（封面圖片：作者建立的胰高血糖素調(diào)節(jié)模型,，背景中的胰島α細(xì)胞（紅色）表達(dá)囊泡谷氨酸轉(zhuǎn)運(yùn)體（綠色）,，而β細(xì)胞分泌胰島素（藍(lán)色）。圖片提供：Nathan Bress）
生物谷報道：美國和瑞典科學(xué)家聯(lián)合在《細(xì)胞—代謝》（Cell Metabolism）上發(fā)表封面文章,，證實(shí)人類胰島α細(xì)胞能表達(dá)一種對于胰高血糖素的釋放非常關(guān)鍵的促離子型谷氨酸受體（ionotropic glutamate receptor iGluRs）,。
血糖穩(wěn)態(tài)（glucose homeostasis）的一個重要特征是胰島α細(xì)胞有效的釋放胰高血糖素（glucagon），胰高血糖素又被稱為抗胰島素或是胰島素B,。人類胰高血糖素是以N-末端組氨酸為起點(diǎn)，C-末端蘇氨酸為終點(diǎn)的29個氨基酸組成的一條單鏈肽,，分子量為3485,。其主要作用是對抗胰島素，起著使血糖增加的作用,。然而目前,，科學(xué)家對于調(diào)節(jié)胰高血糖素分泌過程的分子學(xué)機(jī)制還知之甚少。
實(shí)驗(yàn)中,，研究人員分析了谷氨酸鹽（glutamate）作為正向自分泌信號在人類,、猴子、小鼠胰島的胰高血糖素釋放過程中的作用,。結(jié)果發(fā)現(xiàn),，谷氨酸鹽的正反饋極大的促進(jìn)了胰高血糖素的分泌，而一旦血糖濃度上升,，胰高血糖素的分泌就會受到胰島素以及鋅離子或是γ-氨基丁酸（GABA）的限制,。
血糖濃度的下降能促使胰島α細(xì)胞釋放谷氨酸鹽。谷氨酸鹽接著作用于AMPA和kainate型的促離子型谷氨酸受體,，并使得細(xì)胞膜去極化,，鈣離子通道被打開，最終使得細(xì)胞質(zhì)中的自由鈣離子濃度增加,，從而促進(jìn)胰高血糖素的釋放,。在小鼠的活體實(shí)驗(yàn)中，阻礙促離子型谷氨酸受體將會降低胰高血糖素的釋放,，并加劇胰島素導(dǎo)致的血糖過低癥狀,。因此，谷氨酸鹽的自分泌反饋環(huán)路使得胰島α細(xì)胞具有了有效加強(qiáng)自身分泌活性的能力，這是在任何生理?xiàng)l件下保證充足的胰高血糖素釋放不可或缺的先決條件,。（生物谷www.bioon.com）
生物谷推薦原始出處：
Cell Metabolism,，Vol 7, 545-554, 04 June 2008，Over Cabrera, Per-Olof Berggren
Glutamate Is a Positive Autocrine Signal for Glucagon Release
Over Cabrera,1,2 M. Caroline Jacques-Silva,1 Stephan Speier,2 Shao-Nian Yang,2 Martin Köhler,2 Alberto Fachado,1 Elaine Vieira,3 Juleen R. Zierath,3 Richard Kibbey,4 Dora M. Berman,1 Norma S. Kenyon,1 Camillo Ricordi,1 Alejandro Caicedo,1, and Per-Olof Berggren1,2,
1 Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
2 The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden
3 Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden
4 Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA
Corresponding author
Alejandro Caicedo
[email protected]
Corresponding author
Per-Olof Berggren
[email protected]
Summary
An important feature of glucose homeostasis is the effective release of glucagon from the pancreatic α cell. The molecular mechanisms regulating glucagon secretion are still poorly understood. We now demonstrate that human α cells express ionotropic glutamate receptors (iGluRs) that are essential for glucagon release. A lowering in glucose concentration results in the release of glutamate from the α cell. Glutamate then acts on iGluRs of the AMPA/kainate type, resulting in membrane depolarization, opening of voltage-gated Ca2+ channels, increase in cytoplasmic free Ca2+ concentration, and enhanced glucagon release. In vivo blockade of iGluRs reduces glucagon secretion and exacerbates insulin-induced hypoglycemia in mice. Hence, the glutamate autocrine feedback loop endows the α cell with the ability to effectively potentiate its own secretory activity. This is a prerequisite to guarantee adequate glucagon release despite relatively modest changes in blood glucose concentration under physiological conditions.
