Track topics on Twitter Track topics that are important to you
This pilot study will evaluate the safety and effectiveness of leptin therapy in two children with severe insulin resistance syndrome. Patients with this condition often have high blood sugar levels and may have hormone imbalances, a constant feeling of warmth, fertility problems, large appetite, and enlarged liver due to fat accumulation. Leptin is a hormone produced by fat cells. It influences appetite, affects levels of reproductive hormones, and possibly manages how the body reacts to insufficient food. Certain people with severe insulin resistance syndromes have decreased amounts of fat tissue and make little or no leptin.
A 13-year-old male and an 11-year-old female with severe insulin resistance will participate in this study. They will have the following tests and procedures before beginning 4 months of leptin therapy:
- Insulin tolerance test - measures blood sugar levels after intravenous (IV) administration of insulin. Blood samples are collected through the IV tube at various intervals during the 1-hour test.
- Ultrasound of the liver and, if abnormalities are found, possibly liver biopsies.
- Fasting blood tests - to measure blood count, blood lipids, and various hormones and assess liver function.
- Resting metabolic rate - to measure the amount of oxygen breathed at rest in order to calculate how many calories are required to maintain resting body functions.
- Magnetic resonance imaging of the liver and other organs, and of muscle and fat.
- Pelvic ultrasound in female patient - to detect ovarian cysts.
- Estimation of body fat - measurements of height, weight, waist, hip size, and skin folds over the arms and abdomen to estimate body fat content.
- Oral glucose tolerance test - measures blood sugar and insulin levels. The patient drinks a very sweet drink containing glucose (sugar), after which blood samples are collected through an IV tube in an arm vein at various intervals during the 3-hour test.
- Intravenous glucose tolerance test - measures tissue response to insulin and glucose after glucose injection and insulin infusion. Blood is collected over 3 hours to measure insulin and glucose levels.
- Appetite level and food intake - to measure hunger level and caloric intake. Patients are questioned about their hunger level, given a variety of foods they may choose to eat and questioned again at various intervals about hunger level. On another day, patients are given breakfast (usually a milkshake) and when they want to eat again, the appetite level and caloric intake study is repeated.
- Hormone function tests - the function of three hormones influenced by leptin (corticotropin-releasing hormone, thyrotropin-releasing hormone and luteinizing hormone-releasing hormone) are assessed. The hormones are injected intravenously and then blood samples are drawn.
- Questionnaire - patients complete a questionnaire about their activities and how they feel.
- 24-hour urine collections - to measure specific hormones, proteins and sugars excreted in the urine.
When the above tests are completed, leptin therapy will start. The drug is injected under the skin twice a day for 4 months. Patients will record their symptoms weekly throughout the study. Those with diabetes will measure their blood glucose levels daily before each meal and at bedtime. Follow-up visits at 1, 2 and 4 months after therapy will include a physical examination, blood tests and a meeting with a dietitian. At the 4-month visit, the tests done at the beginning of the study will be repeated.
Over the course of the year, we have observed that recombinant leptin has the potential to act as an insulin-sensitizer in subjects with lipoatrophy and leptin deficiency. The exact mechanisms of this effect are not known. We would like to test whether leptin will work as an insulin-sensitizer in a situation where the mechanism of insulin resistance is known, namely in a situation where there is a known defect on the insulin receptor. This will allow us to learn if leptin can overcome a receptor defect by activating some of the down-stream molecules in insulin signaling cascade.
We would like to begin exploring this question in two patients with mutations on their insulin receptor, who are in need of improved treatment. In fact, in these two patients, the conventional therapeutic options have not provided adequate control of blood sugar levels. Furthermore, the circulating leptin concentrations in these two patients are lower than the 15th percentile of normal population. Therefore, a strategy to achieve physiological concentrations of leptin hormone using recombinant leptin (A100, recombinant methionyl-human leptin) will be justified.
We also plan to keep the initial observation period short. Since we have observed insulin-sensitizing effects of leptin in lipoatrophy within 4 months, we will limit the initial treatment period to 4 months. The regime will be similar to the regimen used in lipoatrophic patients. The starting dose will be 50% of replacement dose and this will be incrementally increased to 200% replacement dose within the course of two months. The medication will be administered subcutaneously in two divided doses. Plasma glucose concentrations and HbA1c are designated as primary outcome measures. Data on the effects of leptin hormone on appetite, insulin secretion and sensitivity and other pituitary hormones will also be collected as pilot data. At the end of 4 months, we will make a decision to continue therapy and to broaden the study by opening recruitment to other similar patients.
Endpoint Classification: Safety/Efficacy Study, Primary Purpose: Treatment
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institutes of Health Clinical Center (CC)
Published on BioPortfolio: 2014-08-27T03:56:27-0400
The purpose of this study is to examine whether replacing leptin to normal levels can reverse the changes in fat distribution, lipid profile, and other metabolic problems associated with h...
We will assess the endocrine and immune effects of leptin replacement in leptin-deficient children, from a consanguineous Turkish family. We hypothesize that leptin replacement will have ...
Obesity is a chronic inflammatory disorder in which leptin, adiponectin and C reactive protein (CRP) play an important role. This study aimed to investigate the relationship between marker...
The purpose of this study is to determine whether patients with HIV lipodystrophy (fat wasting) benefit from taking the combination of two drugs, one insulin sensitizer (either metformin o...
Our previous studies have demonstrated that there is substantial metabolic opposition to the maintenance of an altered body weight. Leptin is a protein secreted by fat cells and the circu...
Leptin and adiponectin are adipokines which have opposing roles in the development of insulin resistance and metabolic syndrome (MetS). Leptin/adiponectin ratio (L/A ratio) has been proposed as a good...
Leptin and adiponectin have opposite effects on subclinical inflammation and insulin resistance, both involved in the development of metabolic syndrome (MS). We aimed to investigate whether leptin/adi...
Insulin and leptin have an overlapping anorexigenic action as well as opposite effects on glucose and lipid metabolism. The study focuses on the biochemical and clinical relevance of new indices of in...
Leptin is a hormone expressed by adipose tissue that regulates body energy homeostasis and weight loss by activating leptin receptors in the hypothalamus. Leptin receptors are also expressed in astroc...
We summarize the biological impact of leptin signaling as well as the molecular and cellular characteristics of leptin action. Our focus is principally in the central nervous system and we describe th...
Cell surface receptors for obesity factor (LEPTIN), a hormone secreted by the WHITE ADIPOCYTES. Upon leptin-receptor interaction, the signal is mediated through the JAK2/STAT3 pathway to regulate food intake, energy balance and fat storage.
A 16-kDa peptide hormone secreted from WHITE ADIPOCYTES. Leptin serves as a feedback signal from fat cells to the CENTRAL NERVOUS SYSTEM in regulation of food intake, energy balance, and fat storage.
Condition with a variable constellation of phenotypes due to deletion polymorphisms at chromosome location 22q11. It encompasses several syndromes with overlapping abnormalities including the DIGEORGE SYNDROME, VELOCARDIOFACIAL SYNDROME, and CONOTRUNCAL AMOMALY FACE SYNDROME. In addition, variable developmental problems and schizoid features are also associated with this syndrome. (From BMC Med Genet. 2009 Feb 25;10:16) Not all deletions at 22q11 result in the 22q11deletion syndrome.
Polypeptides produced by the ADIPOCYTES. They include LEPTIN; ADIPONECTIN; RESISTIN; and many cytokines of the immune system, such as TUMOR NECROSIS FACTOR-ALPHA; INTERLEUKIN-6; and COMPLEMENT FACTOR D (also known as ADIPSIN). They have potent autocrine, paracrine, and endocrine functions.
Rare congenital disorder with multiple anomalies including: characteristic dysmorphic craniofacial features, musculoskeletal abnormalities, neurocognitive delay, and high prevalence of cancer. Germline mutations in H-Ras protein can cause Costello syndrome. Costello syndrome shows early phenotypic overlap with other disorders that involve MAP KINASE SIGNALING SYSTEM (e.g., NOONAN SYNDROME and cardiofaciocutaneous syndrome).
Pediatrics is the general medicine of childhood. Because of the developmental processes (psychological and physical) of childhood, the involvement of parents, and the social management of conditions at home and at school, pediatrics is a specialty. With ...
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...