Clinical trial NCT00657605: Effects of Human Leptin Replacement
Official title: Effects of Human Leptin Replacement
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Obesity
Metabolic Syndrome
Diabetes
Keywords: Congenital leptin deficiency
Obesity
Metabolic syndrome
Diabetes
Lead sponsor: University of Miami
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2008-04-14
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will test the hypothesis that leptin contributes to the regulation of the dynamics of human endocrine function.

Detailed description: The study aims to elucidate the role of leptin in the regulation of human endocrine function approached by a carefully designed, prospective clinical study of the rapidly-sampled dynamics of endocrine rhythms during the course of leptin-replacement treatment in the only three adult individuals identified in the world so far who are leptin-naive due to a functional leptin gene mutation. A study of leptin-naive subjects avoids all confounding factors and pitfalls, because the only bioactive leptin to which they will be exposed is the exogenously administered recombinant protein. Thus, this proposal will permit us to ascertain the endocrine effects of human leptin.

Eligibility criteria: Inclusion Criteria:

* Congenital leptin deficiency (these are only 3 adult individuals in the world that have been identified as leptin-naïve thus far).

Exclusion Criteria:

* Pregnant, trying to become pregnant, breast-feeding an infant or sexually active women, not using contraception.
* Subjects with hemoglobin levels below 12 g/dl.
* Subjects whose body contains a ferromagnetic implanted device that might produce a safety hazard during fMRI.

Primary outcomes:
measure: Change in Weight
timeFrame: Baseline, 107 months
Secondary outcomes:
measure: Change in Glucose Levels
timeFrame: Baseline, 107 months
Other outcomes:
Locations:
city: Miami
country: United States
facility: University of Miami Miller School of Medicine, Center on Pharmacogenomics
state: Florida
Study officials:
affiliation: University of Miami
name: Julio Licinio, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998 Mar;18(3):213-5. doi: 10.1038/ng0398-213. No abstract available.
citation: Baicy K, London ED, Monterosso J, Wong ML, Delibasi T, Sharma A, Licinio J. Leptin replacement alters brain response to food cues in genetically leptin-deficient adults. Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18276-9. doi: 10.1073/pnas.0706481104. Epub 2007 Nov 6.
citation: Licinio J, Ribeiro L, Busnello JV, Delibasi T, Thakur S, Elashoff RM, Sharma A, Jardack PM, Depaoli AM, Wong ML. Effects of leptin replacement on macro- and micronutrient preferences. Int J Obes (Lond). 2007 Dec;31(12):1859-63. doi: 10.1038/sj.ijo.0803703. Epub 2007 Aug 7.
citation: Licinio J, Milane M, Thakur S, Whelan F, Yildiz BO, Delibasi T, de Miranda PB, Ozata M, Bolu E, Depaoli A, Wong ML. Effects of leptin on intake of specific micro- and macronutrients in a woman with leptin gene deficiency studied off and on leptin at stable body weight. Appetite. 2007 Nov;49(3):594-9. doi: 10.1016/j.appet.2007.03.228. Epub 2007 Apr 6.
citation: Williamson DA, Ravussin E, Wong ML, Wagner A, Dipaoli A, Caglayan S, Ozata M, Martin C, Walden H, Arnett C, Licinio J. Microanalysis of eating behavior of three leptin deficient adults treated with leptin therapy. Appetite. 2005 Aug;45(1):75-80. doi: 10.1016/j.appet.2005.01.002.
citation: Matochik JA, London ED, Yildiz BO, Ozata M, Caglayan S, DePaoli AM, Wong ML, Licinio J. Effect of leptin replacement on brain structure in genetically leptin-deficient adults. J Clin Endocrinol Metab. 2005 May;90(5):2851-4. doi: 10.1210/jc.2004-1979. Epub 2005 Feb 15.
citation: Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O'Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4531-6. doi: 10.1073/pnas.0308767101. Epub 2004 Mar 9.
citation: Mantzoros CS, Ozata M, Negrao AB, Suchard MA, Ziotopoulou M, Caglayan S, Elashoff RM, Cogswell RJ, Negro P, Liberty V, Wong ML, Veldhuis J, Ozdemir IC, Gold PW, Flier JS, Licinio J. Synchronicity of frequently sampled thyrotropin (TSH) and leptin concentrations in healthy adults and leptin-deficient subjects: evidence for possible partial TSH regulation by leptin in humans. J Clin Endocrinol Metab. 2001 Jul;86(7):3284-91. doi: 10.1210/jcem.86.7.7644.
citation: Ozata M, Ozdemir IC, Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab. 1999 Oct;84(10):3686-95. doi: 10.1210/jcem.84.10.5999.
citation: Paz-Filho G, Wong ML, Licinio J. The procognitive effects of leptin in the brain and their clinical implications. Int J Clin Pract. 2010 Dec;64(13):1808-12. doi: 10.1111/j.1742-1241.2010.02536.x.
citation: Paz-Filho G, Delibasi T, Erol HK, Wong ML, Licinio J. Congenital leptin deficiency and thyroid function. Thyroid Res. 2009 Nov 4;2(1):11. doi: 10.1186/1756-6614-2-11.
citation: Paz-Filho G, Esposito K, Hurwitz B, Sharma A, Dong C, Andreev V, Delibasi T, Erol H, Ayala A, Wong ML, Licinio J. Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients. Am J Physiol Endocrinol Metab. 2008 Dec;295(6):E1401-8. doi: 10.1152/ajpendo.90450.2008. Epub 2008 Oct 14.
citation: Andreev VP, Paz-Filho G, Wong ML, Licinio J. Deconvolution of insulin secretion, insulin hepatic extraction post-hepatic delivery rates and sensitivity during 24-hour standardized meals: time course of glucose homeostasis in leptin replacement treatment. Horm Metab Res. 2009 Feb;41(2):142-51. doi: 10.1055/s-0028-1082048. Epub 2008 Aug 22.