Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.
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.
Ebihara
Ken
K
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kyoto 606-8507, Japan. Kebihara@kuhp.kyoto-u.ac.jp
Kusakabe
Toru
T
Hirata
Masakazu
M
Masuzaki
Hiroaki
H
Miyanaga
Fumiko
F
Kobayashi
Nozomi
N
Tanaka
Tomohiro
T
Chusho
Hideki
H
Miyazawa
Takashi
T
Hayashi
Tatsuya
T
Hosoda
Kiminori
K
Ogawa
Yoshihiro
Y
DePaoli
Alex M
AM
Fukushima
Masanori
M
Nakao
Kazuwa
K
D000293:Adolescent; D000328:Adult; D000419:Albuminuria / Q000150:complications / Q000188:drug therapy; D001786:Blood Glucose / Q000187:drug effects; D002648:Child; D048909:Diabetes Complications / Q000150:complications / Q000188:drug therapy; D005234:Fatty Liver / Q000188:drug therapy; D005260:Female; D005500:Follow-Up Studies; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D020249:Hormone Replacement Therapy / Q000379:methods*; D006801:Humans; D006946:Hyperinsulinism; D007279:Injections, Subcutaneous; D007333:Insulin Resistance; D020738:Leptin / Q000008:administration & dosage* / Q000009:adverse effects; D008060:Lipodystrophy / Q000150:complications / Q000188:drug therapy*; D008297:Male; D013997:Time Factors; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D020738:Leptin; D014280:Triglycerides