Central Nervous System GLP-1 Receptors Regulate Islet Hormone Secretion and Glucose Homeostasis in Male Rats
Central Nervous System GLP-1 Receptors Regulate Islet Hormone Secretion and Glucose Homeostasis in Male Rats
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DOI：
10.1210/en.2016-1826
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发表时间：
2017-07-01
期刊：
影响因子：
4.8
通讯作者：
D'Alessio, David
中科院分区：
文献类型：
--
作者：
Jessen, Lene;Smith, Eric P.;D'Alessio, David
胰高血糖素样肽1（GLP-1）系统在血糖调节中起重要作用，其在很大程度上通过协调控制胰岛素和胰高血糖素分泌。这些作用通常归因于外周部位（主要是肠道）产生的GLP-1。GLP-1也在后脑神经元中产生，其通过参与代谢调节的脑区域中表达的GLP-1受体（GLP-1 rs）发出信号。中枢神经系统（CNS）中的GLP-1可诱导饱腹感、内脏疾病和应激反应。然而，最近的证据表明CNS GLP-1也参与葡萄糖调节。为了检验中枢GLP-1调节胰岛激素分泌的假设，在禁食或静脉注射葡萄糖引起的高血糖期间，向清醒大鼠脑室内（ICV）给予GLP-1、GLP-1 r拮抗剂exendin-[9-39]（Ex-9）或生理盐水。CNS GLP-1给药增加了空腹血糖、胰高血糖素、皮质酮和肾上腺素，并减弱了对高血糖症的胰岛素分泌。奇怪的是，用ICV Ex-9阻断GLP-1 r也减少了葡萄糖估计的胰岛素分泌，并且向自由进食大鼠给予ICV Ex-9引起轻度葡萄糖耐受不良。因此，直接给予CNS GLP-1影响胰岛激素分泌，与外周给予GLP-1所观察到的相反，这种作用可能是由于刺激交感神经系统活性。相反，脑GLP-1 r的阻断支持CNS GLP-1在葡萄糖刺激的胰岛素分泌和餐后葡萄糖控制中的作用。这些发现提示了一种模型，其中内源性肽激活CNS GLP-1 r可促进葡萄糖耐量，这种作用可被外源性GLP-1刺激的应激反应所抵消。
The glucagon-like peptide 1 (GLP-1) system plays an important role in blood glucose regulation, in great part through coordinate control of insulin and glucagon secretion. These effects are generally attributed to GLP-1 produced in peripheral sites, principally the intestine. GLP-1 is also produced in hindbrain neurons that signal through GLP-1 receptors (GLP-1rs) expressed in brain regions involved in metabolic regulation. GLP-1 in the central nervous system (CNS) induces satiety, visceral illness, and stress responses. However, recent evidence suggests CNS GLP-1 is also involved in glucose regulation. To test the hypothesis that central GLP-1 regulates islet hormone secretion, conscious rats were given intracerebroventricular (ICV) GLP-1, GLP-1r antagonist exendin-[9-39] (Ex-9), or saline during fasting or hyperglycemia from intravenous glucose. Administration of CNS GLP-1 increased fasting glucose, glucagon, corticosterone, and epinephrine and blunted insulin secretion in response to hyperglycemia. Paradoxically, GLP-1r blockade with ICV Ex-9 also reduced glucosestimulated insulin secretion, and administration of ICV Ex-9 to freely feeding rats caused mild glucose intolerance. Thus, direct administration of CNS GLP-1 affected islet hormone secretion counter to what is seen with peripherally administered GLP-1, an effect likely due to stimulation of sympathetic nervous system activity. In contrast, blockade of brain GLP-1r supports a role for CNS GLP-1 on glucose-stimulated insulin secretion and glucose control after a meal. These findings suggest a model in which activation of CNS GLP-1r by endogenous peptide promotes glucose tolerance, an effect that can be overridden by stress responses stimulated by exogenous GLP-1.