Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy
Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy
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DOI：
10.1210/jc.2006-1546
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发表时间：
2007-02-01
影响因子：
5.8
通讯作者：
Nakao, Kazuwa
中科院分区：
文献类型：
--
作者：
Ebihara, Ken;Kusakabe, Toru;Nakao, Kazuwa
背景资料：瘦素缺乏与全身性脂肪代谢障碍的胰岛素抵抗和其他代谢异常有关;然而，瘦素替代疗法在全身性脂肪代谢障碍患者中的疗效、安全性和潜在机制尚不清楚。7例日本全身性脂肪营养不良患者，2例获得性和5例先天性，在最初的4个月住院期间接受生理替代剂量的重组瘦素治疗，随后进行长达36个月的门诊随访。每天注射两次的瘦素替代疗法显著改善了空腹血糖（平均+/- SE，172 +/- 20至120 +/- 12 mg/dl，P < 0.05）和甘油三酯水平（平均+/- SE，700 +/- 272至260 +/- 98 mg/dl，P < 0.05）。通过正糖钳夹法评估，瘦素替代疗法可降低胰岛素抵抗，并增加糖耐量试验中的胰岛素分泌，但获得性和先天性类型的反应不同。还观察到脂肪肝的改善。每日一次注射的有效性和安全性与每日两次注射相当。瘦素替代治疗改善了大量和微量白蛋白尿，并显示这些患者的神经病变和视网膜病变没有恶化。瘦素替代治疗对糖尿病并发症和脂肪代谢障碍有一定的疗效。两名患者产生抗瘦素抗体，但没有中和抗体。该疗法耐受性良好，其效果维持长达36个月，没有任何显着的不良反应，如低血糖，高血压，或减少骨矿物质density.Conclusions：本研究表明，长期的瘦素替代疗法的有效性和安全性和可能的机制，瘦素行动的患者全身性脂肪代谢障碍。
Background: Lack of leptin is implicated in insulin resistance and other metabolic abnormalities in generalized lipodystrophy; however, the efficacy, safety, and underlying mechanisms of leptin-replacement therapy in patients with generalized lipodystrophy remain unclear.Methods: Seven Japanese patients with generalized lipodystrophy, two acquired and five congenital type, were treated with the physiological replacement dose of recombinant leptin during an initial 4-month hospitalization followed by outpatient follow-up for up to 36 months.Results: The leptin-replacement therapy with the twice-daily injection dramatically improved fasting glucose (mean +/- SE, 172 +/- 20 to 120 +/- 12 mg/dl, P < 0.05) and triglyceride levels (mean +/- SE, 700 +/- 272 to 260 +/- 98 mg/dl, P < 0.05) within 1 wk. The leptin-replacement therapy reduced insulin resistance evaluated by euglycemic clamp method and augmented insulin secretion at glucose tolerance test with different responses between acquired and congenital types. Improvement of the fatty liver was also observed. The efficacy and safety of the once-daily injection were comparable to those of the twice-daily injection. The leptin-replacement therapy ameliorated macro-and microalbuminuria and showed no deterioration of neuropathy and retinopathy of these patients. The leptin-replacement therapy is beneficial to diabetic complications and lipodystrophic ones. Two patients developed antileptin antibodies but not neutralizing antibodies. The therapy was well tolerated, and its effects were maintained for up to 36 months without any notable adverse effects such as hypoglycemia, high blood pressure, or reduction of bone mineral density.Conclusions: The present study demonstrates the efficacy and safety of the long-term leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.