GLUT8 Overexpression in Cardioprotection

描述(申请人提供)：II型糖尿病(T2 DM)在美国是一种新兴的流行病。T2 DM的头号死因是心血管疾病(CVD)。本实验室建立了转基因小鼠模型，研究葡萄糖转运蛋白功能丧失和功能恢复对T2 DM和CVD发生发展的影响。研究表明，心肌能量代谢的改变在糖尿病心肌病的发生、发展中起一定作用。我们已经证明，没有胰岛素反应性葡萄糖转运体GLUT4(G4Null)的小鼠心脏肥厚，意外地摄取了比正常数量更多的葡萄糖，并表现出糖酵解和糖原合成增加。在体外，与野生型(WT)相比，G4Null心脏在缺血/再灌注(I/R)后损伤更小，恢复更多的功能。G4空白小鼠表现出葡萄糖转运蛋白家族的新成员GLUT8的表达增加。考虑到这些结果，仅在心脏(H8)过表达GLUT8的转基因小鼠已经产生，以评估GLUT8在心脏保护中的作用。与WT小鼠相比，H8小鼠对I/R损伤的抵抗力显著增强，并伴随着脂肪酸代谢葡萄糖基因的上调。这一建议的中心假设是，随着心脏功能的增加，GLUT8的过度表达增加了心脏的代谢能力，表现为葡萄糖和脂肪酸的利用以及糖原储存的增加。H8心脏代谢表型应能使H8心脏抵抗病理性全身代谢的有害影响。预计H8心脏将在全身代谢应激(即高脂饮食[HF])条件下保持代谢灵活性，并抵抗I/R后的损伤和功能丧失。开发增加心脏中GLUT8表达的治疗方法可能有助于减轻糖尿病心肌病的影响。公共卫生相关性：糖尿病患者的头号死因是心血管疾病，这些人的葡萄糖摄取和代谢受到影响。这项建议的初步研究表明，过度表达GLUT8葡萄糖转运体的心脏对缺血损伤具有抵抗力。GLUT8在糖尿病模型中的过度表达的治疗潜力将在这项提案中进行评估。

DESCRIPTION (provided by applicant): Type II diabetes mellitus (T2DM) is a burgeoning epidemic in the United States. The number one cause of death in T2DM is cardiovascular disease (CVD). Our laboratory has generated transgenic mouse models to study the effects of loss and gain of function of glucose transporters on the development and progression of T2DM and CVD. Studies indicate that alterations in myocardial energy metabolism play a role in the etiology and progression of diabetic cardiomyopathy. We have shown that mice without the insulin responsive glucose transporter, GLUT4 (G4 Null), have hypertrophied hearts that unexpectedly take up more than normal amounts of glucose and exhibit increased glycolysis and glycogen synthesis. In vitro, G4 Null hearts also sustain less injury and regain more function than wild-type (WT) after ischemia/reperfusion (I/R). G4 Null mice show an increased expression of GLUT8, a new member of the glucose transporter family. Considering these results, transgenic mice overexpressing GLUT8 in the heart only (H8) have been generated to assess the role of GLUT8 in cardioprotection. The H8 mice exhibit significantly increased resistance to I/R damage compared to WT that is accompanied by upregulation of genes of both glucose of fatty acid metabolism. The central hypothesis of this proposal is that overexpression of GLUT8 with gain of function in the heart increases cardiac metabolic capacity as manifested by increases in both glucose and fatty acid utilization and glycogen storage. The H8 cardiac metabolic phenotype should enable the H8 heart to resist the deleterious effects of pathological systemic metabolism. It is expected that the H8 heart will maintain metabolic flexibility and resist injury and loss of function after I/R under conditions of systemic metabolic stress (i.e. high fat diet [HF]). Development of therapies that increase the expression of GLUT8 in the heart may help to attenuate the effects of diabetic cardiomyopathy. PUBLIC HEALTH RELEVANCE: The number one cause of death of diabetics is cardiovascular disease and glucose uptake and metabolism is compromised in these individuals. Preliminary studies in this proposal show that hearts overexpressing the GLUT8 glucose transporter are resistant to ischemic injury. The therapeutic potential of GLUT8 overexpression in diabetic models will be assessed in this proposal.