给予生长抑素抗体期间，GLP-1仍能显著抑制胰高血糖素分泌，但效果不如对照实验明显（p<0.018）。共同输注SSTR2拮抗剂完全消除了GLP-1诱导的胰高血糖素分泌抑制。相反，生长抑素抗体或SSTR2拮抗剂的给予既未改变GIP诱导的胰高血糖素释放刺激，也未改变其被20 mmol/l葡萄糖抑制的情况。
结论/解读：我们得出结论，即使在β细胞无分泌产物的情况下，GLP-1也能够抑制胰高血糖素分泌。极有可能是通过生长抑素与大鼠α细胞上的SSTR2相互作用介导的。相比之下，GIP和葡萄糖似乎独立于生长抑素分泌影响α细胞。
