Short-term Effects of Leptin in People With Lipodystrophy

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Brief Title

Short-term Effects of Leptin in People With Lipodystrophy

Official Title

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

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Total Body Insulin Sensitivity

Secondary Outcome

 Insulin-mediated Suppression of Hepatic Glucose Production

Condition

Lipodystrophy

Intervention

Metreleptin

Study Arms / Comparison Groups

 Leptin naive
Description:  Studied for 5 days without metreleptin, then 14 days while taking metreleptin

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

25

Start Date

January 26, 2013

Completion Date

February 23, 2018

Primary Completion Date

February 23, 2018

Eligibility 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 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).
      

Gender

All

Ages

14 Years - 70 Years

Accepts Healthy Volunteers

No

Contacts

Rebecca J Brown, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01778556

Organization ID

130057

Secondary IDs

13-DK-0057

Responsible Party

Sponsor

Study Sponsor

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


Study Sponsor

Rebecca J Brown, M.D., Principal Investigator, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)


Verification Date

February 25, 2019