FGF19 action in the brain induces insulin-independent glucose lowering
FGF19 action in the brain induces insulin-independent glucose lowering
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DOI：
10.1172/jci70710
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发表时间：
2013-11-01
影响因子：
15.9
通讯作者：
Schwartz, Michael W.
中科院分区：
文献类型：
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作者：
Morton, Gregory J.;Matsen, Miles E.;Schwartz, Michael W.
胰岛素非依赖性葡萄糖处置（称为葡萄糖有效性[GE]）对葡萄糖稳态至关重要，直到最近，人们才认为它是不变的。然而，GE在2型糖尿病中减少，在瘦素缺乏的ob/ob小鼠中显著减少。因此，旨在增加GE的策略应该能够改善这些动物的葡萄糖耐量。肠源性激素FGF 19先前已显示在ob/ob小鼠中发挥有效的抗糖尿病作用。在ob/ob小鼠中，我们发现全身给予FGF 19通过其在脑中的作用改善了葡萄糖耐量，并且单次低剂量i. c. v.注射FGF 19在2小时内显著改善了葡萄糖耐受不良。在频繁采样的静脉内葡萄糖耐量试验期间获得的葡萄糖和胰岛素数据的最小模型分析表明，静脉内FGF 19的抗糖尿病作用仅仅是由于GE增加，而不是胰岛素分泌或胰岛素敏感性的变化。这种作用的机制似乎涉及葡萄糖代谢为乳酸盐的增加。总之，这些发现暗示大脑参与了全身性FGF 19的抗糖尿病作用，并建立了大脑快速、有效和选择性地增加胰岛素非依赖性葡萄糖处置的能力。
Insulin-independent glucose disposal (referred to as glucose effectiveness [GE]) is crucial for glucose homeostasis and, until recently, was thought to be invariable. However, GE is reduced in type 2 diabetes and markedly decreased in leptin-deficient ob/ob mice. Strategies aimed at increasing GE should therefore be capable of improving glucose tolerance in these animals. The gut-derived hormone FGF19 has previously been shown to exert potent antidiabedc effects in ob/ob mice. In ob/ob mice, we found that systemic FGF19 administration improved glucose tolerance through its action in the brain and that a single, low-dose i.c.v. injection of FGF19 dramatically improved glucose intolerance within 2 hours. Minimal model analysis of glucose and insulin data obtained during a frequently sampled i.v. glucose tolerance test showed that the antidiabetic effect of i.c.v. FGF19 was solely due to increased GE and not to changes of either insulin secretion or insulin sensitivity. The mechanism underlying this effect appears to involve increased metabolism of glucose to lactate. Together, these findings implicate the brain in the antidiabetic action of systemic FGF19 and establish the brain's capacity to rapidly, potently, and selectively increase insulin-independent glucose disposal.