Glucose-regulated insulin production in the liver improves glycemic control in type 1 diabetic mice.
Glucose-regulated insulin production in the liver improves glycemic control in type 1 diabetic mice.
复制标题
肝脏中葡萄糖调节的胰岛素产生可改善 1 型糖尿病小鼠的血糖控制。
DOI：
10.1016/j.molmet.2014.10.005
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发表时间：
2015
影响因子：
8.1
通讯作者：
Dong,HHenry
中科院分区：
文献类型：
--
作者：
Zhang,Ting;Dong,HHenry
目的：1型糖尿病是胰腺β细胞自身免疫破坏的结果。我们的目标是在肝脏中重建一个葡萄糖反应系统来调节肝脏胰岛素的产生，以改善1型糖尿病的血糖控制。方法从乙酰辅酶a羧化酶（ACC）启动子中克隆了葡萄糖反应元件（GRE）， ACC是一种酶，在肝脏对葡萄糖的反应中催化脂肪酸合成的限速步骤。为了增加葡萄糖诱导的幅度，我们通过基因复制将GRE DNA复制四倍。我们测试了生成的GRE多聚体（4×GRE）在肝细胞和胰岛素缺乏型糖尿病小鼠中驱动大鼠胰岛素原cDNA表达的能力。结果我们发现，这种多定向的葡萄糖反应系统以葡萄糖依赖的方式在肝细胞中产生胰岛素。当通过腺病毒介导的基因转移进入肝脏时，这种葡萄糖反应性胰岛素产生系统能够将高血糖逆转到正常范围，而不会在葡萄糖挑战或一夜禁食后引起低血糖。胰岛素载体治疗的糖尿病小鼠在葡萄糖耐量的反应中表现出显著改善的血糖谱，这与肝脏中胰岛素的产生有关。我们在链脲佐菌素诱导的糖尿病CD1小鼠和自身免疫性非肥胖糖尿病小鼠中总结了这些发现。我们的数据表明ACC启动子中的GRE基序是一个有效的葡萄糖反应元件，并提供了4×GRE-mediated肝脏胰岛素产生能够纠正胰岛素缺乏和改善1型糖尿病血糖控制的概念证明。
ObjectiveType 1 diabetes results from autoimmune destruction of beta-cells in the pancreas. Our objective is to reconstitute a glucose-responsive system in the liver to regulate hepatic insulin production for improving glycemic control in type 1 diabetes.MethodsWe have cloned the glucose-responsive element (GRE) from the promoter of acetyl-CoA carboxylase (ACC), an enzyme that catalyzes the rate-limiting step in fatty acid synthesis in the liver in response to glucose. To increase the amplitude of glucose induction, we quadruplicated the GRE DNA by gene duplication. The resulting GRE multimer (4×GRE) was tested for its ability to drive rat proinsulin cDNA expression in hepatocytes and insulin-deficient diabetic mice.ResultsWe showed that this GRE multimer-directed glucose-responsive system produced insulin in hepatocytes in a glucose-dependent manner. When delivered into the liver by adenovirus-mediated gene transfer, this glucose-responsive insulin production system was able to reverse hyperglycemia to a normal range without causing hypoglycemia after glucose challenge or overnight fasting. Insulin vector-treated diabetic mice exhibited significantly improved blood glucose profiles in response to glucose tolerance, correlating with insulin production in the liver. We recapitulated these findings in streptozotocin-induced diabetic CD1 mice and autoimmune non-obese diabetic mice.ConclusionOur data characterized the GRE motif from the ACC promoter as a potent glucose-responsive element, and provided proof-of-concept that the 4×GRE-mediated hepatic insulin production is capable of correcting insulin deficiency and improving glycemic control in type 1 diabetes.