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Development of gene therapy for diabetes associated with obesity

肥胖相关糖尿病基因疗法的开发

基本信息

批准号：
15390282
负责人：
KATAGIRI Hideki
金额：
$ 9.28万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390282/
关键词：
diabetes obesity metabolic syndrome insulin resistance gene therapy

项目摘要

An explosive increase in the number of diabetic patients, which has become a major public health concern in most industrialized countries in recent decades, is mainly the result of excess energy intake and physical inactivity. Excess energy intake results in obesity, a common condition associated with diabetes, hyperlipidemia and premature heart disease. However, the major treatment modalities for diabetes, including insulin injection and oral sulfonylureas, aim at lowering blood glucose levels by driving glucose into cells in peripheral tissues such as muscle and fat. This further exacerbates insulin resistance when energy intake is in excess, resulting in a vicious cycle. Therefore, novel therapies which promote increased energy expenditure are needed.Inefficient metabolism, such as the generation of heat instead of ATP, is a potential treatment strategy for type 2 diabetes associated with obesity. Therefore, to examine whether dissipating excess energy in the liver is a possible the … More rapeutic approach to high fat diet-induced metabolic disorders, we attempted to express uncoupling protein-1 (UCP1) ectopically in murine liver using adenoviral vectors. Once diabetes with obesity developed, hepatic UCP1 expression increased energy expenditure, decreased body weight, and reduced fat in the liver and adipose tissues, resulting in markedly improved insulin resistance, and thus, diabetes and dyslipidemia. Hepatic UCP1 expression also reversed high fat diet-induced hyperphagia and hypothalamic leptin resistance, as well as insulin resistance in muscle. In contrast, intriguingly, in standard chow-fed lean mice, hepatic UCP1 expression did not significantly affect energy expenditure or hepatic ATP contents. Furthermore, no alterations in blood glucose levels, body weight, or adiposity were observed. These findings suggest that ectopic UCP1 in the liver dissipates surplus energy without affecting required energy and exerts minimal metabolic effects in lean mice. Thus, this gene therapy is a new potential therapeutic strategy for the metabolic syndrome. Less

近几十年来，糖尿病患者人数的爆炸性增长已成为大多数工业化国家的主要公共卫生问题，这主要是能量摄入过量和缺乏身体活动的结果。过量的能量摄入会导致肥胖，这是一种与糖尿病、高脂血症和早发性心脏病相关的常见疾病。然而，糖尿病的主要治疗方式，包括胰岛素注射和口服磺脲类药物，旨在通过将葡萄糖驱动到外周组织（如肌肉和脂肪）中的细胞中来降低血糖水平。当能量摄入过量时，这进一步加剧了胰岛素抵抗，导致恶性循环。因此，需要新的治疗方法，促进增加能量消耗。低效代谢，如产生热量而不是ATP，是与肥胖相关的2型糖尿病的潜在治疗策略。因此，为了检查是否消散肝脏中多余的能量是一种可能的方法， ...更多信息为探讨高脂饮食诱导的代谢紊乱的治疗方法，我们尝试用腺病毒载体在小鼠肝脏中异位表达解偶联蛋白1（UCP 1）。一旦糖尿病伴肥胖症发展，肝脏UCP1表达增加能量消耗，降低体重，减少肝脏和脂肪组织中的脂肪，导致胰岛素抵抗显著改善，从而导致糖尿病和血脂异常。肝脏UCP1的表达也逆转了高脂饮食诱导的摄食过多和下丘脑瘦素抵抗，以及肌肉中的胰岛素抵抗。相反，有趣的是，在标准的饲料喂养的瘦小鼠，肝脏UCP1的表达并没有显着影响能量消耗或肝脏ATP含量。此外，未观察到血糖水平、体重或肥胖的变化。这些发现表明，肝脏中的异位UCP1消耗多余的能量而不影响所需的能量，并在瘦小鼠中产生最小的代谢影响。因此，这种基因治疗是一种新的潜在的治疗代谢综合征的策略。少