Short-term Effects of Leptin in People With Lipodystrophy

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 After this, leptin will be withdrawn from leptin treated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.

- 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).