Clinical utility of leptin therapy in syndromic forms of insulin resistance.

瘦素疗法在胰岛素抵抗综合征中的临床应用。

• 批准号: 8741470
• 负责人: PHILLIP GORDEN
• 金额: $ 19.92万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8741470
• 关键词: Adipocytes; Adipose tissue; Amino Acids; Animal Model; Blood Glucose; Body Weight decreased; Clinical; Clinical Trials; Cooperative Research and Development Agreement; Dyslipidemias; Eating; Endocrine; Endocrine Glands; Fasting; Fatty acid glycerol esters; Gene Mutation; Genes; Glycosylated hemoglobin A; Gonadotropins; Hormones; Human; Insulin; Insulin Resistance; Leptin; Leptin deficiency; Leptin resistance; Licensing; Lipodystrophy; Liver; Liver Function Tests; Measures; Menstruation; Metabolic; Metabolic Diseases; Metabolic syndrome; Mus; Mutation; Obese Mice; Obesity; Organ; Oxidative Stress; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Recombinants; Replacement Therapy; Rodent; Severities; Steatohepatitis; Tissues; Triglycerides; Weight; adipokines; base; follow-up; islet amyloid polypeptide; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; polypeptide; reproductive

Leptin was discovered when the gene mutation in the ob/ob mouse, an animal model of obesity, was identified. Leptin is a polypeptide of 167 amino acids that is encoded by the obese (ob) gene. Ob/ob mice make a defective leptin product and are extremely obese and hyperphagic. Since leptin administration causes a dramatic reduction in weight and food intake in these mice, it was hoped that leptin could be used to treat obesity in humans. As leptin is produced and secreted by fat cells, leptin levels are proportional to fat tissue mass and are high in obese humans. Exogenous leptin has limited effect in inducing weight loss, suggesting that obese humans have leptin resistance. Nevertheless, the discovery of leptin was pivotal for a number of reasons. It identified adipose tissue as an endocrine organ and was the first of the adiopocyte-derived hormones, later termed adipokines, to be recognized. It led to the discovery of a monogenic form of obesity in rodents and humans in which mutations in the leptin gene cause congenital leptin deficiency. Finally, it presented a form of treatment for patients with leptin gene mutations and patients with lipodystrophy. Our major effort has been in a clinical trial of leptin therapy in lipodystrophy. Leptin levels are low in these patients and leptin replacement therapy results in a reduction in hemoglobin A1c, fasting blood glucose, triglyceride values, liver size, and liver function test abnormalities. Furthermore, in those patients who have normal reproductive organs, leptin therapy results in a robust increase in gonadotropin secretion following GNRH administration; this is associated with the beginning of menses in these otherwise amenorrheic patients. Thus, leptin therapy appears to have a major beneficial effect on the metabolic and endocrine abnormalities seen in these patients. In lipodystrophic patients, nonalcoholic steatohepatitis (NASH) is a common finding. Our studies have shown that leptin therapy not only reduces steatosis, but also decreases the severity of the NASH score, which largely measures the degree of oxidative stress. We continue the follow-up of these patients and our involvement in a CRADA with Amylin Pharmaceuticals. On the basis of our studies, the company is presenting a new drug application (NDA)to the FDA to license recombinant leptin. If approved, it will be the first novel therapy for extreme insulin resistance since the discovery of insulin over 85 years ago.

瘦素是在肥胖动物模型 ob/ob 小鼠的基因突变被发现时发现的。 瘦素是由肥胖 (ob) 基因编码的 167 个氨基酸的多肽。 Ob/ob 小鼠产生有缺陷的瘦素产物，并且极度肥胖且贪食。 由于施用瘦素会导致这些小鼠的体重和食物摄入量急剧减少，因此人们希望瘦素可以用于治疗人类的肥胖症。 由于瘦素是由脂肪细胞产生和分泌的，因此瘦素水平与脂肪组织质量成正比，并且在肥胖人群中瘦素水平很高。 外源性瘦素在诱导体重减轻方面效果有限，表明肥胖人群存在瘦素抵抗。 然而，由于多种原因，瘦素的发现至关重要。 它将脂肪组织确定为内分泌器官，并且是第一个被认可的脂肪细胞衍生激素，后来被称为脂肪因子。 它导致在啮齿动物和人类中发现了一种单基因肥胖，其中瘦素基因突变导致先天性瘦素缺乏。 最后，它提出了一种针对瘦素基因突变患者和脂肪营养不良患者的治疗方法。 我们的主要工作是进行瘦素疗法治疗脂肪营养不良的临床试验。 这些患者的瘦素水平较低，瘦素替代疗法会导致糖化血红蛋白、空腹血糖、甘油三酯值、肝脏大小和肝功能测试异常的减少。 此外，在那些具有正常生殖器官的患者中，瘦素治疗会导致 GNRH 给药后促性腺激素分泌显着增加。这与这些闭经患者的月经开始有关。 因此，瘦素治疗似乎对这些患者的代谢和内分泌异常具有重要的有益作用。 在脂肪营养不良患者中，非酒精性脂肪性肝炎 (NASH) 是常见现象。 我们的研究表明，瘦素治疗不仅可以减少脂肪变性，还可以降低 NASH 评分的严重程度，该评分主要衡量氧化应激的程度。 我们将继续对这些患者进行随访，并与 Amylin Pharmaceuticals 一起参与 CRADA。 根据我们的研究，该公司正在向 FDA 提交重组瘦素的新药申请 (NDA)。 如果获得批准，这将是自 85 年前发现胰岛素以来第一个针对极端胰岛素抵抗的新疗法。