Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients.
Leptin replacement rescues the phenotype of morbid obesity and hypogonadism in leptin-deficient adults. However, leptin's effects on insulin resistance are not well understood. Our objective was to evaluate the effects of leptin on insulin resistance. Three leptin-deficient adults (male, 32 yr old, BMI 23.5 kg/m(2); female, 42 yr old, BMI 25.1 kg/m(2); female, 46 yr old, BMI 31.7 kg/m(2)) with a missense mutation of the leptin gene were evaluated during treatment with recombinant methionyl human leptin (r-metHuLeptin). Insulin resistance was determined by euglycemic hyperinsulinemic clamps and by oral glucose tolerance tests (OGTTs), whereas patients were on r-metHuLeptin and after treatment was interrupted for 2-4 wk in the 4th, 5th, and 6th years of treatment. At baseline, all patients had normal insulin levels, C-peptide, and homeostatic model assessment of insulin resistance index, except for one female diagnosed with type 2 diabetes. The glucose infusion rate was significantly lower with r-metHuLeptin (12.03 +/- 3.27 vs. 8.16 +/- 2.77 mg.kg(-1).min(-1), P = 0.0016) but did not differ in the 4th, 5th, and 6th years of treatment when all results were analyzed by a mixed model [F(1,4) = 0.57 and P = 0.5951]. The female patient with type 2 diabetes became euglycemic after treatment with r-metHuLeptin and subsequent weight loss. The OGTT suggested that two patients showed decreased insulin resistance while off treatment. During an off-leptin OGTT, one of the patients developed a moderate hypoglycemic reaction attributed to increased posthepatic insulin delivery and sensitivity. We conclude that, in leptin-deficient adults, the interruption of r-metHuLeptin decreases insulin resistance in the context of rapid weight gain. Our results suggest that hyperleptinemia may contribute to mediate the increased insulin resistance of obesity.
Dept. of Psychiatry & Behavioral Sciences, Univ. of Miami Miller School of Medicine, Miami, FL 33136, USA.
Gilberto
G
Paz-Filho
Karin
K
Esposito
Barry
B
Hurwitz
Anil
A
Sharma
Chuanhui
C
Dong
Victor
V
Andreev
Tuncay
T
Delibasi
Halil
H
Erol
Alejandro
A
Ayala
Ma-Li
ML
Wong
Julio
J
Licinio
D000328:Adult; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D005947:Glucose / Q000008:administration & dosage; D005951:Glucose Tolerance Test; D020249:Hormone Replacement Therapy; D006801:Humans; D007006:Hypogonadism / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007260:Infusion Pumps; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D020738:Leptin / Q000031:analogs & derivatives* / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D008019:Life Style; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; C122136:recombinant methionyl human leptin; D005947:Glucose