Short-term Effects of Leptin in People With Lipodystrophy

October 21, 2019 updated by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Short Term Effects of Leptin Withdrawal or Initiation in Lipodystrophy Independent of Energy Intake

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

25

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

12 years to 68 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • 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 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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Leptin naive
Studied for 5 days without metreleptin, then 14 days while taking metreleptin
Biological: Metreleptin
Recombinant analog of the human hormone, leptin
Experimental: On-leptin
Studied for 5 days while taking metreleptin, then 14 days during metreleptin withdrawal
Biological: Metreleptin
Recombinant analog of the human hormone, leptin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Total Body Insulin Sensitivity
Time Frame: 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)
Intervention 1 (5 days), Intervention 2 (14 days), and Long-term follow-up (6 months)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Insulin-mediated Suppression of Hepatic Glucose Production
Time Frame: 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)
Intervention 1 (5 days), Intervention 2 (14 days), and Long-term follow-up (6 months)
Endogenous Rate of Appearance of Palmitate
Time Frame: 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.
Intervention 1 (5 days), Intervention 2 (14 days), and Long-term follow-up (6 months)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 26, 2013

Primary Completion (Actual)

February 23, 2018

Study Completion (Actual)

February 23, 2018

Study Registration Dates

First Submitted

January 26, 2013

First Submitted That Met QC Criteria

January 26, 2013

First Posted (Estimate)

January 29, 2013

Study Record Updates

Last Update Posted (Actual)

November 13, 2019

Last Update Submitted That Met QC Criteria

October 21, 2019

Last Verified

February 25, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 130057
  • 13-DK-0057

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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