Patient case: 54-year-old male with malignant hyperthermia; genetic feature: RYR1

Clinical trial: Short-term Effects of Leptin in People With Lipodystrophy

Summary: Background:
  - Lipodystrophy is a condition where people do not have enough fat in the body. People with lipodystrophy can have problems such as diabetes or an enlarged liver. Researchers are looking at how leptin, a hormone produced by fat cells, can help people with these problems. Leptin helps control appetite and how the body stores food. Taking leptin can help people with lipodystrophy eat less food, which may help treat diabetes and other problems. To better understand how leptin works, researchers want to do an inpatient study on leptin treatment in people with lipodystrophy.
  Objectives:
  - To study how leptin treatment affects lipodystrophy.
  Eligibility:
  - Individuals between 14 and 70 years of age who have lipodystrophy.
  Design:
  -  All participants will have a 19-day stay at the National Institutes of Health Clinical Center. One group of participants will have tests for 5 days before starting to take leptin. They will then take leptin for 2 weeks, and have more tests. The other group of participants will have tests for 5 days while taking leptin. They will then take stop taking leptin for 2 weeks, and have more tests, and then they will start taking leptin again.
  -  Participants will have regular blood and urine tests during the visit. Some of the blood tests will look at insulin levels. Some will look at how the body metabolizes sugar and fat. Other tests will check hormone levels, especially of reproductive hormones.
  -  During the visit, participants will spend 3 separate days in a metabolic chamber, a special room that measures how many calories the body uses. Urine samples will be collected during these stays.
  -  Participants will also have several body imaging studies, including magnetic resonance imaging and a body composition scan.
  -  Physical activity will be tested with an exercise bicycle and an electronic activity monitor.
  -  Participants will be asked questions about hunger and comfort levels throughout the stay.

Detailed description: Background
  Leptin is an adipocyte-derived hormone that can be thought of as a signal from adipose tissue to the rest of the body conveying information about long-term nutritional status. Patients with lipodystrophy have leptin deficiency secondary to lack of adipose tissue, and thus represent a natural model for studying the effects of leptin deficiency and replacement in humans. Leptin replacement in lipodystrophy ameliorates metabolic and endocrine abnormalities, including reducing food intake, improving insulin resistance and diabetes, reducing ectopic lipid, and normalizing reproduction. The reduction in energy intake induced by leptin replacement is likely responsible for part of the improvements observed in glucose and lipid metabolism. The clinical effects of leptin that are independent of changes in energy intake, and the mechanisms underlying these effects, have been poorly explored in humans.
  Aim
  The primary aim of this study is to determine the energy intake-independent effects of leptin on energy metabolism in lipodystrophic subjects. The major aspects of energy metabolism to be studied are:
  1. Lipid metabolism, including fasting lipids, lipolysis and fatty acid turnover, and ectopic lipid storage.
  2. Glucose metabolism, including fasting glucose, endogenous glucose production, and insulin sensitivity
  3. Energy expenditure, including total and resting energy expenditure, skeletal muscle work efficiency, and spontaneous physical activity
  In addition, the effects of leptin on endocrine and autonomic function will be examined, including effects on the thyroid, gonadal, and adrenal axes, as well as blood pressure, body temperature, and heart rate variability.
  Methods
  This is a non-randomized, parallel group study. Two groups of patients aged 14 to 70 years with lipodystrophy will be studied: leptin naive and leptin treated. Minors will only be included in the leptin naive arm. All subjects will be stabilized on a weight maintenance diet for 5 days (Period 1). After this, leptin will be withdrawn from leptin treated subjects, and leptin will be initiated in leptin naive subjects for a period of 14 days (Period 2). The same isocaloric diet will be continued throughout both Periods, permitting study of leptin s effects independent of energy intake.
  All subjects will undergo metabolic testing on admission, at the end of Period 1, and throughout Period 2, to generate a detailed short-term time course of the effects of leptin initiation or withdrawal. At the end of Period 2, leptin will be continued in the leptin naive subjects, and restarted in the leptin treated subjects. Repeat metabolic testing will be performed 6-12 months after leptin initiation in the leptin-naive cohort to generate information on leptin s long-term effects.

Eligibility: -  INCLUSION CRITERIA:
  -  Age 14-70 years (children under age 18 will only be enrolled in the leptin-naive arm of the study
  -  Clinically-significant lipodystrophy as defined in protocol 02-DK-0022 (Long Term Efficacy of Leptin Replacement in the Treatment of Lipodystrophy). Relevant inclusion criteria for enrollment in protocol 02-DK-0022 are (summarized):
  -  Lipodystrophy identified by the study physician during physical examination as an absence of fat outside the range of normal
  -  Circulating leptin levels < 12.0 ng/mL in females and < 8.0 ng/mL in males
  -  Presence of at least one of the following metabolic abnormalities:
  1. Diabetes as defined by the 2007 American Diabetes Association criteria
  2. Fasting insulin >30 microU/mL
  3. Fasting hypertriglyceridemia >200 mg/dL
  -  Co-enrolled in protocol 02-DK-0022 and either:
  -  Leptin na(SqrRoot) ve, with plans to initiate leptin treatment during the current study. For the purpose of this study, leptin naive will be defined as having received no exogenous leptin in the 4 months prior to study participation. Thus, subjects who previously received leptin therapy, discontinued, and wish to restart are eligible.
  Or
  --Leptin treated, meaning the subject has taken a stable dose of exogenous leptin for a minimum of 4 months (adults over age 18, only)
  EXCLUSION CRITERIA:
  In leptin treated subjects only, the following exclusion criteria apply:
  -  Poorly controlled diabetes at study entry (hemoglobin A1c greater than or equal to 9%)
  -  Poorly controlled hypertriglyceridemia at study entry (serum triglycerides > 800 mg/dL)
  -  Extreme hypertriglyceridemia prior to leptin (triglycerides greater than 2000 mg/dL at initiation of leptin treatment)
  -  History of chronic or recurrent acute pancreatitis (> 1 episode), or a single episode of pancreatitis while receiving leptin treatment
  -  Lipase greater than the upper limit of normal (491 units/L) at study entry
  In all subjects (leptin treated and leptin naive), the following exclusion criteria apply:
  -  Known HIV infection or HIV-associated lipodystrophy
  -  History of diabetic ketoacidosis
  -  Active inflammatory disease (e.g. dermatomyositis)
  -  Change in diabetes or lipid-lowering medications within the past 6 weeks
  -  Estimated glomerular filtration rate < 30 mL/minute
  -  Current or recent (past 2 weeks) use of systemic glucocorticoids
  -  Inadequately controlled hypothyroidism (TSH < 0.4 or >4 mcIU/L) or change in thyroid medication in the past 8 weeks.
  -  Pregnancy or breast-feeding
  -  Psychiatric disorder impeding competence or compliance
  -  Any medical condition or medication that will increase risk to the subject (e.g. ischemic heart disease, decompensated liver disease) or that will interfere with interpretation of study data (e.g. Cushing s syndrome).

Relevance to patient case: not relevant