Lipodystrophy
Conditions
Keywords
Lipodystrophy, Leptin, Energy Expenditure, Diabetes, Hypertriglyceridemia
Brief 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.
Interventions
BIOLOGICALMetreleptin
Recombinant analog of the human hormone, leptin
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
14 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* 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 naive, 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Body Insulin Sensitivity | Intervention 1 (5 days), Intervention 2 (14 days), and Long-term follow-up (6 months) | Total body insulin sensitivity (measured as glucose disposal rate during a hyperinsulinemic, euglycemic clamp) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin-mediated Suppression of Hepatic Glucose Production | Intervention 1 (5 days), Intervention 2 (14 days), and Long-term follow-up (6 months) | Hepatic insulin sensitivity (measured as suppression of endogenous glucose production during a hyperinsulinemic, euglycemic clamp) |
| Endogenous Rate of Appearance of Palmitate | Intervention 1 (5 days), Intervention 2 (14 days), and Long-term follow-up (6 months) | Endogenous Rate of Appearance of Palmitate is measured in plasma. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Leptin Naive Studied for 5 days without metreleptin, then 14 days while taking metreleptin
Metreleptin: Recombinant analog of the human hormone, leptin | 15 |
| On-leptin Studied for 5 days while taking metreleptin, then 14 days during metreleptin withdrawal
Metreleptin: Recombinant analog of the human hormone, leptin | 8 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Intervention 1 (5 Days) | Protocol Violation | 0 | 1 |
| Intervention 1 (5 Days) | Withdrawal by Subject | 0 | 1 |
| Intervention 2 (14 Days) | Protocol Violation | 1 | 0 |
| Long-term Follow-up | noncompliance with metreleptin | 1 | 0 |
Baseline characteristics
| Characteristic | On-leptin | Total | Leptin Naive |
|---|---|---|---|
| Age, Continuous | 25 years STANDARD_DEVIATION 6 | 28 years STANDARD_DEVIATION 14 | 32 years STANDARD_DEVIATION 17 |
| Endogenous leptin level | 1.2 ng/dl STANDARD_DEVIATION 0.5 | 7.4 ng/dl STANDARD_DEVIATION 10.1 | 9.5 ng/dl STANDARD_DEVIATION 10.2 |
| Race/Ethnicity, Customized African American | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 2 Participants | 6 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 13 Participants | 9 Participants |
| Sex: Female, Male Female | 5 Participants | 17 Participants | 12 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 3 Participants |
| Subtype of lipodystrophy Acquired generalized lipodystrophy | 1 Participants | 1 Participants | 0 Participants |
| Subtype of lipodystrophy Congenital generalized lipodystrophy | 7 Participants | 10 Participants | 3 Participants |
| Subtype of lipodystrophy Familial partial lipodystrophy | 0 Participants | 12 Participants | 12 Participants |
| Type of lipodystrophy Generalized | 8 Participants | 11 Participants | 3 Participants |
| Type of lipodystrophy Partial | 0 Participants | 12 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 0 / 15 | 2 / 15 | 4 / 15 | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 15 | 1 / 15 | 2 / 15 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Total Body Insulin Sensitivity
Total body insulin sensitivity (measured as glucose disposal rate during a hyperinsulinemic, euglycemic clamp)
Time frame: Intervention 1 (5 days), Intervention 2 (14 days), and Long-term follow-up (6 months)
Population: One patient at Period 2 (14 days) in Leptin naive arm was withdrew due to protocol violation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Leptin Naive | Total Body Insulin Sensitivity | Intervention 1 (5 days) | 4.4 mg/kg fat-free mass/min | Standard Deviation 2.3 |
| Leptin Naive | Total Body Insulin Sensitivity | Intervention 2 (14 days) | 5.8 mg/kg fat-free mass/min | Standard Deviation 2.2 |
| Leptin Naive | Total Body Insulin Sensitivity | Long-term follow-up (6 months) | 8.0 mg/kg fat-free mass/min | Standard Deviation 4 |
| On-leptin | Total Body Insulin Sensitivity | Intervention 1 (5 days) | 10.9 mg/kg fat-free mass/min | Standard Deviation 4.1 |
| On-leptin | Total Body Insulin Sensitivity | Intervention 2 (14 days) | 6.4 mg/kg fat-free mass/min | Standard Deviation 1.8 |
Secondary
Endogenous Rate of Appearance of Palmitate
Endogenous Rate of Appearance of Palmitate is measured in plasma.
Time frame: Intervention 1 (5 days), Intervention 2 (14 days), and Long-term follow-up (6 months)
Population: Measurements were not available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Leptin Naive | Endogenous Rate of Appearance of Palmitate | Long-term follow-up (6 months) | 2.2 μmol/kg fat-free mass/min | Standard Deviation 0.7 |
| Leptin Naive | Endogenous Rate of Appearance of Palmitate | Intervention 1 (5 days) | 3.2 μmol/kg fat-free mass/min | Standard Deviation 1.3 |
| Leptin Naive | Endogenous Rate of Appearance of Palmitate | Intervention 2 (14 days) | 2.8 μmol/kg fat-free mass/min | Standard Deviation 1 |
| On-leptin | Endogenous Rate of Appearance of Palmitate | Intervention 2 (14 days) | 1.7 μmol/kg fat-free mass/min | Standard Deviation 0.6 |
| On-leptin | Endogenous Rate of Appearance of Palmitate | Intervention 1 (5 days) | 1.4 μmol/kg fat-free mass/min | Standard Deviation 0.7 |
Secondary
Insulin-mediated Suppression of Hepatic Glucose Production
Hepatic insulin sensitivity (measured as suppression of endogenous glucose production during a hyperinsulinemic, euglycemic clamp)
Time frame: Intervention 1 (5 days), Intervention 2 (14 days), and Long-term follow-up (6 months)
Population: Measurements were not available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Leptin Naive | Insulin-mediated Suppression of Hepatic Glucose Production | Intervention 1 (5 days) | 61.2 percentage | Standard Deviation 23.4 |
| Leptin Naive | Insulin-mediated Suppression of Hepatic Glucose Production | Intervention 2 (14 days) | 75.2 percentage | Standard Deviation 33.1 |
| Leptin Naive | Insulin-mediated Suppression of Hepatic Glucose Production | Long-term follow-up (6 months) | 85.6 percentage | Standard Deviation 17.9 |
| On-leptin | Insulin-mediated Suppression of Hepatic Glucose Production | Intervention 1 (5 days) | 77.1 percentage | Standard Deviation 42.7 |
| On-leptin | Insulin-mediated Suppression of Hepatic Glucose Production | Intervention 2 (14 days) | 63.8 percentage | Standard Deviation 31.7 |