{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:22:14Z","timestamp":1791332534404,"version":"4.3.1"},"reference-count":37,"publisher":"American Diabetes Association","issue":"7","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2005,7,1]]},"abstract":"<jats:p>Ectopic fat accumulation has been implicated as a contributing factor in the abnormal metabolic state of obesity. One human model of ectopic fat deposition is generalized lipodystrophy. Generalized lipodystrophy is a rare disorder characterized by a profound deficiency of adipose tissue with resultant loss of triglyceride storage capacity and reduced adipokines, including leptin. Subjects with generalized lipodystrophy and reduced leptin levels often have an increased appetite leading to hyperphagia. Excess fuel consumption, coupled with a lack of adipose tissue, contributes to the significant ectopic triglyceride accumulation in the muscle and liver seen in these subjects. This ectopic fat, along with the deficiency in leptin signaling and perhaps other adipokines, likely contributes to insulin resistance, diabetes, and hepatic steatosis. We report here the long-term effects of leptin replacement in a cohort of these subjects. Fifteen patients with generalized lipodystrophy were treated with twice-daily recombinant methionyl human leptin (r-metHuLeptin) for 12 months. We evaluated metabolic parameters at baseline and every 4 months. Antidiabetes medications were decreased or discontinued as necessary. Reductions were seen in serum fasting glucose (from 205 \u00b1 19 to 126 \u00b1 11 mg\/dl; P &amp;lt; 0.001), HbA1c (from 9 \u00b1 0.4 to 7.1 \u00b1 0.5%; P &amp;lt; 0.001), triglycerides (from 1,380 \u00b1 500 to 516 \u00b1 236 mg\/dl; P &amp;lt; 0.001), LDL (from 139 \u00b1 16 to 85 \u00b1 7 mg\/dl; P &amp;lt; 0.01), and total cholesterol (from 284 \u00b1 40 to 167 \u00b1 21 mg\/dl; P &amp;lt; 0.01). HDL was unchanged (from 31 \u00b1 3 to 29 \u00b1 2 mg\/dl; P = 0.9). Liver volumes were significantly reduced (from 3,663 \u00b1 326 to 2,190 \u00b1 159 cm3; P &amp;lt; 0.001), representing loss of steatosis. Decreases were seen in total body weight (from 61.8 \u00b1 3.6 to 57.4 \u00b1 3.4 kg; P = 0.02) and resting energy expenditure (from 1,929 \u00b1 86 to 1,611 \u00b1 101 kcal\/24 h; P &amp;lt; 0.001). R-metHuLeptin led to significant and sustained improvements in glycemia, dyslipidemia, and hepatic steatosis. Leptin represents the first novel, effective, long-term treatment for severe forms of lipodystrophy.<\/jats:p>","DOI":"10.2337\/diabetes.54.7.1994","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"1994-2002","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":198,"title":["Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy"],"prefix":"10.2337","volume":"54","author":[{"given":"Edward D.","family":"Javor","sequence":"first","affiliation":[{"name":"Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine K.","family":"Cochran","sequence":"additional","affiliation":[{"name":"Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Musso","sequence":"additional","affiliation":[{"name":"Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice Ryan","family":"Young","sequence":"additional","affiliation":[{"name":"Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex M.","family":"DePaoli","sequence":"additional","affiliation":[{"name":"Amgen, Thousand Oaks, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip","family":"Gorden","sequence":"additional","affiliation":[{"name":"Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031208121796000_R1","doi-asserted-by":"crossref","unstructured":"Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM: Positional cloning of the mouse obese gene and its human homologue. 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