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2015年1月16日讯 /生物谷BIOON/ --2型糖尿病是一项全球性健康问题，而其发病特点在于高企的血糖无法刺激胰岛 细胞分泌足够的胰岛素使血糖恢复并维持在正常水平。针对胰岛 细胞的新型治疗策略被认为具有巨大的临床前景。 本文报道了表达与小鼠和人类胰岛细胞表面的短链脂肪酸受体2（FFA2，由FFAR2基因编码）和短链脂肪酸受体3（FFA3，由FFAR3基因编码）通过和G型G蛋白偶联能够抑制胰岛素的分泌。与非肥胖的正常对照小鼠相比，研究者们同时发现在饮食诱导的肥胖和2型糖尿病模型小鼠的胰腺和血液中产生了更多的乙酸，而乙酸是FFA2和FFA3的内源性激活剂。肥胖小鼠体内升高的乙酸水平能够解释为什么它们体内的胰岛细胞不能响应高糖刺激而产生足够的胰岛素。 之后研究者们通过基因敲除的方法将这两个受体敲掉，使它们失去功能，并在高脂饮食诱导的肥胖小鼠模型中研究它们的功能。不出所料敲除这两个受体之后，无论是小鼠的全身循环系统还是胰岛细胞中胰岛素分泌都得到了增强，并极大的缓解了肥胖小鼠的葡萄糖耐受现象。此外，在小肠细胞中敲除这两个受体后并未观察到糖尿病小鼠的葡萄糖耐受得到改善。由此可以推断胰岛细胞上的短链脂肪酸受体2和3通过一种细胞自控的方式调节胰岛素的分泌。 综上所述，糖尿病患者体内产生过量的乙酸，通过激活胰岛细胞上的短链脂肪酸受体2和3来抑制正常的葡萄糖刺激产生胰岛素的效应。那么针对短链脂肪酸受体2和3开发的拮抗剂必然会对肥胖导致的2型糖尿病产生积极的治疗作用，而这将很可能成为新的2型糖尿病治疗策略。（生物谷Bioon.com） 本文系生物谷原创编译整理，欢迎转载！转载请注明来源并附原文链接。谢谢！ 生物谷推荐的英文摘要：  Nature Medicine doi:10.1038/nm.3779 Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes Cong Tang, Kashan Ahmed, Andreas Gille, Shun Lu, Hermann-Josef Gr?ne, Sorin Tunaru & Stefan Offermanns Type 2 diabetes is a major health problem worldwide, and one of its key features is the inability of elevated glucose to stimulate the release of sufficient amounts of insulin from pancreatic beta cells to maintain normal blood glucose levels1, 2. New therapeutic strategies to improve beta cell function are therefore believed to be beneficial3, 4. Here we demonstrate that the short-chain fatty acid receptors FFA2 (encoded by FFAR2) and FFA3 (encoded by FFAR3) are expressed in mouse and human pancreatic beta cells and mediate an inhibition of insulin secretion by coupling to Gi-type G proteins. We also provide evidence that mice with dietary-induced obesity and type 2 diabetes, as compared to non-obese control mice, have increased local formation by pancreatic islets of acetate, an endogenous agonist of FFA2 and FFA3, as well as increased systemic levels. This elevation may contribute to the insufficient capacity of beta cells to respond to hyperglycemia in obese states. Indeed, we found that genetic deletion of both receptors, either on the whole-body level or specifically in pancreatic beta cells, leads to greater insulin secretion and a profound improvement of glucose tolerance when mice are on a high-fat diet compared to controls. On the other hand, deletion of Ffar2 and Ffar3 in intestinal cells did not alter glucose tolerance in diabetic animals, suggesting these receptors act in a cell-autonomous manner in beta cells to regulate insulin secretion. In summary, under diabetic conditions elevated acetate acts on FFA2 and FFA3 to inhibit proper glucose-stimulated insulin secretion, and we expect antagonists of FFA2 and FFA3 to improve insulin secretion in type 2 diabetes. |
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