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: 9356121
• 负责人: PHILLIP GORDEN
• 金额: $ 20.96万
• 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/9356121
• 关键词: Adipocytes; Adipose tissue; Amino Acids; Animal Model; Blood Glucose; Body Weight decreased; Clinical; Clinical Trials; Dyslipidemias; Eating; Endocrine; Endocrine Glands; FDA approved; Familial generalized lipodystrophy; Fasting; Fatty acid glycerol esters; GNRH1 gene; Gene Mutation; Genes; Glycosylated hemoglobin A; Gonadotropins; Hormones; Human; Insulin; Insulin Resistance; Leptin; Leptin deficiency; Leptin resistance; Lipodystrophy; Liver; Liver Function Tests; Measures; Menstruation; Metabolic; Metabolic Diseases; Metabolic syndrome; Mus; Mutation; Obese Mice; Obesity; Oxidative Stress; Patients; Replacement Therapy; Rodent; Severities; Steatohepatitis; Tissues; Triglycerides; Weight; adipokines; base; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; novel therapeutics; polypeptide; reproductive organ

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. On the basis of our studies, the FDA approved leptin for the treatment of generalized lipodystrophy in February, 2014. This is the first novel therapy for extreme insulin resistance since the discovery of insulin over 85 years ago.

当鉴定出OB/OB小鼠中的基因突变（一种肥胖的动物模型）时，发现了瘦素。 瘦素是由肥胖基因编码的167种氨基酸的多肽。 OB/OB小鼠会产生有缺陷的瘦素产物，并且非常肥胖和倍感。 由于瘦素的给药会导致这些小鼠的体重和食物摄入量显着减轻，因此希望可以使用瘦素来治疗人类的肥胖症。 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，并且肥胖人类高。 外源瘦素对诱导体重减轻的作用有限，表明肥胖人具有瘦素耐药性。 然而，由于多种原因，瘦素的发现至关重要。 它将脂肪组织鉴定为内分泌器官，是adiopopocyte衍生的激素中的第一个，后来称为脂肪因子，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形式，在啮齿动物和人类中，瘦素基因中的突变会导致先天性瘦素缺乏症。 最后，它为患有瘦素基因突变和脂肪营养不良患者的患者提供了一种治疗形式。 我们的主要努力是在脂肪营养不良的瘦素治疗的临床试验中。 这些患者的瘦素水平较低，瘦素替代疗法导致血红蛋白A1C，空腹血糖，甘油三酸酯值，肝脏大小和肝功能测试异常的降低。 此外，在那些患有正常生殖器官的患者中，瘦素治疗在GNRH给药后会导致促性腺激素分泌的强劲增加。这与这些原本闭经患者的月经的开始有关。 因此，瘦素疗法似乎对这些患者的代谢和内分泌异常具有重大有益作用。 在脂肪营养不良的患者中，非酒精性脂肪性肝炎（NASH）是一个普遍发现。 我们的研究表明，瘦素疗法不仅降低了脂肪变性，而且还降低了NASH评分的严重程度，这在很大程度上衡量了氧化应激的程度。 根据我们的研究，FDA在2014年2月批准了瘦素治疗广义脂肪营养不良。这是自85年前发现胰岛素以来发现胰岛素以来对极端胰岛素耐药性的第一种新型疗法。