Development of gene therapy for diabetes associated with obesity

近几十年来，糖尿病患者的数量急剧增加，这在大多数工业化国家已经成为一个主要的公共卫生问题，这主要是能量摄入过多和缺乏运动的结果。过多的能量摄入会导致肥胖，这是一种常见的疾病，与糖尿病、高脂血症和早产儿心脏病有关。然而，糖尿病的主要治疗方法，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肌肉和脂肪等外围组织的细胞中来降低血糖水平。当能量摄入过多时，这会进一步加剧胰岛素抵抗，导致恶性循环。因此，需要新的治疗方法来促进能量消耗的增加。低效代谢，如产生热量而不是三磷酸腺苷，是治疗肥胖相关的2型糖尿病的潜在策略。因此，为了检查在肝脏中消散过剩能量是否可能是一种…对于高脂饮食诱导的代谢紊乱，我们尝试用腺病毒载体在小鼠肝脏异位表达解偶联蛋白-1(UCP1)。一旦糖尿病合并肥胖，肝脏UCP1的表达就会增加能量消耗，减轻体重，减少肝脏和脂肪组织中的脂肪，从而显著改善胰岛素抵抗，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吞噬功能亢进和下丘脑瘦素抵抗，以及肌肉中的胰岛素抵抗。相比之下，有趣的是，在标准饮食喂养的瘦小鼠中，肝脏UCP1的表达并没有显著影响能量消耗或肝脏ATP含量。此外，没有观察到血糖水平、体重或肥胖的变化。这些发现表明，肝脏中的异位UCP1在不影响所需能量的情况下分散了多余的能量，并对瘦小鼠产生了最小的代谢影响。因此，这种基因治疗是治疗代谢综合征的一种新的潜在的治疗策略。较少

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